buprenorphine and Pain

Opioid use disorder (OUD) is commonly seen in older adults in primary care offices. OUD when left untreated, often leads to overdose deaths, emergency department visits, and hospitalizations due to opioid-related adverse effects, especially respiratory and central nervous system depression. Primary care providers are on the front lines of efforts for its prevention, early detection, and treatment. This includes using the lowest doses of opioids for the shortest possible time for management of pain, routine screening, brief intervention, opioid withdrawal management, prescription of naloxone to prevent overdose death, and treatment with medications and psychosocial interventions for OUD. Referral to addiction treatment centers may be needed in complex cases. This review explores the epidemiology, screening, as well as management of OUD as it pertains to the elderly population.

Topics: Aged; Analgesics, Opioid; Buprenorphine; Humans; Opioid-Related Disorders; Pain; Primary Health Care

Buprenorphine formulations (including buprenorphine/naloxone) are effective treatments of pain and opioid use disorder (OUD). Historically, perioperative management of patients prescribed buprenorphine involved abstinence from buprenorphine sufficient to allow for unrestricted mu-opioid receptor availability to full agonist opioid (FAO) treatment. Evidence is mounting that a multimodal analgesic strategy, including simultaneous administration of buprenorphine and FAO, nonopioid adjuncts such as acetaminophen and nonsteroidal anti-inflammatory drugs, and regional anesthesia, is a safe and effective perioperative strategy for the patient prescribed long-term buprenorphine treatment of OUD. This strategy will likely simplify management and more seamlessly provide continuous buprenorphine treatment of OUD after hospital discharge.

Topics: Acetaminophen; Aged; Analgesics, Non-Narcotic; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Arthroplasty, Replacement, Hip; Buprenorphine; Combined Modality Therapy; Drug Compounding; Female; Humans; Interdisciplinary Communication; Male; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Pain Management; Pain, Postoperative; Perioperative Care; Receptors, Opioid, mu

Pain is a common symptom accompanying several clinical conditions and causes serious distress to patients. Addressing pain management is an important aspect of disease treatment, including cancer therapy. Opioid analgesics used to manage pain in human and veterinary medicine have been associated with substance dependence and other adverse effects, thereby limiting their application. Thus, the development of opioid analgesics with good safety profiles with minimal adverse effects and no addictive effects, is presently the focus of pain research. As a new potential analgesic, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028) has fewer adverse effects than other analgesics and is expected to be a safer alternative. In this review, we discuss the development of the opioid analog BU08028 and summarize its analgesic effects and biological characteristics, including efficiency, safety, and tolerance. Furthermore, we elaborate on studies showing the bifunctional effect of BU08028, which targets both mu opioid peptide and nociceptin-orphanin FQ peptide receptors, as well as the unique advantages of using BU08028 over single-target opioid agonists. Previous studies have suggested that BU08028 can not only weaken the reward and abuse effects of opioids and other drugs, but also enhance the anti-nociceptive effect of the mu opioid peptide receptors, making it a potent analgesic. Besides, we describe studies suggesting that BU08028 inhibits the effects of alcohol, making it a candidate drug for the management of alcohol addiction. Our review suggests that BU08028 is a potential novel medicine for managing pain and addiction.

Topics: Analgesics; Buprenorphine; Humans; Pain; Pain Management; Receptors, Opioid

To review the pharmacology of buprenorphine, the evolution of buprenorphine dosing recommendations, and the current literature regarding its recommendations for the perioperative period.. There is a consensus that for all surgeries, buprenorphine should be continued throughout the perioperative period. If the surgery is a minimal to mild pain surgery, no dose adjustment is needed. There is no clear consensus regarding moderate to severe pain. With all surgeries, multimodal analgesia should be utilized, with regional anesthesia when possible. Patients taking buprenorphine should continue their buprenorphine perioperatively; whether to decrease or maintain dosing is up for debate. Multimodal analgesia should also be used throughout the perioperative period, and communication between the patient and all provider teams is of the utmost importance to provide adequate analgesia during the perioperative period, as well as to arrange safe analgesia upon discharge.

Topics: Analgesia; Analgesics, Opioid; Buprenorphine; Humans; Pain; Pain Management; Pain, Postoperative

Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Drug Tolerance; Humans; Isoquinolines; Naltrexone; Nociceptin; Opioid Peptides; Pain; Phenylpropionates; Receptors, Opioid, mu

Opiates have a long history of medical use as effective analgesics associated with well-described side effects, including euphoria, respiratory depression, constipation, bradycardia, and histamine release, among others. The search for opiate analogs that retain effective analgesic qualities without detrimental side effects has yielded numerous compounds, including buprenorphine. Early studies of buprenorphine demonstrated analgesic effectiveness with a favorable safety profile, leading to the approval of formulations for use in humans. Since then, advances in receptor theory and molecular cloning of opioid receptors have led to a deeper understanding of buprenorphine pharmacology. More recent studies of receptor affinity and intrinsic activity have shown that buprenorphine is a μ- and κ-opioid receptor agonist, a nociceptin orphanin peptide agonist, and a δ-opioid receptor antagonist. Buprenorphine appears to have a primary spinal analgesic mechanism with complex supraspinal actions. It is considered a full agonist for pain but a partial agonist for other clinical endpoints such as respiratory depression. In feline medicine, buprenorphine is approved as low- and high-concentration injectable solutions, in addition to the most recently introduced long-acting transdermal formulation. Several investigational and compounded formulations have also been evaluated. There are contrasting differentiable features that include pharmacokinetics, onsets- and durations-of-action, routes of administration, and formulation constituents. Available buprenorphine formulations allow clinicians to select a formulation based on the anticipated duration of pain associated with various surgical procedures, and to provide interventions as needed. In light of the newly approved transdermal buprenorphine solution in cats and progress in buprenorphine pharmacology, the objective of this review is to examine the history and pharmacology of buprenorphine relative to full opioid agonists, where appropriate, integrating these insights into advances within feline medicine.

Topics: Analgesics; Analgesics, Opioid; Animals; Buprenorphine; Cat Diseases; Cats; Pain; Respiratory Insufficiency

With the aging population, an increasing number of older adults (> 65 years) will be affected by problematic opioid use and opioid use disorder (OUD), with both illicit and prescription opioids. Problematic opioid use is defined as the use of opioids resulting in social, medical or psychological consequences, whereas OUD is a form of problematic use that meets diagnostic criteria as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Problematic use of opioids by older adults is associated with a number of pertinent adverse effects, including sedation, cognitive impairment, falls, fractures and constipation. Risk factors for problematic opioid use in this population include pain, comorbid medical illnesses, concurrent alcohol use disorder and depression. Treatment of OUD consists of acute detoxification and maintenance therapy. At this time, there have been no randomized controlled trials examining the effectiveness of pharmacological interventions for OUD in this population, with recommendations based on data from younger adults. Despite this, opioid agonist therapy (OAT) is recommended for both stages of treatment in older adults with OUD. Buprenorphine is recommended as a first line agent over methadone in the older adult population, due to a more favourable safety profile and relative accessibility. Use of methadone in this population is complicated by risk of QT interval prolongation and respiratory depression. Available observational data suggests that older adults respond well to OAT and age should not be a barrier to treatment. Further research is required to inform treatment decisions in this population.

Topics: Aged; Analgesics, Opioid; Buprenorphine; Humans; Methadone; Opioid-Related Disorders; Pain

Buprenorphine's unique pharmacologic mechanisms of action lend itself to a higher level of complexity than its typical characterization as a partial agonist at µ-opioid receptors. It is well-documented that its additional activity at Δ- and κ-opioid receptors, and opioid receptor ligand 1 may be associated with varying degrees of analgesia and usual opioid-related adverse effects. However, novel downstream molecular and cellular mechanisms from µ-opioid receptor activation contain potential new insights into its overall unique effects. These include buprenorphine's peculiar ability to induce analgesia at escalating doses, while exhibiting a plateaued effect on respiratory depression, euphoria, gastrointestinal (GI) motility, depression, anxiety, and addictive potential. Thus, this review aims to discuss several of these emerging mechanisms to gain a better understanding of these curious actions, as well as support much of this in vitro evidence with various human clinical trial data to further support buprenorphine's place on the analgesic ladder.

Topics: Analgesia; Analgesics, Opioid; Buprenorphine; Humans; Pain; Receptors, Opioid

Pain is a common symptom in pediatric patients with cancer, and most patients in palliative care will receive opioids. Traditional opioids have several drawbacks, including their adverse effects, inconsistent or diminishing efficacy, and limited available routes of administration. Buprenorphine is an attractive option for pain management because of its safety profile, unique pharmacology, and availability in transdermal, buccal, parenteral, and sublingual (SL) dosage forms. Unfortunately, data supporting the use of buprenorphine in pediatric pain patients, particularly SL buprenorphine, are lacking. This case report describes the feasibility of SL buprenorphine use in pediatric patients with complex cancer-related pain.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Cancer Pain; Child; Humans; Neoplasms; Pain

With more than 800,000 deaths by suicide each year and 20 to 30 times more suicide attempts worldwide, suicide is a major public health problem. Current treatments of SB are mainly based on pharmacological treatments that are not specific of SB (e.g. antidepressants), and new therapeutic targets are urgently needed. Recent data strengthen the ancient conception pain (social, psychic, physical) that is at the core of the suicidal process and should be incorporated in the clinical assessment of suicide risk. Then, the mechanisms involved in the regulation of pain may open new avenues regarding therapeutic perspectives. Opiates appear to be a promising candidate in treatment of SB. Indeed, since the last two decades, growing evidences suggest an implication of the opioid system in the pathophysiology of SB, this conduct to the elaboration of randomized controlled trials (RCTs) using opiates in patients with SB. Results suggesting an anti-suicidal effect of buprenorphine and the potential opioidergic-related anti-suicidal effect of ketamine both contribute to the growing interest in opiates use in SB. In this review, we will summarize a large part of the evidence that leads researchers and clinicians to be interested in the use of opiates for SB treatment and discuss on new opioid pharmacological options for suicidal patients.

Topics: Buprenorphine; Humans; Opiate Alkaloids; Pain; Suicidal Ideation; Suicide, Attempted

Parenteral potent opioid availability is becoming an issue in acute pain management. Two opioids, nalbuphine and buprenorphine, are available which can be substituted for hydromorphone, fentanyl, and morphine. There are advantages and disadvantages in using these 2 opioids which are discussed, and potential dosing strategies are outlined.

Topics: Analgesics, Opioid; Buprenorphine; Fentanyl; Humans; Hydromorphone; Morphine; Nalbuphine; Pain

Kappa opioid receptor (KOP) is a G-protein coupled receptor mainly expressed in the cerebral cortex and hypothalamus. It is implicated in nociception, diuresis, emotion, cognition, and immune system functions. KOP agonists possess a strong analgesic effect accompanied by a feeling of dysphoria. On the other hand, antagonists of this receptor were found to block depression, anxiety, and drug-seeking behaviors in animal models. Recently, great interest has been given to the development of selective KOP antagonists as an addiction treatment that does not cause dependence itself or show high relapse rates like the currently used agents. This review provides a comprehensive survey of the KOP antagonists developed for this purpose together with their in vivo studies and clinical trials. In addition, a future perspective and recommendations for the work needed to develop clinically relevant KOP antagonists are presented.

Topics: Animals; Humans; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Receptors, Opioid, kappa

Topics: Analgesics, Opioid; Buprenorphine; Chronic Disease; Humans; Opioid-Related Disorders; Pain; Pain Management

Abuse-deterrent formulations (ADFs) are technologically sophisticated pharmaceutical formulations that impede manipulation and extraction of opioids and/or provoke unpleasant effects when they are taken in excessive quantity. This is implemented by creating physical barriers, inseparably combining the opioid with an opioid antagonist or adding aversive agents to the formulation. These pharmaceutical changes may potentially alter the pharmacokinetics and consequently the pharmacodynamics of the opioid. In this review, comparative evidence on pharmacokinetic differences between abuse-deterrent and classical formulations of the same opioids is summarized; furthermore, pharmacodynamic differences, with a focus on analgesia and abuse-related symptoms, are addressed. Most of the 12 studies comparing opioid pharmacokinetics have judged the physically intact ADF as being bioequivalent to the corresponding classical formulation. Pharmacokinetic differences have, however, been reported with physically manipulated ADFs and have ranged from moderate deviations from bioequivalence to complete changes in the pharmacokinetic profile (e.g. from a sustained-release formulation to a fast-release formulation). Pharmacodynamic effects were assessed in 14 comparative studies, which reported that intact ADFs usually provided clinically equivalent analgesia and clear advantages with respect to their addiction potential. However, withdrawal symptoms could be induced by the ADFs, although rarely and, in particular, when the ADFs had been physically altered. This evidence suggests that opioid ADFs are a working concept resulting in mostly minor pharmacokinetic and pharmacodynamic differences in comparison with classical formulations; however, they may deviate from this equivalence when physically altered.

Topics: Analgesics, Opioid; Buprenorphine; Chemistry, Pharmaceutical; Humans; Morphine; Oxycodone; Oxymorphone; Pain

Buprenorphine and the mixed agonists/antagonists nalbuphine and pentazocine, formerly classified as µ-opioid (MOP) receptor antagonists, have more recently been shown to be partial to full agonists of the human MOP receptor. These receptors do not necessarily have to be maximally activated for a full physiological response. Partial agonists can also sufficiently stimulate signaling processes leading to a full analgesic response, as shown by the effectiveness of buprenorphine, nalbuphine and pentazocine in animal pain models and in clinical settings where these drugs induce analgesia with full efficacy without a ceiling effect. Submaximal doses of MOP receptor analgesics combined with submaximal doses of buprenorphine, pentazocine, or nalbuphine result in additive to over-additive antinociceptive effects in animal experiments. Only when doses are given that exceed the therapeutic dose range may the antinociceptive effect be reduced to the effect of either opioid alone. The analgesic effects of pentazocine and nalbuphine combined with morphine are reported to be additive or over-additive in various clinical pain conditions. Buprenorphine, which clinically behaves as a full MOP receptor agonist for pain relief, can be combined with full opioid agonists without precipitating withdrawal. Thus, the overall evidence on the analgesic effects of buprenorphine, pentazocine or nalbuphine combined with opioid analgesics under various clinical pain conditions contradicts the consensus that these compounds diminish MOP receptor analgesia when co-administered with a full MOP receptor agonist.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Humans; Nalbuphine; Narcotic Antagonists; Pain; Pentazocine; Receptors, Opioid

Many patients with cancer experience moderate to severe pain that requires treatment with strong analgesics. Buprenorphine, fentanyl and morphine are examples of strong opioids used for cancer pain relief. However, strong opioids are ineffective as pain treatment in all patients and are not well-tolerated by all patients. The aim of this Cochrane review is to assess whether buprenorphine is associated with superior, inferior or equal pain relief and tolerability compared to other analgesic options for patients with cancer pain.. To assess the effectiveness and tolerability of buprenorphine for pain in adults and children with cancer.. We searched CENTRAL (the Cochrane Library) issue 12 or 12 2014, MEDLINE (via OVID) 1948 to 20 January 2015, EMBASE (via OVID) 1980 to 20 January 2015, ISI Web of Science (SCI-EXPANDED & CPCI-S) to 20 January 2015, ISI BIOSIS 1969 to 20 January 2015. We also searched ClinicalTrials.gov (http://clinicaltrials.gov/; metaRegister of Controlled Trials (mRCT) (http://www.controlled-trials.com/mrct/), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/) and the Proceedings of the Congress of the European Federation of International Association for the Study of Pain (IASP; via European Journal of Pain Supplements) on 16 February 2015. We checked the bibliographic references of identified studies as well as relevant studies and systematic reviews to find additional trials not identified by the electronic searches. We contacted authors of included studies for other relevant studies.. We included randomised controlled trials, with parallel-group or crossover design, comparing buprenorphine (any formulation and any route of administration) with placebo or an active drug (including buprenorphine) for cancer background pain in adults and children.. Two review authors independently extracted data pertaining to study design, participant details (including age, cancer characteristics, previous analgesic medication and setting), interventions (including details about titration) and outcomes, and independently assessed the quality of the included studies according to standard Cochrane methodology. As it was not feasible to meta-analyse the data, we summarised the results narratively. We assessed the overall quality of the evidence for each outcome using the GRADE approach.. In this Cochrane review we identified 19 relevant studies including a total of 1421 patients that examined 16 different intervention comparisons.Of the studies that compared buprenorphine to another drug, 11 studies performed comparative analyses between the randomised groups, and five studies found that buprenorphine was superior to the comparison treatment. Three studies found no differences between buprenorphine and the comparison drug, while another three studies found treatment with buprenorphine to be inferior to the alternative treatment in terms of the side effects profile or patients preference/acceptability.Of the studies that compared different doses or formulations/routes of administration of buprenorphine, pain intensity ratings did not differ significantly between intramuscular buprenorphine and buprenorphine suppository. However, the average severity of dizziness, nausea, vomiting and adverse events as a total were all significantly higher in the intramuscular group relatively to the suppository group (one study).Sublingual buprenorphine was associated with faster onset of pain relief compared to subdermal buprenorphine, with similar duration analgesia and no significant differences in adverse event rates reported between the treatments (one study).In terms of transdermal buprenorphine, two studies found it superior to placebo, whereas a third study found no difference between placebo and different doses of transdermal buprenorphine.The studies that examined different doses of transdermal buprenorphine did not report a clear dose-response relationship.The quality of this evidence base was limited by under-reporting of most bias assessment items (e.g., the patient selection items), by small sample sizes in several included studies, by attrition (with data missing from 8.2% of the enrolled/randomised patients for efficacy and from 14.6% for safety) and by limited or no reporting of the expected outcomes in a number of cases. The evidence for all the outcomes was very low quality.. Based on the available evidence, it is difficult to say where buprenorphine fits in the treatment of cancer pain with strong opioids. However, it might be considered to rank as a fourth-line option compared to the more standard therapies of morphine, oxycodone and fentanyl, and even there it would only be suitable for some patients. However, palliative care patients are often heterogeneous and complex, so having a number of analgesics available that can be given differently increases patient and prescriber choice. In particular, the sublingual and injectable routes seemed to have a more definable analgesic effect, whereas the transdermal route studies left more questions.

Topics: Administration, Cutaneous; Administration, Oral; Administration, Sublingual; Adult; Analgesics, Opioid; Buprenorphine; Child; Humans; Neoplasms; Pain; Randomized Controlled Trials as Topic

The fentanyl patch is one of the great commercial successes in transdermal drug delivery. The suitability of this molecule for delivery through skin had been identified in the 1970s, and subsequently, a number of transdermal formulations became available on the market. This article reviews the development of fentanyl patch technology with particular emphasis on the pharmacokinetics and disposition of the drug when delivered through the skin. The various patch designs are considered as well as the bioequivalence of the different designs. The influence of heat on fentanyl permeation is highlighted. Post-mortem redistribution of fentanyl is discussed in light of the reported discrepancies in serum levels reported in patients after death compared with therapeutic levels in living subjects. Finally, alternatives to patch technology are considered, and recent novel transdermal formulations are highlighted.

Topics: Administration, Cutaneous; Analgesics; Analgesics, Opioid; Buprenorphine; Clinical Trials as Topic; Drug Delivery Systems; Drug Industry; Fentanyl; Humans; Pain; Pharmaceutical Preparations; Skin; Temperature; Time Factors; Transdermal Patch

Methadone and buprenorphine are maintenance replacement therapies for opioid dependence; they are also used for pain management. Methadone and buprenorphine (to a lesser extent) have seen sharp increases in mortality associated with their use. They have distinct routes of metabolism (mostly cytochrome P450 dependent), and distinct pharmacologic activity of metabolites. As such, metabolism may play a role in differences in their toxicity.. This article reviews peer-reviewed literature obtained from PubMed searches and literature referenced within. The review considers first an overview of drug use and mortality over the past decade. It then provides extensive detail on the in vitro and in vivo human metabolism of methadone and buprenorphine. Using both human and experimental animal studies it then presents the pharmacodynamic activity of parent drug and metabolites at the mu-opioid receptor, as P-glycoprotein substrates and plasma/brain concentration ratios, and activity at the hERG K(+) channel. Lessons learned from drug interaction studies in humans are then examined in an attempt to bring together the combined information.. The use and misuse of these drugs contributes to the epidemic in opioid-associated mortalities. A better understanding of metabolism-, transport- and co-medication-induced changes will contribute to their safer use.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Drug Interactions; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pain

This study aimed to synthesize the available evidence on the efficacy and safety of transdermal (TD) buprenorphine.. We searched studies in electronic databases. Randomized controlled trials (RCTs) assessing the efficacy of TD buprenorphine comparing with placebo or other comparator drug in relieving cancer pain were included. The primary end points are patient-reported pain intensity and pain relief. For dichotomous data, the summary relative risk (RR) and its 95 % confidence interval (CI) were derived using random-effect model in view of heterogeneity testing.. Eight clinical trials (n = 909) were included in the analysis. Only a few studies reported the same outcome in similar way, which created difficulty in the pooling of outcome data. Two studies (n = 288) assessed 'responders' and showed a significant difference between TD buprenorphine and placebo in all three doses of TD buprenorphine, 35.5, 52.5, or 70 μg/h (RR 1.74, 95 % CI 1.31-2.32; I (2) 0 %); the numbers-needed-to-treat was 5.8 (3.9-11). Two studies (n = 331) showed a comparable requirement for rescue SL buprenorphine between TD buprenorphine and placebo (RR 1.25, 95 % CI 0.84-1.88; I (2) 0 %). The preferred outcome measure '50 % pain relief' was not reported in any included studies. On the basis of summary quality, further research is likely to have an important impact on our confidence in the estimate.. Transdermal buprenorphine has an increasing role for the relief of cancer pain. Further research in this field is needed. Multicentre studies in this field using a common protocol and strict supervision will be more practicable.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Humans; Neoplasms; Pain; Palliative Care; Randomized Controlled Trials as Topic; Treatment Outcome

Opioid substitution therapy (OST) for opioid dependence is common, and injection drug users have significant medical and psychiatric comorbidity. Many physicians will encounter OST patients in their usual practice. This article provides guidance on management of common clinical problems in this population, including OST management in hepatic failure, respiratory disease, pain management and potential drug interactions.

Topics: Analgesics; Australia; Buprenorphine; Comorbidity; Drug Interactions; Female; Humans; Liver Diseases; Mental Disorders; Methadone; Naloxone; Opiate Substitution Treatment; Pain; Pain Management; Palliative Care; Polypharmacy; Pregnancy; Pregnancy Complications; Respiratory Insufficiency; Substance-Related Disorders; Virus Diseases

To systematically assess efficacy and safety of buprenorphine patch versus fentanyl patch in patients with chronic moderate to severe pain.. Fifteen databases were searched up to December 2010. Randomised and quasi-randomised trials assessing the efficacy in patients with chronic pain were included. Quantitative methods for data synthesis were used and two network meta-analyses were conducted.. Fourteen unique trials (17 publications) were included. No head-to-head randomised trials of buprenorphine patch compared with fentanyl patch were identified. Therefore, less robust evidence from indirect comparisons was used. Results from a network meta-analysis of non-enriched designs (eight trials), using trials versus placebo and trials versus morphine for indirect comparisons, indicated that transdermal fentanyl, in comparison with transdermal buprenorphine, showed significantly more nausea (odds ratio [OR] 4.66, 95% confidence interval (CI) 1.07 to 20.39), a significantly higher number of treatment discontinuations due to adverse events (OR 5.94, 95% CI 1.78 to 19.87), and non-significant differences on all other outcomes, including pain measures. In comparison with morphine, transdermal buprenorphine had a significantly higher decrease of pain intensity (MD [mean difference] -16.20, 95% CI -28.92 to -3.48) while morphine caused more cases of constipation (OR 7.50, 95% CI 1.45 to 38.85) and a significantly higher number of treatment discontinuations due to adverse events (OR 5.80, 95% CI 1.68 to 20.11). All other outcomes showed non-significant differences between transdermal buprenorphine and morphine. The results were similar when also including six trials using enriched designs with the exception of more cases of vomiting for fentanyl (OR 17.32, 95% CI 4.43 to 67.71) and morphine (OR 15.85, 95% CI 3.92 to 64.13) compared to buprenorphine.. The findings indicate comparability of transdermal buprenorphine and transdermal fentanyl for pain measures with significantly fewer adverse events (nausea and treatment discontinuation due to adverse events) caused by transdermal buprenorphine.

Topics: Administration, Oral; Analgesics, Opioid; Buprenorphine; Chronic Pain; Constipation; Fentanyl; Humans; Morphine; Nausea; Pain; Pain Measurement; Transdermal Patch; Treatment Outcome

The increased use of opioid pain medication has been mirrored by the increased misuse and abuse of these drugs. As part of a multidisciplinary approach to this epidemic, pharmaceutical companies, with the encouragement of the Food and Drug Administration, have increased the development of abuse-deterrent formulations. While all have the goal of treating pain while mitigating misuse and abuse, there are different technologies utilized to impart the abuse-deterrent properties. The goal of this paper is to review the basis of abuse-deterrent formulations, the different types and approaches of some of the abuse-deterrent products, and their current regulatory status in the USA.

Topics: Analgesics, Opioid; Buprenorphine; Chemistry, Pharmaceutical; Dextroamphetamine; Humans; Lisdexamfetamine Dimesylate; Morphine; Naltrexone; Opioid-Related Disorders; Pain; Prescription Drug Misuse; United States; United States Food and Drug Administration

The transdermal therapeutic system (TTS) with buprenorphine is currently being used 'off-label' to treat chronic pediatric pain. We compiled available pharmacokinetic (PK), pharmacodynamic (PD), and clinical pediatric data on buprenorphine to rationalize treatment regimens.. We conducted a systematic biomedical literature review focusing on pediatric buprenorphine data.. There are few relevant pediatric buprenorphine data, particularly in children suffering chronic pain. There are no pediatric PK and PD data for children with chronic pain given sublingual or TTS formulations. Children given single dose buprenorphine have increased drug clearance referenced to bodyweight with a possible paradoxical longer duration of action. Buprenorphine metabolism is independent of renal function, which is advantageous in renal insufficiency. The risk of respiratory depression after buprenorphine is difficult to quantify. A concentration-response relationship for respiratory effects has not been described and it is unknown whether children have a ceiling effect similar to that described in healthy adult volunteers.. Buprenorphine is of interest in pediatric postoperative pain and cancer pain control because of its multiple administration routes, long duration of action, and metabolism largely independent of renal function. There is little reason to expect buprenorphine effects in children out of infancy are fundamentally different to those in adults. From the limited pediatric data available, it appears that buprenorphine has no higher adverse potential than the more commonly used opioids. There is an urgent need for focused PK, PD, and safety studies in children before use in children becomes more widespread.

Topics: Administration, Cutaneous; Adolescent; Adult; Analgesics, Opioid; Buprenorphine; Child; Drug Delivery Systems; Drug Eruptions; Female; Humans; Male; Pain; Pain, Postoperative; Receptors, Opioid, mu; Respiratory Insufficiency; Substance Withdrawal Syndrome; Young Adult

Cancer patients with moderate-to-severe pain require opioids for analgesia. Whereas early guidelines recommend oral morphine as the 'drug of choice', newer synthetic opioids can be given by a reliable and effective nonoral transdermal route. We examine the mode of action of transdermal patches and we review the evidence on two drugs, which are currently available in this formulation - buprenorphine and fentanyl - covering physicochemical characteristics and pharmacokinetics of the patches, clinical efficacy data and adverse effects.. Both buprenorphine and fentanyl possess ideal characteristics for transdermal delivery, being small molecules with high lipophilicity. Studies of buprenorphine patches show benefits but there is poor randomized controlled trial evidence comparing them with oral opioids. Fentanyl patches have been used for longer and have a larger body of evidence supporting their use, with data to suggest improved pain relief and reduced opioid side effects compared with sustained release oral morphine. Patients who have used both oral morphine and transdermal fentanyl express a preference for the patch drug.. Transdermal buprenorphine and fentanyl are now established for moderate-to-severe cancer pain. There is still a need for further comparative studies with other opioids, especially for buprenorphine.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Evidence-Based Medicine; Fentanyl; Humans; Neoplasms; Pain; Pain Management

Topics: Analgesics; Buprenorphine; Humans; Methadone; Naltrexone; Narcotic Antagonists; Opiate Substitution Treatment; Pain; Prescription Drugs; Substance-Related Disorders

In Australia and New Zealand, in parallel with other developed countries, the number of patients prescribed opioids on a long-term basis has grown rapidly over the last decade. The burden of chronic pain is more widely recognised and there has been an increase in the use of opioids for both cancer and non-cancer indications. While the prevalence of illicit opioid use has remained relatively stable, the diversion and abuse of prescription opioids has escalated, as has the number of individuals receiving methadone or buprenorphine pharmacotherapy for opioid addiction. As a result, the proportion of opioid-tolerant patients requiring acute pain management has increased, often presenting clinicians with greater challenges than those faced when treating the opioid-naïve. Treatment aims include effective relief of acute pain, prevention of drug withdrawal, assistance with any related social, psychiatric and behavioural issues, and ensuring continuity of long-term care. Pharmacological approaches incorporate the continuation of usual medications (or equivalent), short-term use of sometimes much higher than average doses of additional opioid, and prescription of non-opioid and adjuvant drugs, aiming to improve pain relief and attenuate opioid tolerance and/or opioid-induced hyperalgesia. Discharge planning should commence at an early stage and may involve the use of a 'Reverse Pain Ladder' aiming to limit duration of additional opioid use. Legislative requirements may restrict which drugs can be prescribed at the time of hospital discharge. At all stages, there should be appropriate and regular consultation and liaison with the patient, other treating teams and specialist services.

Topics: Acute Disease; Analgesics; Analgesics, Opioid; Animals; Australia; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Drug Tolerance; Humans; Hyperalgesia; Illicit Drugs; Methadone; Naloxone; Narcotic Antagonists; Narcotics; New Zealand; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Pain, Postoperative; Patient Discharge; Preoperative Care; Substance Withdrawal Syndrome

This article reviews the pharmacology, therapeutic efficacy and tolerability profile of the 7-day lower-dose (5, 10 and 20 μg/h) buprenorphine transdermal patch (BuTrans®, Norspan®) in the management of chronic non-malignant pain, with a focus on European labelling for the drug. Buprenorphine is a semi-synthetic opioid analgesic that acts primarily as a partial agonist at the mu opioid receptor. The transdermal formulation provides continuous delivery of buprenorphine, resulting in relatively consistent plasma drug concentrations throughout the 7-day dosing interval. The analgesic efficacy of transdermal buprenorphine in patients with osteoarthritis of the hip and/or knee has been demonstrated in several randomized controlled trials, which have shown the formulation to be equivalent to sublingual buprenorphine, noninferior to prolonged-release tramadol tablets, noninferior to codeine plus paracetamol (acetaminophen) combination tablets (when transdermal buprenorphine was used together with regularly scheduled oral paracetamol) and generally superior to a matching transdermal placebo patch. Transdermal buprenorphine was significantly more effective than placebo in reducing chronic low back pain of at least moderate severity in two randomized, double-blind, crossover trials. Other clinical trials, including a randomized, double-blind, maintenance-of-analgesia study, have also demonstrated the analgesic efficacy of transdermal buprenorphine in patients with chronic non-malignant pain of various causes. In general, serious adverse events with transdermal buprenorphine are similar to those for other opioid analgesics. Transdermal buprenorphine has a ceiling effect for respiratory depression, and the main risk is when it is combined with other CNS depressants. The most frequently reported adverse events with transdermal buprenorphine are headache, dizziness, somnolence, constipation, dry mouth, nausea, vomiting, pruritus, erythema, application site pruritus and application site reactions. Transdermal buprenorphine was better tolerated than sublingual buprenorphine in a 7-week, randomized, double-blind trial in patients with osteoarthritis pain. Nevertheless, as with other opioids, persistence with transdermal buprenorphine therapy is difficult for many patients because of adverse events or other reasons. Thus, transdermal buprenorphine has generally demonstrated good efficacy and tolerability in clinical trials in chronic non-malignant pain, providing effective

Topics: Analgesics, Opioid; Buprenorphine; Chronic Disease; Dose-Response Relationship, Drug; Humans; Pain; Pain Measurement; Randomized Controlled Trials as Topic; Time Factors; Transdermal Patch; Treatment Outcome

Patients on drug-assisted rehabilitation have the same right to pain relief as others. Techniques that reduce the need for opioids should be used when possible in opioid-dependent individuals who need treatment of acute and post-operative pain. Substitution treatment should always be continued. In some situations a switch to a different opioid or route of administration is required. Higher doses of opioids than those needed in other patients may be required for analgesia. Well-designed clinical studies are lacking in this field.

Topics: Acetaminophen; Acute Disease; Analgesics, Non-Narcotic; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Glucocorticoids; Humans; Ketamine; Methadone; Opioid-Related Disorders; Pain; Pain, Postoperative; Surgical Procedures, Operative

This study compared the availability and the licensing status of analgesic drugs marketed in three European countries (Italy, France and the UK) and evaluated the evidence on safety and efficacy in the paediatric population of the drugs reported in the European Medicines Evaluation (EMA) document "Assessment of Pediatric Needs: Pain" (2005). Ten of 17 drugs reported in the EMA document were marketed with a paediatric licence in all three countries but with wide differences concerning age groups. In all, 594 randomised controlled trials (RCTs) concerning the 17 drugs in the EMA list were found through biomedical literature databases. Bupivacaine was the drug with the most trials retrieved (171 RCTs, 29%); 32 (5%) RCTs concerned clonidine not licensed for pain control, and 51 (9%) concerned ketamine licensed for paediatric use only in the UK. Access to, and the rational use, of drugs to prevent or control pain and its functional consequences pose a considerable challenge. There is a pressing need for further research and clinical development in the assessment and management of pain in children.

Topics: Adolescent; Analgesics; Buprenorphine; Child; Child, Preschool; Clonidine; Drug and Narcotic Control; Europe; Humans; Infant; Infant, Newborn; Ketamine; Pain; Practice Guidelines as Topic; Randomized Controlled Trials as Topic

To identify users and use of opioids in Denmark three databases were combined. The latest fifteen years an increase in users has been noted, and the costs of opioids have increased from 175 million DKK (1994) to 540 million DKK (2008). Oxycodone and transdermal fentanyl constitute 60% of the total annual costs, and together with the increasing costs of buprenorphine, the three opioids constitute 70% of the total costs in the primary health care sector. The largest group of users is individuals with acute pain, however, the highest consumption is generated by individuals with chronic non-malignant pain.

Topics: Analgesics, Opioid; Buprenorphine; Databases, Factual; Denmark; Drug Costs; Drug Utilization; Fentanyl; Humans; Neoplasms; Oxycodone; Pain; Substance-Related Disorders

Pediatric palliative care (PPC) is provided to children experiencing life-limiting diseases (LLD) or life-threatening diseases (LTD). Sixty to 90% of children with LLD/LTD undergoing PPC receive opioids at the end of life. Analgesia is often insufficient. Reasons include a lack of knowledge concerning opioid prescribing and adjustment of opioid dose to changing requirements. The choice of first-line opioid is based on scientific evidence, pain pathophysiology, and available administration modes. Doses are calculated on a bodyweight basis up to a maximum absolute starting dose. Morphine remains the gold standard starting opioid in PPC. Long-term opioid choice and dose administration is determined by the pathology, analgesic effectiveness, and adverse effect profile. Slow-release oral morphine remains the dominant formulation for long-term use in PPC with hydromorphone slow-release preparations being the first rotation opioid when morphine shows severe adverse effects. The recently introduced fentanyl transdermal therapeutic system with a drug-release rate of 12.5 microg/hour matches the lower dose requirements of pediatric cancer pain control. Its use may be associated with less constipation compared with morphine use. Though oral transmucosal fentanyl citrate has reduced bioavailability (25%), it inherits potential for breakthrough pain management. However, the gold standard breakthrough opioid remains immediate-release morphine. Buprenorphine is of special clinical interest as a result of its different administration routes, long duration of action, and metabolism largely independent of renal function. Antihyperalgesic effects, induced through antagonism at the kappa-receptor, may contribute to its effectiveness in neuropathic pain. Methadone also has a long elimination half-life (19 [SD 14] hours) and NMDA receptor activity although dose administration is complicated by highly variable morphine equianalgesic equivalence (1 : 2.5-20). Opioid rotation to methadone requires special protocols that take this into account. Strategies to minimize adverse effects of long-term opioid treatment include dose reduction, symptomatic therapy, opioid rotation, and administration route change. Patient- or nurse-controlled analgesia devices are useful when pain is rapidly changing, or in terminal care where analgesic requirements may escalate. In this article, we present detailed pediatric pharmacokinetic and pharmacodynamic data for opioids, their indications and contr

Topics: Administration, Cutaneous; Administration, Oral; Analgesics, Opioid; Buprenorphine; Child; Delayed-Action Preparations; Fentanyl; Humans; Hydromorphone; Methadone; Morphine; Narcotics; Pain; Palliative Care

Buprenorphine is a partial mu agonist opioid that is FDA-approved to manage opioid addiction in settings outside of traditional methadone clinics. The clinical uses, pharmacokinetics, pharmacodynamics, toxicology, and management of overdoses of buprenorphine are reviewed.

Topics: Analgesics, Opioid; Buprenorphine; Drug Overdose; Humans; Narcotic Antagonists; Opioid-Related Disorders; Pain

Opioids are more frequently used in the treatment of chronic non-cancer pain. The aim is not only to reduce pain intensity, but also the patients' reintegration into their social environment, including the possibility of driving their own car. Various studies have investigated the impact of opioids on driving ability. Two studies showed that a group of patients with chronic pain receiving sustained treatment with transdermal fentanyl or buprenorphine performed significantly better in tests than healthy persons with legally relevant 0,05% concentration of blood alcohol. These results indicate that stable opioid treatment does not necessarily impair driving ability of patients in chronic pain. However, so far published studies do not provide clear evidence for saying that persons on sustained opioid treatment can drive a car without any problem. Nor do they indicate that such persons should not drive.

Topics: Accidents, Traffic; Administration, Cutaneous; Analgesics, Opioid; Automobile Driving; Buprenorphine; Fentanyl; Humans; Oxycodone; Pain; Psychomotor Performance; Reaction Time

Opioids have been regarded for millennia as among the most effective drugs for the treatment of pain. Their use in the management of acute severe pain and chronic pain related to advanced medical illness is considered the standard of care in most of the world. In contrast, the long-term administration of an opioid for the treatment of chronic noncancer pain continues to be controversial. Concerns related to effectiveness, safety, and abuse liability have evolved over decades, sometimes driving a more restrictive perspective and sometimes leading to a greater willingness to endorse this treatment. The past several decades in the United States have been characterized by attitudes that have shifted repeatedly in response to clinical and epidemiological observations, and events in the legal and regulatory communities. The interface between the legitimate medical use of opioids to provide analgesia and the phenomena associated with abuse and addiction continues to challenge the clinical community, leading to uncertainty about the appropriate role of these drugs in the treatment of pain. This narrative review briefly describes the neurobiology of opioids and then focuses on the complex issues at this interface between analgesia and abuse, including terminology, clinical challenges, and the potential for new agents, such as buprenorphine, to influence practice.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Chronic Disease; Drug Tolerance; History, Ancient; Humans; Narcotic Antagonists; Nervous System; Opioid-Related Disorders; Pain; Substance Withdrawal Syndrome

Dependence on and abuse of prescription opioid drugs is now a major health problem, with initiation of prescription opioid abuse exceeding cocaine in young people. Coincident with the emergence of abuse and dependence on prescription opioids, there has been an increased emphasis on the treatment of pain. Pain is now the "5th vital sign" and physicians face disciplinary action for failure to adequately relieve pain. Thus, physicians are whipsawed between the imperative to treat pain with opioids and the fear of producing addiction in some patients. In this article, the authors characterize the emerging epidemic of prescription opioid abuse, discuss the utility of buprenorphine in the treatment of addiction to prescription opioids, and present illustrative case histories of successful treatment with buprenorphine.

Topics: Analgesics, Opioid; Buprenorphine; Disease Outbreaks; Humans; Male; Middle Aged; Narcotic Antagonists; Opioid-Related Disorders; Pain; Prescription Drugs; Substance-Related Disorders; United States

Chronic pain in the elderly is a significant problem. Pharmacokinetic and metabolic changes associated with increased age makes the elderly vulnerable to side effects and overdosing associated with analgesic agents. Therefore the management of chronic cancer pain and chronic nonmalignant pain in this growing population is an ongoing challenge. New routes of administration have opened up new treatment options to meet this challenge. The transdermal buprenorphine matrix allows for slow release of buprenorphine and damage does not produce dose dumping. In addition the long-acting analgesic property and relative safety profile makes it a suitable choice for the treatment of chronic pain in the elderly. Its safe use in the presence of renal failure makes it an attractive choice for older individuals. Recent scientific studies have shown no evidence of a ceiling dose of analgesia in man but only a ceiling effect for respiratory depression, increasing its safety profile. It appears that transdermal buprenorphine can be used in clinical practice safely and efficaciously for treating chronic pain in the elderly.

Topics: Administration, Cutaneous; Age Factors; Aged; Analgesics, Opioid; Buprenorphine; Chronic Disease; Delayed-Action Preparations; Humans; Pain; Pain Measurement; Treatment Outcome

Our understanding of the pathophysiologic mechanisms of chronic pain progresses; the complexity of the problem justifies our need for new molecules and new ways of administration that will help to further optimise and better individualize our pharmacologic therapies. Whereas acute pain can be considered an alarm signal, chronic pain constitutes, per se, a syndrome that requires a meticulous selection of the analgesic drug(s). Since pain is permanent, the continuous administration of the analgesic is recommended rather than an on demand administration. Transdermic modes of administration are of value for the treatment of chronic pain because they allow a progressive delivery of the active compound together with the maintenance of stable plasma levels of the drug. Buprenorphine is a semi-synthetic opioid that is available in the sublingual, injectable, or transdermic forms. The matrix patch of buprenorphine represents a major asset for the treatment of chronic pain, whether it be cancerous in origin, or not. Its efficacy and safety have been clearly demonstrated in randomised double blind trials as well as in post-marketing surveillance observations. Buprenorphine, administered as a transdermal therapeutic system, induces a dose-related pain relief, whatever the nature of the pain and the age of the patient. Buprenorphine also exerts an analgesic action on neuropathic pain. It differs from other opioids by its affinity as a partial agonist on mu and kappa receptors, and as a complete agonist of ORL-1 receptors. Therefore, transdermal buprenorphine will be useful to all physicians having to control severe pain by powerful opioids.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Chronic Disease; Humans; Pain

Topics: Administration, Cutaneous; Administration, Oral; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Cyclooxygenase 2 Inhibitors; Humans; Naloxone; Osteoarthritis; Pain; Risk Factors; Tilidine; Tramadol

This article addresses common questions that clinicians face when treating pregnant women with opioid dependence. Guidance, based on both research evidence and the collective clinical experience of the authors, which include investigators in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, is provided to aid clinical decision making. The MOTHER project is a double-blind, double-dummy, flexible-dosing, parallel-group clinical trial examining the comparative safety and efficacy of methadone and buprenorphine for the treatment of opioid dependence in pregnant women and their neonates. The article begins with a discussion of appropriate assessment during pregnancy and then addresses clinical management stages including maintenance medication selection, induction, and stabilization; opioid agonist medication management before, during, and after delivery; pain management; breast-feeding; and transfer to aftercare. Lastly, other important clinical issues including managing co-occurring psychiatric disorders and medication interactions are discussed.

Topics: Analgesics, Opioid; Buprenorphine; Clinical Trials as Topic; Decision Making; Female; Humans; Infant, Newborn; Methadone; Opioid-Related Disorders; Pain; Pregnancy; Pregnancy Complications

To assess the adverse effects of transdermal opiates treating moderate-severe cancer pain in comparison with slow release oral morphine.. A systematic review of the literature in the MEDLINE and EMBASE databases from 1966 to June 2007 was independently performed by two authors. All phase 3 randomized trials comparing transdermal opiates and slow-release oral morphine in the treatment of moderate-severe cancer pain were considered eligible and included in the analysis. The primary end point was the overall adverse effects odds ratio (OR); secondary end points were the overall gastrointestinal adverse effects, constipation, nausea, somnolence, patients' preference, and trial withdrawal. Heterogeneity was analyzed using the Mantel-Haenszel test, and outcome analysis was performed using a random effect model; an alpha error lower than 5% was assumed as statistically significant.. Four trials met the selection criteria. The safety of transdermal opiates (fentanyl and buprenorphine) and slow-release oral morphine was analyzed in 425 patients. A significant difference in favor of transdermal opiates was observed for constipation (OR=0.38, p<0.001), and patients' preference (OR=0.43, p=0.014, in the three trials investigating transdermal fentanyl). No significant differences were observed for overall adverse effects, overall gastrointestinal adverse effects, overall neurologic adverse effects, nausea, somnolence, hypoventilation, trial withdrawal, and changes in opiate treatments.. Although no difference in the overall adverse effect profile exists between transdermal opiates and slow release oral morphine, the difference in some adverse effects (mainly constipation) seems to favor transdermal opiates in the preference of patients with moderate-severe cancer pain.

Topics: Administration, Cutaneous; Administration, Oral; Analgesics, Opioid; Buprenorphine; Delayed-Action Preparations; Fentanyl; Humans; Morphine; Neoplasms; Pain; Randomized Controlled Trials as Topic

Pain in older cancer patients is a common event, and many times it is undertreated. Barriers to cancer pain management in the elderly include concerns about the use of medications, the atypical manifestations of pain in the elderly, and side effects related to opioid and other analgesic drugs. The care of older cancer patients experiencing pain involves a comprehensive assessment, which includes evaluation for conditions that may exacerbate or be exacerbated by pain, affecting its expression, such as emotional and spiritual distress, disability, and comorbid conditions. It is important to use appropriate tools to evaluate pain and other symptoms that can be related to it. Pain in older cancer patients should be managed in an interdisciplinary environment using pharmacologic and nonpharmacologic interventions whose main goals are decreasing suffering and improving quality of life. In this two-part article, the authors present a review of the management of pain in older cancer patients, emphasizing the roles of adequate assessment and a multidisciplinary team approach.

Topics: Age Factors; Aged; Aged, 80 and over; Analgesics; Analgesics, Opioid; Buprenorphine; Female; Fentanyl; Humans; Male; Neoplasms; Pain; Pain Management

Neuropathic pain occurs in 1% of the population and is difficult to manage. Responses to single drugs are limited in benefit. Thirty percent will fail to respond altogether. This is a review of newer drugs and treatment paradigms.. A literature review was performed pertinent to new drugs and treatment algorithms in the management of neuropathic pain.. New information on opioids (tramadol and buprenorphine) suggests benefits in the management of neuropathic pain and has increased interest in their use earlier in the course of illness. Newer antidepressants, selective noradrenaline, and serotonin reuptake inhibitors (SNRIs) have evidence for benefit and reduced toxicity without an economic disadvantage compared to tricyclic antidepressants (TCAs). Pregabalin and gabapentin are effective in diabetic neuropathy and postherpetic neuralgia. Treatment paradigms are shifting from sequential single drug trials to multiple drug therapies. Evidence is needed to justify this change in treatment approach.. Drug choices are now based not only on efficacy but also toxicity and drug interactions. For this reason, SNRIs and gabapentin/pregabalin have become popular though efficacy is not better than TCAs. Multiple drug therapies becoming an emergent treatment paradigm research in multiple drug therapy are needed.

Topics: Buprenorphine; Drug Therapy, Combination; Humans; Narcotics; Neuralgia; Pain; Selective Serotonin Reuptake Inhibitors; Tramadol

There is a paucity of relevant pediatric data on buprenorphine, especially with respect to the long-term application in children suffering chronic pain or to pediatric pharmacokinetic as well as pharmacodynamic data after repeated sublingual or long-term transdermal administration. Compared to adults, after single-dose buprenorphine, children seem to exhibit a larger clearance related to body weight and a longer duration of action. If combined with other opioids or sedatives or if the metabolite norbuprenorphine cumulates, it is difficult to estimate the risk of respiratory depression. Clear-cut evidence is missing that in children there is a ceiling of buprenorphine-induced respiratory depression. Due to its various application routes, long duration of action, and metabolism largely independent of renal function buprenorphine is of special clinical interest in pediatrics, especially for postoperative pain and cancer pain control. There is no reason to expect effects fundamentally different from those in adults.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Child; Humans; Metabolic Clearance Rate; Pain; Pediatrics

More patients with opioid addiction are receiving opioid agonist therapy (OAT) with methadone and buprenorphine. As a result, physicians will more frequently encounter patients receiving OAT who develop acutely painful conditions, requiring effective treatment strategies. Undertreatment of acute pain is suboptimal medical treatment, and patients receiving long-term OAT are at particular risk. This paper acknowledges the complex interplay among addictive disease, OAT, and acute pain management and describes 4 common misconceptions resulting in suboptimal treatment of acute pain. Clinical recommendations for providing analgesia for patients with acute pain who are receiving OAT are presented. Although challenging, acute pain in patients receiving this type of therapy can effectively be managed.

Topics: Acute Disease; Adult; Analgesics, Opioid; Buprenorphine; Female; Heroin Dependence; Humans; Methadone; Narcotic Antagonists; Pain; Recurrence; Ulna Fractures

Impairment of renal function is common among elderly patients due to an age-related decline in renal excretory function. In addition, many diseases such as hypertension and diabetes mellitus are associated with an accelerated decline in renal function. Renal dysfunction affects the metabolism of compounds and thus has important therapeutic consequences for drug safety. For pain patients who have reduced renal function such as those in palliative care, most opioids used for chronic pain treatment should be administered at reduced dosages, with increased dosage intervals, or not at all because of the risk of accumulation of the parent compound or its metabolites. For instance, for morphine or codeine, active metabolites are formed in the liver and cleared by the kidney and may therefore accumulate in cases of renal dysfunction. In contrast, buprenorphine can be administered at normal doses in patients with renal dysfunction because it is mainly excreted through the liver. In patients undergoing regular haemodialysis treatment, removal of an opioid during dialysis varies between individuals based upon a number of factors including the dialysis technique used. Morphine appears to be difficult to process in haemodialysis patients due to possible 'rebound' of metabolites between dialysis sessions. By contrast, the pharmacokinetics of buprenorphine are unchanged in haemodialysis patients, which means that there is no need for dose-reduction with this drug. Thus, in patients with reduced renal function, chronic renal insufficiency and haemodialysis, buprenorphine appears to be a safe choice when opioid treatment is initiated.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Contraindications; Humans; Kidney; Kidney Function Tests; Middle Aged; Morphine; Morphine Derivatives; Pain; Renal Dialysis; Renal Insufficiency, Chronic

Transdermal buprenorphine has been assessed as a therapy for chronic cancer and non-cancer pain in both clinical and postmarketing surveillance studies. Data from 239 patients who had participated in a follow-up study of up to six years have shown efficacy and safety, and good tolerability over prolonged treatment periods with a marked stability of doses. From the cancer pain population (134 patients), 20% stayed on transdermal buprenorphine until the end of their lives. Postmarketing surveillance study data from 13,179 patients, including 3690 cancer patients assessed during a 10-week observation period, showed that 81% of patients achieved good/very good pain relief with transdermal buprenorphine. Furthermore, 49.6% of patients did not require any analgesic comedication or rescue therapy, a point that is particularly important in the elderly population. Results from the Spanish Pain Society on transdermal buprenorphine in chronic non-cancer, neuropathic and cancer-related pain, and on switching from morphine, also confirmed its beneficial efficacy and safety, and showed that buprenorphine does not antagonize pain relief, or cause withdrawal when combined with full micro-agonists. The effectiveness of buprenorphine is further supported by evidence of its pronounced anti-hyperalgesic effect in a human pain model, which may be a factor in explaining the efficacy of buprenorphine in neuropathic pain. When switching of opioids is indicated to improve pain relief or reduce adverse events, equipotency dosage ratios are important. The equipotency ratio for morphine to buprenorphine, previously established as 75:1, is now being questioned as new data from a retrospective cohort study were published indicating a ratio of 100:1. Moreover, transdermal buprenorphine has superior safety in respect to respiratory depression, immunological and renal effects compared with standard World Health Organization step III opioids, which makes it highly suitable for treating moderate-to-severe pain also in cancer patients, a per se vulnerable patient population requiring a sensible selection of potent analgesics.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Drug Interactions; Fentanyl; Humans; Narcotic Antagonists; Neoplasms; Pain; Pain Measurement; Palliative Care

In most cancer patients pain can be successfully treated with pharmacological measures using opioid analgesics alone or in combination with adjuvant analgesics (coanalgesics). Weak opioids are usually recommended in the treatment of moderate cancer pain. There is still a debate as to whether the second step of the WHO analgesic ladder comprising opioid analgesics such as tramadol, codeine, dihydrocodeine, and dextropropoxyphene is still needed for the treatment of cancer pain. On the basis of our experience and review of the literature we think that there is definitely a place for weak opioids in the treatment of moderate cancer pain. One of the most interesting and useful weak opioids is tramadol (Adolonta, Contramal, Nobligan, Top-Algic, Tramal, Tramal Long, Tramal Retard, Tramundin, Trodon, Ultram, Zydol). Its unique mechanism of action, analgesic efficacy and profile of adverse reactions have been the reason of performing many experimental and clinical studies with tramadol. In this article we summarize data on pharmacology, mechanisms of action, pharmacokinetics, side effects and clinical experience assessing analgesic efficacy, adverse reactions and safety of tramadol in cancer pain.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Humans; Neoplasms; Pain; Pain Measurement; Tramadol

Topics: Analgesics, Opioid; Animals; Buprenorphine; Dopamine; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Humans; Pain; Pleasure-Pain Principle; Potassium Channels, Inwardly Rectifying; Presynaptic Terminals; Receptors, Opioid, mu

New effective analgesics are needed for the treatment of pain. Buprenorphine, a partial mu-opioid agonist which has been in clinical use for over 25 years, has been found to be amenable to new formulation technology based on its physiochemical and pharmacological profile. Buprenorphine is marketed as parenteral, sublingual, and transdermal formulations. Unlike full mu-opioid agonists, at higher doses, buprenorphine's physiological and subjective effects, including euphoria, reach a plateau. This ceiling may limit the abuse potential and may result in a wider safety margin. Buprenorphine has been used for the treatment of acute and chronic pain, as a supplement to anesthesia, and for behavioral and psychiatric disorders including treatment for opioid addiction. Prolonged use of buprenorphine can result in physical dependence. However, withdrawal symptoms appear to be mild to moderate in intensity compared with those of full mu agonists. Overdoses have primarily involved buprenorphine taken in combination with other central nervous system depressants.

Topics: Analgesics, Opioid; Buprenorphine; Humans; Pain

The transdermal matrix patch formulation of buprenorphine has been shown to be effective in managing moderate-to-severe cancer pain and severe pain unresponsive to nonopioid analgesics. Clinical trials have revealed that it is possible to switch from weak opioids or low doses of step III opioids to transdermal buprenorphine without any problems. With buprenorphine patches, the sublingual buprenorphine intake was dose-dependently reduced and was superior to placebo in this respect. The proportion of responders increased with the buprenorphine dose, and a higher proportion of patients receiving buprenorphine patches reported uninterrupted sleep for longer than 6 h compared with those receiving placebo. In a long-term, open, follow-up study in which the mean duration of treatment was 7.5 months, analgesia was rated as at least satisfactory by 90% of patients. Almost 60% of patients could manage their pain with one patch alone or with one additional sublingual tablet a day during the whole period of treatment, indicating a low incidence of tolerance development. The buprenorphine transdermal patch was assessed as user friendly by 94.6% of patients. In a postmarketing surveillance study, pain relief with transdermal buprenorphine was rated as good or very good by 70% of the responders. Postmarketing surveillance studies have shown that transdermal buprenorphine is also effective in the management of nociceptive and neuropathic pain, which some studies have shown to be relatively insensitive to mu-opioid analgesics, such as morphine. Transdermal buprenorphine was well tolerated. Most adverse events were either local reactions to the patch that generally subsided within 24 h or systemic events typical of treatment with opioid analgesics, such as nausea, vomiting and constipation.

Topics: Administration, Cutaneous; Buprenorphine; Chronic Disease; Humans; Pain; Pain Measurement

Buprenorphine is a broad spectrum, highly lipophilic, and long-acting partial mu opioid receptor agonist that is noncross tolerant to other opioids. Buprenorphine can be given by several routes. Metabolism is through CYP3A4 and CYP2C8 and by conjugases. Constipation and sexual dysfunction appear to be less with buprenorphine than with other opioids. The recent development of a polymer matrix patch delivery system for buprenorphine prevents "dose dumping" and facilitates pain management in those unable to take oral analgesics. Sublingual buprenorphine has been combined with naloxone to prevent illicit conversion to parenteral administration. Buprenorphine has been used extensively to control cancer pain. In certain clinical situations, buprenorphine may have particular advantages over other opioids.

Topics: Analgesics, Opioid; Buprenorphine; Humans; Neoplasms; Pain

The recent approval of office-based treatment for opioid addiction and US Food and Drug Administration approval of buprenorphine will expand treatment options for opioid addiction. Buprenorphine is classified as a partial micro opioid agonist and a weak kappa antagonist. It has a high affinity for the micro receptor, with slow dissociation resulting in a long duration of action and an analgesic potency 25 to 40 times more potent than morphine. At higher doses, its agonist effects plateau and it begins to behave more like an antagonist, limiting the maximal analgesic effect and respiratory depression. This "ceiling effect" confers a high safety profile clinically, a low level of physical dependence, and only mild withdrawal symptoms on cessation after prolonged administration. Suboxone contains a mixture of buprenorphine and naloxone. The naloxone is poorly absorbed sublingually and is designed to discourage intravenous use. Subutex, buprenorphine only, will also be available primarily as an initial test dose. Clinicians will be using this drug for detoxification or for maintenance of opioid addiction. Patients with recent illicit opioid use may develop a mild precipitated withdrawal syndrome with the induction of buprenorphine. Acute buprenorphine intoxication may present with some diffuse mild mental status changes, mild to minimal respiratory depression, small but not pinpoint pupils, and relatively normal vital signs. Naloxone may improve respiratory depression but will have limited effect on other symptoms. Patients with significant symptoms related to buprenorphine should be admitted to the hospital for observation because symptoms will persist for 12 to 24 hours.

Topics: Buprenorphine; Drug and Narcotic Control; Drug Overdose; Emergency Medicine; Humans; Narcotic Antagonists; Opioid-Related Disorders; Pain; United States

Buprenorphine is an opioid analgesic, derived from thebaine. Buprenorphine was initially classified as a "mixed agonist-antagonist analgesic" or a narcotic antagonist analgesic. The work of Martin et al (1976) on the animal model of the chronic spinal dog substantiated the substance's action as partial agonist at the mu-opioid receptor. These findings were underscored by the substance's general pharmacological profile. Further, buprenorphine was one of the first narcotic analgesics to be assessed for its abuse liability in humans. The lower abuse liability of the drug in humans soon turned it into a widely used therapeutic agent in patients with opioid dependence. Interest in buprenorphine spanning more than 30 years has been attributed to its unique pharmacological characteristics, including moderate intrinsic activity, high affinity to and slow dissociation from mu-opioid receptors. Early pharmacological studies demonstrated buprenorphine's strong binding to opioid receptors, and an inverted U-shaped dose-response curve in rodents. In the rat paw formalin test, although buprenorphine demonstrated a bell-shaped dose-response curve against an acute noxious stimulus, it showed a classic sigmoidal curve in the later phase of the assay. In most preclinical antinociceptive tests, buprenorphine was shown to be fully efficacious, with an antinociceptive potency 25 to 40 times higher than morphine. A ceiling effect for respiratory depression (but not for analgesia) has been demonstrated in humans. Current studies are focusing on norbuprenorphine, an N-dealkylated metabolite of buprenorphine. Norbuprenorphine is a likely contributor to the overall pharmacology of buprenorphine; in the mouse writhing test, norbuprenorphine provides antinociceptive efficacy similar to buprenorphine, with analgesic activity shown to be dose-dependent.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Constipation; Dose-Response Relationship, Drug; Gastrointestinal Transit; Humans; Mice; Nociceptors; Pain; Rats

A system for the transdermal administration of the opioid drug buprenorphine has recently been introduced. Buprenorphine has physico-chemical properties, including a low molecular weight and high analgesic potency, that make it an excellent compound for transdermal drug delivery. The new technology (buprenorphine TDS, Transtec) is an advanced system that contains the active drug incorporated into a polymer matrix, which is at the same time the adhesive layer. The patch precisely controls the rate of drug delivery and produces stable plasma concentrations. It is available in three doses (release rates of 35, 52.5 and 70 microg/h), and the suggested duration of use per patch is three days. Buprenorphine TDS was developed for the treatment of moderate to severe cancer pain and severe pain which does not respond to non-opioid analgesics. Not only does this transdermal system provide excellent analgesia and a low incidence of adverse events, but its ease of use results in greater compliance. The patch provides excellent adhesion and has a low susceptibility to damage that might lead to toxicity or opioid abuse.

Topics: Administration, Cutaneous; Administration, Sublingual; Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Humans; Pain

Buprenorphine, a powerful opioid, is newly available for delivery in a transdermal formulation. The transdermal system's matrix patch provides rate-controlled administration of the drug. Three double-blind, placebo-controlled trials were conducted to evaluate efficacy and tolerability of the buprenorphine transdermal system (buprenorphine TDS, Transtec). A total of 445 patients were enrolled in the studies. All suffered from moderate to severe and very severe pain, both cancer- or non-cancer-related. The percentage of responders increased as the rate of buprenorphine delivered by the transdermal system rose, ranging from a 29% (cancer) and 36% (non-cancer) response rate associated with the lowest dose (35 microg/h), to 40% (cancer) and 46% (non-cancer) with the highest dose (70 microg/h). Patients receiving buprenorphine TDS slept longer, uninterrupted by pain, than patients from the placebo group. Systemic adverse effects reported in the drug cohorts included nausea, vomiting and dizziness, and were typical of those reported in other studies of opioids; local adverse events, most commonly erythema and pruritus, were transient and mild to moderate. In an open-label, follow-up trial, in which 239 patients from the original clinical studies participated, 90% of patients reported that their analgesia was satisfactory or even better over a mean duration of 4.7 months; nearly 95% of patients found the patch to be user-friendly. The new buprenorphine TDS appears to be an important new modality for administering analgesia in patients with non-acute pain.

Topics: Analgesics, Opioid; Attitude to Health; Buprenorphine; Humans; Multicenter Studies as Topic; Pain; Randomized Controlled Trials as Topic; Treatment Outcome

Buprenorphine is a low molecular weight, lipophilic, opioid analgesic. Recently, a transdermal matrix patch formulation of buprenorphine has become available in three dosage strengths designed to release buprenorphine at 35, 52.5 and 70 micro g/h over a 72-hour period. At least satisfactory analgesia with minimal requirement for rescue medication (50% of patients treated with transdermal buprenorphine, in two trials. Furthermore, despite the availability of rescue medication to all patients, those receiving transdermal buprenorphine tended to experience greater pain relief, reduced pain intensity and longer pain-free sleep. Transdermal buprenorphine was generally well tolerated. Systemic adverse events were typical of opioid treatment or were attributable to the underlying disease.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Pain; Pain, Intractable

In contrast to other opioids, fentanyl and buprenorphine share a number of physicochemical properties that render both agents potentially suitable for transdermal delivery. However, there are significant differences between them in terms of their pharmacological profiles, as fentanyl is a full mu opioid receptor agonist capable of exerting a maximal response in certain tissues, while buprenorphine is a partial agonist unable to exert this maximum effect even at high doses. This review examines the hypothesis that partial opioid agonists would confer a number of benefits over full agonists, namely effective analgesia with a better tolerability and a lower propensity for addiction, with respect to fentanyl and buprenorphine. An attempt is also made to correlate clinical differences between these drugs with their respective agonist profiles and other differential pharmacokinetic/pharmacodynamic properties. Despite a dearth of directly comparative trials, the pharmacology of fentanyl and buprenorphine is well documented. Considerable data concerning buprenorphine suggest that the advantages initially espoused for partial opioid agonists are not borne out in clinical practice. Indeed, it may be postulated that full mu opioid agonists, particularly those with high selectivity and potency such as fentanyl, have a superior clinical profile and fulfill the above criteria more closely. Relative receptor binding, selectivity, potency and intrinsic efficacy of the opioids appear to be key determinants of their individual pharmacological profiles, contributing significantly to the heterogeneity of this class of analgesics.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Drug Delivery Systems; Drug Tolerance; Fentanyl; Humans; Pain; Receptors, Opioid, mu; Substance-Related Disorders

Although the optimal route of administration of opioids is by mouth, some patients may require alternative routes during the course of their illnesses for several reasons. These include bowel obstruction, severe emesis, or severe dysphagia. In these cases, the alternatives include the subcutaneous or rectal route. The transdermal route also provides a simple, comfortable method that produces stable blood drug concentrations. The high potency and lipid solubility of fentanyl make it suitable for this route of administration. Iontophoresis can provide a rapid drug delivery rate, but no clinical studies exist to document the long-term effectiveness of this method in controlling pain. The transmucosal route is recommended only for those opioids with high solubility, such as buprenorphine, the fentanyl series, and methadone. Oral transmucosal fentanyl (Actiq) provides a rapid onset of pain relief and is appropriate for treating episodes of breakthrough pain.

Topics: Administration, Oral; Administration, Topical; Analgesics, Opioid; Buprenorphine; Fentanyl; Humans; Injections, Subcutaneous; Neoplasms; Pain; Treatment Outcome

Topics: Buprenorphine; Chronic Disease; Hemodynamics; Humans; Intraoperative Period; Pain; Pain Measurement; Receptors, Opioid; Respiration

Topics: Buprenorphine; Delayed-Action Preparations; Humans; Methadone; Morphine; Pain; Palliative Care

The mixed agonist-antagonist analgesics do not have a major role in the treatment of chronic pain. Pentazocine, the first and most widely used of this group of drugs has two major limitations: by mouth it is not a strong analgesic, but is closer in efficacy to the peripherally acting drugs aspirin and paracetamol than the weak opioids; and its use is associated with psychotomimetic side effects in 10-20 percent of patients. The weak opioid analgesics codeine and dextropropoxyphene are more effective and better tolerated than pentazocine. Buprenorphine is the most useful of the agonist-antagonists in chronic pain patients. It is potent, long-acting (6-9 h) and effective when given sublingually. However, it has a limited effective dose range and produces the same side effects as morphine-like drugs, possibly more frequently at equianalgesic doses. It may be used in the treatment of cancer pain, or in patients with chronic arthritides or other forms of chronic non-cancer pain who require a potent conventional analgesic, as an alternative to the weak opioids or to morphine in low doses. Nalbuphine and butorphanol are only available for parenteral administration which means that their usefulness in the treatment of chronic pain is limited. Meptazinol is restricted by its manufacturers to 'short term' treatment and there is little information on its use in chronic pain patients.

Topics: Analgesics, Opioid; Buprenorphine; Chronic Disease; Humans; Narcotic Antagonists; Pain

Successful pain management using opiates requires both an analgesic with sufficient intrinsic activity and an effective administration system. Most instances of unsatisfactory pain control, however, are due to failure to achieve and maintain adequate blood concentrations of the chosen drug. Newer techniques of administration aim to overcome this problem. Oral opiate therapy with conventional or sustained-release formulations of morphine provide good control of terminal cancer pain provided that a regular dosing pattern is established and reviewed according to the patient's needs. This represents a significant departure from the traditional 'as required' prescription of this type of drug. In the management of acute severe pain, sublingual and intravenous opiates--self-administered as needed, or given by mandatory dosing schedules--have also been shown to overcome the limitations of intermittent intramuscular injections. A further novel development, stemming from basic neuroscience research, is the selective application of opiates to the spinal cord via the epidural or intrathecal route. This controversial technique has led to major improvements in treatment of some types of acute and chronic pain.

Topics: Administration, Oral; Buprenorphine; Delayed-Action Preparations; Humans; Injections, Intravenous; Injections, Spinal; Kinetics; Narcotics; Pain; Self Administration

This randomised, prospective, masked clinical trial evaluated the postoperative analgesic efficacy of an ultrasound-guided transversus abdominis plane block (TAPB) with bupivacaine in cats undergoing ovariohysterectomy.. Thirty-two healthy adult female cats undergoing elective ovariohysterectomy were randomised to undergo TAPB with bupivacaine (treatment group [TG], n = 16) vs placebo (control group [CG], n = 16) in addition to preoperative analgesia with buprenorphine (0.02 mg/kg IM). All patients received a general anaesthetic and, before surgical incision, a bilateral two-point (subcostal and lateral-longitudinal) TAPB was performed using 1 ml/kg bupivacaine 0.25% (0.25 ml/kg/point) or saline. Each cat was assessed by a blinded investigator before premedication (0 h) and at 1, 2, 3, 4, 8, 10 and 24 h postoperatively using the UNESP-Botucatu Feline Pain Scale - short form. Buprenorphine (0.02 mg/kg IV) and meloxicam (0.2 mg/kg SC) were administered when pain scores were ⩾4/12. Ten hours postoperatively, meloxicam was administered to cats that did not receive rescue analgesia. Statistical analysis included Student's. Of the 32 cats enrolled, three in the CG were excluded from the analysis. The prevalence of rescue analgesia was significantly higher in the CG (n = 13/13) than in the TG (n = 3/16;. A bilateral ultrasound-guided two-point TAPB with bupivacaine in combination with systemic buprenorphine provided superior postoperative analgesia than buprenorphine alone in cats undergoing ovariohysterectomy.

Topics: Abdominal Muscles; Analgesics; Animals; Bupivacaine; Buprenorphine; Cats; Female; Meloxicam; Pain; Prospective Studies; Ultrasonography, Interventional

Cats in this study were previously onychectomized and exhibited inappropriate behaviors (inappropriate elimination, biting), exhibited pain associated with the onychectomy site or had behavioral improvements when put on a 2-week buprenorphine trial. A detailed history was obtained, including verification of proper litter box placement and management. Physical examinations included a close analysis of the onychectomized digits for resistance to extension and pain on palpation. Only cats with a normal urinalysis were included in the study. High-resolution radiographic imaging was performed on all study cats. A total flexor tenectomy was performed on cats with hyperflexion of the proximal interphalangeal joints.. All 42 cats included in the study benefited from total flexor tenectomy surgery. Two cats remained biters, even after a long course of analgesic medication. All cats walked more comfortably post-tenectomy surgery.. Onychectomy can lead to pain, inappropriate elimination and aggressive behavior. The presented salvage tenectomy procedure can alleviate or eliminate inappropriate behaviors by reducing the pain from the original onychectomy.

Topics: Animals; Buprenorphine; Cats; Pain

Extended-release (ER) local anesthetics can be used in multi-modal analgesia or in situations in which systemic analgesics may alter animal physiology and thus introduce interpretational confounds. In this study, we compared the analgesic efficacy of an ER buprenorphine formulation with that of a synergistic combination of ER bupivacaine and meloxicam. Female and male CD1 mice were randomly assigned to receive subcutaneous buprenorphine (3.25mg/kg) preemptively, subcutaneous infiltration of bupivacaine???meloxicam (0.03mL at incision closure (bupivacaine, 35mg/kg; meloxicam, 1mg/kg), or saline (10mL/kg SC) after induction of anesthesia. After laparotomy, mice were assessed for changes in daily body weight, rearing frequency, nest consolidation scores, time-to-integrate-nest test (TINT), and response to von Frey testing at 4, 8, 24, 48, and 72h after surgery. Daily weight, nest consolidation scores and rearing frequency were not significantly different among the 3 groups. TINT had fallen significantly response at 24 and 48h after injection in the ER buprenorphine group as compared with the saline and ER bupivacaine-meloxicam groups. Nociceptive thresholds, as assessed with von Frey testing, differed between saline controls and both analgesic groups at 4, 8, 24, 48, and 72 h after surgery. None of the mice in the bupivacaine???meloxicam group developed signs of neurotoxicity, a potential side effect of high-dose local anesthetics. This study demonstrates that local ER bupivacaine???meloxicam may be a useful alternative to systemic, ER buprenorphine for the relief of pain after laparotomy in mice.

Topics: Analgesics; Analgesics, Opioid; Anesthetics, Local; Animals; Bupivacaine; Buprenorphine; Female; Laparotomy; Male; Meloxicam; Mice; Pain; Pain, Postoperative; Rodent Diseases

Identifying early indicators of distress in mice is difficult using either periodic monitoring or current technology. Likewise, poor pain identification remains a barrier to providing appropriate pain relief in many mouse models. The Time to Incorporate to Nest Test (TINT), a binary measure of the presence or absence of nesting behavior, was developed as a species-specific method of identifying moderate to severe distress and pain in mice. The current study was designed to evaluate alterations in nesting behavior after routine surgery and to validate the TINT's ability to measure pain-related behavioral changes. CD1 mice undergoing carotid artery catheterization as part of a commercial surgical cohort were randomly assigned various nesting, surgery, and analgesia conditions. To provide context for the TINT outcomes, we measured other variables affected by pain, such as weight loss, food consumption, and scores derived from the Mouse Grimace Scale (MGS). Mice that had surgery were more likely to have a negative TINT score as compared with controls. All mice were more likely to fail the TINT after receiving postoperative buprenorphine, suggesting that buprenorphine may have contributed to the failures. The TINT, MGS live scoring, and scoring MGS images all loaded strongly on a single component in a principal component analysis, indicating strong convergent validity between these measures. These data indicate that the TINT can provide a quick, objective indicator of altered welfare in mice, with the potential for a wide range of uses.

Topics: Analgesia; Analgesics, Opioid; Animals; Buprenorphine; Laboratory Animal Science; Mice; Nesting Behavior; Pain; Pain Management; Pain Measurement; Pain, Postoperative; Species Specificity

Topics: Ambystoma mexicanum; Analgesia; Analgesics; Animals; Behavior, Animal; Buprenorphine; Butorphanol; Laboratory Animal Science; Pain; Pain Management; Pain Measurement

This study aimed to evaluate the analgesic efficacy of two dosage regimens using two different concentrations of buprenorphine in cats undergoing dental extractions. Twenty-three cats with oral disease (8.2 ± 2.2 years old; 4.9 ± 0.9 kg) were included in a prospective, blinded, randomized clinical trial. Cats randomly received either Simbadol (1.8 mg/mL; 0.24 mg/kg, subcutaneously, every 24h: SG, n = 11) or Vetergesic (0.3 mg/mL; 0.02 mg/kg, intramuscularly, every 8h: VG, n = 12) throughout the study. They were admitted at day 0, underwent oral examination/radiographs/treatment under general anesthesia (buprenorphine-propofol-isoflurane-meloxicam-local anesthetic blocks) at day 1 and discharged at day 4. Sedation and pain were scored using the dynamic interactive visual analog scale (day 1) and the Glasgow Composite Measure Pain Scale-Feline (CMPS-F; up to postoperative 8 hours at day 1, 8 am, 4 pm and midnight at days 2 and 3, and 8 am at day 4), respectively. Rescue analgesia was administered with hydromorphone (0.05 mg/kg intravenously on day 1 or 0.1 mg/kg intramuscularly after day 2) when CMPS-F ≥ 5. Resentment defined as any type of escape behavior associated with aversion to drug administration was recorded. Sedation and pain scores, the prevalence of rescue analgesia and resentment during drug administration were analyzed using linear mixed models and Fisher's exact test, respectively (p < 0.05). Pain and sedation scores were not significantly different between groups. Sedation scores were significantly higher up to postoperative 2 hours in both groups. Pain scores in SG and VG were significantly higher up to postoperative 8 hours and 8 am of day 2, respectively, than baseline. Prevalence of rescue analgesia and resentment were not significantly different between groups (SG: 27.3%, VG: 33.3% and SG: 0%, VG: 25%, respectively). Simbadol produced similar analgesic effects to Vetergesic without resentment during drug administration.

Topics: Analgesia; Analgesics; Animals; Buprenorphine; Cats; Double-Blind Method; Female; Male; Pain; Periodontal Diseases; Postoperative Period; Prospective Studies; Severity of Illness Index; Tooth Extraction

Opioid withdrawal symptoms are widely understood to contribute to health risk but have rarely been measured in community samples of opioid using people who inject drugs (PWID).. Using targeted sampling methods, 814 PWID who reported regular opioid use (at least 12 uses in the last 30 days) were recruited and interviewed about demographics, drug use, health risk, and withdrawal symptoms, frequency, and pain. Multivariable regression models were developed to examine factors associated with any opioid withdrawal, withdrawal frequency, pain severity, and two important health risks (receptive syringe sharing and non-fatal overdose).. Opioid withdrawal symptoms were reported by 85 % of participants in the last 6 months, with 29 % reporting at least monthly withdrawal symptoms and 35 % reporting at least weekly withdrawal symptoms. Very or extremely painful symptoms were reported by 57 %. In separate models, we found any opioid withdrawal (adjusted odds ratio [AOR] = 2.75, 95 % confidence interval [CI] = 1.52, 5.00) and weekly or more opioid withdrawal frequency (AOR = 1.94; 95 % CI = 1.26, 3.00) (as compared to less than monthly) to be independently associated with receptive syringe sharing while controlling for confounders. Any opioid withdrawal (AOR = 1.71; 95 % CI = 1.04, 2.81) was independently associated with nonfatal overdose while controlling for confounders. In a separate model, weekly or more withdrawal frequency (AOR = 1.69; 95 % CI = 1.12, 2.55) and extreme or very painful withdrawal symptoms (AOR = 1.53; 95 % CI = 1.08, 2.16) were associated with nonfatal overdose as well.. Withdrawal symptoms among PWID increase health risk. Treatment of withdrawal symptoms is urgently needed and should include buprenorphine dispensing.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Cross-Sectional Studies; Drug Overdose; Female; Health Status; Humans; Male; Middle Aged; Needle Sharing; Opioid-Related Disorders; Pain; Risk Factors; Substance Abuse, Intravenous; Substance Withdrawal Syndrome

Pain management in rabbits can be difficult because they are adept at hiding pain and can be stressed by handling and restraint for injection. The use of opioid analgesics with prolonged durations of activity could alleviate pain, but associated adverse effects including gastrointestinal ileus, inappetence, and tissue reactions have been reported. In this study, we compared gross tissue reactions at the site of injection, food consumption, and fecal production after single injections of buprenorphine HCl (Bup;

Topics: Analgesics, Opioid; Animals; Animals, Laboratory; Buprenorphine; Delayed-Action Preparations; Male; Pain; Pain Management; Pain Measurement; Rabbits

Managing acute pain in buprenorphine-maintained individuals in emergency or perioperative settings is a significant challenge. This study compared analgesic and abuse liability effects of adjunct hydromorphone and buprenorphine using quantitative sensory testing, a model of acute clinical pain, in persons maintained on 12 to 16 mg sublingual buprenorphine/naloxone.. Participants (N = 13) were enrolled in a randomized within-subject, double-blind, placebo-controlled three-session experiment. Each session used a cumulative dosing design with four IV injections (4, 4, 8, and 16 mg of hydromorphone or 4, 4, 8, and 16 mg of buprenorphine); quantitative sensory testing and abuse liability assessments were measured at baseline and after each injection. The primary analgesia outcome was change from baseline cold pressor testing; secondary outcomes included thermal and pressure pain testing, as well as subjective drug effects and adverse events.. A significant two-way interaction between study drug condition and dose was exhibited in cold pressor threshold (F10,110 = 2.14, P = 0.027) and tolerance (F10,110 = 2.69, P = 0.006). Compared to after placebo, participants displayed increased cold pressor threshold from baseline after cumulative doses of 32 mg of IV hydromorphone (means ± SD) (10 ± 14 s, P = 0.035) and 32 mg of buprenorphine (3 ± 5 s, P = 0.0.39) and in cold pressor tolerance after cumulative doses of 16 mg (18 ± 24 s, P = 0.018) and 32 mg (48 ± 73 s, P = 0.041) IV hydromorphone; cold pressor tolerance scores were not significant for 16 mg (1 ± 15 s, P = 0.619) or 32 mg (7 ± 16 s, P = 0.066) buprenorphine. Hydromorphone and buprenorphine compared with placebo showed greater ratings on subjective measures of high, any drug effects, good effects, and drug liking. Adverse events were more frequent during the hydromorphone compared with buprenorphine and placebo conditions for nausea, pruritus, sedation, and vomiting.. In this acute clinical pain model, high doses of IV hydromorphone (16 to 32 mg) were most effective in achieving analgesia but also displayed higher abuse liability and more frequent adverse events. Cold pressor testing was the most consistent measure of opioid-related analgesia.

Topics: Adult; Analgesia; Analgesics, Opioid; Buprenorphine; Double-Blind Method; Female; Humans; Hydromorphone; Male; Opioid-Related Disorders; Pain; Treatment Outcome

Topics: Administration, Cutaneous; Analgesics, Opioid; Animals; Area Under Curve; Buprenorphine; Cross-Over Studies; Dose-Response Relationship, Drug; Fentanyl; Half-Life; Macaca fascicularis; Male; Pain

Because human patients with monkeypox virus (MPXV) infection report painful symptoms, it is reasonable to assume that animals infected with MPXV experience some degree of pain. Understanding whether and how analgesics affect MPXV disease progression is crucial when planning in vivo challenge experiments. In the current study, we challenged prairie dogs with a low dose (4 ×10³ pfu) of MPXV and treated with meloxicam (NSAID) or buprenorphine (opioid); control animals did not receive analgesia or received analgesia without MPXV challenge. Subsets of animals from each group were serially euthanized during the course of the study. Disease progression and viral kinetics were similar between groups, but MXPVinfected, meloxicam-treated animals showed increasing trends of morbidity and mortality compared with other groups. Differences between no-analgesia MPXV-infected control animals and MPXV-infected animals treated with buprenorphine were minimal. The findings in the current study allow more informed decisions concerning the use of analgesics during experimental MPXV challenge studies, thereby improving animal welfare. In light of these findings, we have modified our pain scale for this animal model to include the use of buprenorphine for pain relief when warranted after MPXV challenge.

Topics: Analgesia; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Disease Models, Animal; Female; Meloxicam; Monkeypox virus; Mpox (monkeypox); Pain; Pain Management; Sciuridae

Topics: Analgesics, Opioid; Animals; Area Under Curve; Buprenorphine; Cross-Over Studies; Female; Half-Life; Injections, Subcutaneous; Macaca mulatta; Male; Pain

Objectives The objective of this study was to compare the pharmacokinetics of compounded and commercially available aqueous formulations of buprenorphine after a single buccal dose to healthy cats and to evaluate the concentrations of a compounded buprenorphine solution over 21 days when stored at room temperature (RT; 22-24°C) with exposure to light or when refrigerated at 4°C while protected from light. Methods Six young healthy male cats were administered single buccal doses of compounded and commercially available formulations of buprenorphine (0.03 mg/kg) using a randomized, blinded, two-period crossover design. Blood samples were obtained over a 24 h period and plasma buprenorphine concentrations were determined using ultra-high-pressure liquid chromatography with mass spectrometry detection. Three batches of the compounded formulation were stored at RT or 4°C and aliquots were evaluated over 21 days for buprenorphine concentration using high-performance liquid chromatography with fluorescence detection. Results Plasma concentrations of buprenorphine were above the limit of quantification up to 6 h in some cats and up to 3 h in all cats. The area under the curve was significantly less for the compounded formulation ( P = 0.004). A significant difference was not detected between formulations for time to maximum concentration ( P = 0.11), maximum concentration ( P = 0.06), half-life ( P = 0.88) and mean residence time ( P = 0.57). Buprenorphine concentration in the compounded formulation was not affected by storage condition or time and remained between 90% and 110% of the target concentration at all time points. Conclusions and relevance A buprenorphine solution prepared from sublingual tablets is absorbed after buccal administration in healthy cats. The extent of absorption is significantly less than that of the commercially available formulation. The compounded solution maintains an acceptable buprenorphine concentration for at least 21 days when stored at RT or refrigerated.

Topics: Administration, Buccal; Analgesics, Opioid; Animals; Area Under Curve; Buprenorphine; Cats; Cross-Over Studies; Half-Life; Male; Pain; Pain Measurement; Random Allocation

Objectives The objective of this study was to evaluate the analgesic effect and absorption of buprenorphine after buccal administration in cats with oral disease. Methods Six adult client-owned cats with chronic gingivostomatitis (weighing 5.1 ± 1.1 kg) were recruited for a randomised, prospective, blinded, saline-controlled, crossover study. Pain scores, dental examination, stomatitis score and buccal pH measurement were conducted on day 1 under sedation in all cats. On day 2, animals were randomised into two groups and administered one of the two treatments buccally (group A received buprenorphine 0.02 mg/kg and group B received 0.9% saline) and vice versa on day 3. Pain scores and food consumption were measured at 30, 90 and 360 mins after the administration of buprenorphine. Blood samples were taken at the same time and plasma buprenorphine concentration was measured by liquid chromatography-mass spectrometry. Data were statistically analysed as non-parametric and the level of significance was set as P <0.05. Results There were no major side effects after buprenorphine administration. Buccal pH values ranged between 8.5 and 9.1 and the stomatitis disease activity index between 10 and 22 (17.8 ± 4.5), with the scale ranging from 0-30. The maximum buprenorphine plasma concentration (14.8 ng/ml) was observed 30 mins after administration and there was low inter-individual variability. There was a significant difference between baseline pain scores compared with pain scores after buprenorphine ( P <0.05), and between the saline and buprenorphine group at 30 mins ( P = 0.04) and 90 mins ( P = 0.04). There was also a significant effect of the stomatitis index on the pain score. Regarding the pharmacokinetic parameters, cats with stomatitis showed lower bioavailability and shorter absorption half-life after buccal administration of buprenorphine compared with normal cats in previous studies. Conclusions and relevance Buccal administration of buprenorphine in cats with gingivostomatitis produces an analgesic effect and low inter-individual variability in plasma concentration, and it can be incorporated in their multimodal analgesia plan.

Topics: Administration, Buccal; Analgesics, Opioid; Animals; Buprenorphine; Cat Diseases; Cats; Female; Male; Mouth Diseases; Pain; Pain Measurement; Random Allocation

To investigate the effects of pain treatment on sleep in nursing home (NH) patients with dementia and depression.. A multicenter, 2-armed, double-blinded, placebo-controlled, randomized clinical trial conducted between August 2014 and September 2016. One hundred six long-term patients from 47 NHs in Norway with dementia and depression according to the Mini-Mental State Examination and the Cornell Scale for Depression in Dementia were included. Patients received stepwise pain treatment in which those who did not use analgesics were randomized to receive either paracetamol (3 g/day) or placebo tablets; those who already used pain treatment were allocated to buprenorphine transdermal system (max. 10 μg/h/7 days) or placebo transdermal patches. Sleep was assessed continuously for 14 days by actigraphy, 1 week of baseline measurement, and 1 week of ongoing treatment. The following sleep parameters were evaluated: total sleep time, sleep efficiency (SE), sleep onset latency (SOL), wake after sleep onset, early morning awakening (EMA), and number of wake bouts.. In the intervention group (paracetamol/buprenorphine), SE (70%-72%), SOL (32-24 min), and EMA (50-40 min) improved compared with the control group (SE, 70%-67%; SOL, 47-60 min; EMA, 31-35 min). Treatment effects were significant (P < .01, P < .05, and P < .05, respectively).. Compared with placebo, pain treatment improved sleep as measured with actigraphy. This implies that sleep, pain, and depression in NH patients should be critically evaluated and that pain treatment should be considered to be a potentially beneficial treatment.

Topics: Acetaminophen; Adult; Aged; Analgesics; Buprenorphine; Dementia; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Norway; Nursing Homes; Pain; Pain Management; Pain Measurement; Sleep Wake Disorders; Transdermal Patch

Buprenorphine is routinely used in chinchillas at reported doses of 0.01 to 0.1 mg/kg IM or SC. However, these dose recommendations are based on anecdotal reports or extrapolation from studies in other species. Therefore, the purpose of this study was to evaluate the analgesic efficacy and safety of subcutaneously administered buprenorphine in chinchillas. Using a randomized, blind, controlled, complete crossover design, we evaluated buprenorphine at a single dose of 0.05, 0.1 or 0.2 mg/kg SC (experiment A) and 0.2 mg/kg SC (experiment B). Analgesic efficacy was determined by measuring limb withdrawal latencies in response to a thermal noxious stimulus (Hargreaves method) at 0, 3, 6, 12, and 24 h (experiment A) and at 0, 1, 2, 4, and 8 h (experiment B). In a third experiment, food intake and fecal output were monitored after repeated administration of buprenorphine (0.2 mg/kg SC every 6 h for 3 doses). Buprenorphine at 0.2 mg/kg SC, but not at 0.05 or 0.1 mg/kg SC, significantly increased limb withdrawal latencies for less than 4 h. Self-limiting reduction in food intake and fecal output occurred after administration at the 0.2-mg/kg dose in animals undergoing algesiometry. In chinchillas not undergoing algesiometry, the administration of 3 doses at 0.2 mg/kg SC every 6 h did not reduce food intake but significantly decreased fecal output for the first 24 h. Additional studies are needed to evaluate buprenorphine in different algesiometry models and to establish its pharmacokinetic profile in chinchillas.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Chinchilla; Cross-Over Studies; Female; Laboratory Animal Science; Male; Pain; Random Allocation

Buprenorphine transdermal system is increasingly prescribed in people with advanced dementia, but no clinical trial has investigated the safety and factors associated with discontinuation due to adverse events in this population.. One hundred sixty-two people with advanced dementia and significant depression from 47 nursing homes were included and randomized to active analgesic treatment (acetaminophen/buprenorphine) or identical placebo for 13 weeks. In this secondary analysis, the main outcomes were time to and reasons for discontinuation of buprenorphine due to adverse events. Change in daytime activity as measured by actigraphy was a secondary outcome.. Active buprenorphine had significantly higher risk of discontinuation compared with placebo in people with advanced dementia and depression, mainly due to psychiatric and neurological adverse events. Daytime activity dropped significantly during the first week of treatment. Concomitant use of antidepressants further reduced the tolerability of buprenorphine.

Topics: Administration, Cutaneous; Aged; Analgesics, Opioid; Buprenorphine; Dementia; Drug Delivery Systems; Female; Humans; Male; Nursing Homes; Pain; Pain Measurement

OBJECTIVE To evaluate thermal antinociceptive effects and pharmacokinetics of buprenorphine hydrochloride after IM administration to cockatiels (Nymphicus hollandicus). ANIMALS 16 adult (≥ 2 years old) cockatiels (8 males and 8 females). PROCEDURES Buprenorphine hydrochloride (0.3 mg/mL) at each of 3 doses (0.6, 1.2, and 1.8 mg/kg) and saline (0.9% NaCl) solution (control treatment) were administered IM to birds in a randomized within-subject complete crossover study. Foot withdrawal response to a thermal stimulus was determined before (baseline) and 0.5, 1.5, 3, and 6 hours after treatment administration. Agitation-sedation scores were also determined. For the pharmacokinetic analysis, buprenorphine (0.6 mg/kg) was administered IM to 12 of the birds, and blood samples were collected at 9 time points ranging from 5 minutes to 9 hours after drug administration. Samples were analyzed with liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated with commercial software. RESULTS Buprenorphine at 0.6, 1.2, and 1.8 mg/kg did not significantly change the thermal foot withdrawal response, compared with the response for the control treatment. No significant change in agitation-sedation scores was detected between all doses of buprenorphine and the control treatment. Plasma buprenorphine concentrations were > 1 ng/mL in all 4 birds evaluated at 9 hours. CONCLUSIONS AND CLINICAL RELEVANCE Buprenorphine at the doses evaluated did not significantly change the thermal nociceptive threshold for cockatiels or cause sedative or agitative effects. Additional studies with other pain assessments and drug doses are needed to evaluate the analgesic and adverse effects of buprenorphine in cockatiels and other avian species.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Chromatography, Liquid; Cockatoos; Cross-Over Studies; Female; Male; Pain; Pain Measurement; Random Allocation; Tandem Mass Spectrometry

The aim of this study was to describe the joint pharmacokinetic-pharmacodynamic model and evaluate thermal antinociception of a high-concentration formulation of buprenorphine (Simbadol™) in cats.. Six healthy cats (4.9 ± 0.7 kg) were included in a prospective, randomized, blinded, crossover study. Simbadol™ (1.8 mg mL-1) was administered by the subcutaneous (SC; 0.24 mg kg-1), intravenous (IV; 0.12 mg kg-1) or buccal (OTM; 0.12 mg kg-1) route of administration and thermal thresholds (TT) were compared with a saline group (SAL). Thermal threshold testing and blood sampling were performed at predetermined time points up to 72 hours including a placebo group. Plasma buprenorphine and norbuprenorphine concentrations were measured using liquid chromatography mass spectrometry. A bespoke bicompartmental pharmacokinetic model simultaneously fitted data from two analytes/three routes of administration. Temporal changes in TT were analyzed using one-way ANOVA followed by Dunnett's test and treatment comparisons using two-way ANOVA with Bonferroni's correction (P < 0.05).. Thermal thresholds were significantly increased after SC, IV and OTM from 1-24 hours (except 2 hours), 0.5-8 hours (except 6 hours), and 1-8 hours (except 6 hours), respectively, when compared with baseline. Thermal thresholds were significantly increased after SC (1-30 hours), IV (1-8 hours) and OTM (1-12 hours) when compared with SAL, but not different among buprenorphine-treated cats. The absolute buprenorphine clearance was 0.98 L kg-1 hour-1, volume of distribution at steady state was 7.9 L kg-1 and the elimination-half-life was 12.3 hours. Bioavailability for SC and OTM was 94% and 24%, respectively. Subcutaneous absorption was biphasic. An initial peak (0.08 hours) was followed by a slow (half-life 11.2 hours) and progressive (peak acceleration at 2.8 hours) uptake.. The SC administration of Simbadol™ was characterized by prolonged absorption half-life and sustained plasma concentrations yielding long-lasting antinociception (≥ 24 hours) when compared with the IV and OTM routes.

Topics: Administration, Buccal; Analgesics, Opioid; Animals; Biological Availability; Buprenorphine; Cats; Cross-Over Studies; Disease Models, Animal; Female; Half-Life; Injections, Intravenous; Injections, Subcutaneous; Male; Models, Biological; Pain; Pain Threshold; Placebo Effect; Prospective Studies; Time Factors

To study the effect of transdermal buprenorphine on QTc prolongation at dose levels of 10, 40, and 80 mcg/h, (BTDS 10, BTDS 40, BTDS 80).. Two randomized, placebo- and positive-controlled, parallel-group, dose-escalating clinical studies evaluated healthy adult subjects randomized to BTDS, placebo, or moxifloxacin in the first study; and to BTDS only, BTDS plus naltrexone, naltrexone alone at the same dose, placebo, or moxifloxacin in the second study. QT intervals were corrected for heart rate using data from each individual subject (QTcI).. In the first study (n = 44), the maximum upper bounds of the 90% confidence interval (CI) for mean placebo-corrected change from baseline in QTcI across 13 time points over 24 h were: 10.0 msec for BTDS 10 (Day 6) and 13.3 msec for BTDS 40 (Day 13); and 17.0 msec (Day 6) and 15.5 msec (Day 13) for moxifloxacin, respectively.  Similarly, in the second study (n = 66), the upper bound of the 90% CI for mean placebo-corrected change from baseline for QTcI was under 10 msec at all time points for BTDS 10 (maximum upper bound, 5.63 msec), over 10 msec at 5 time points for BTDS 40 (maximum 11.81 msec) and over 10 msec at all 13 time points for BTDS 80 (maximum, 14.14 msec). Naltrexone administered with BTDS eliminated the QTcI prolongation seen with supratherapeutic BTDS doses (BTDS 40, BTDS 80) administered without naltrexone.. At the therapeutic dose of 10 mcg/h, BTDS has no clinically significant effect on QTc. At supratherapeutic doses of 40 and 80 mcg/h, BTDS treatment produces prolongation of QTcI similar in magnitude to that produced by a 400 mg dose of moxifloxacin. Despite the modest, dose-dependent increase in QTcI noted in these studies, transdermal buprenorphine has not been associated with proarrhythmic effects.

Topics: Administration, Cutaneous; Adult; Arrhythmias, Cardiac; Aza Compounds; Buprenorphine; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluoroquinolones; Healthy Volunteers; Heart Rate; Humans; Male; Middle Aged; Moxifloxacin; Naltrexone; Pain; United States; Young Adult

Buprenorphine, a partial μ-receptor agonist, is approved for the management of moderate to severe pain, but it has low oral bioavailability. Two open-label studies were performed to determine the pharmacokinetic profile of buprenorphine from buccal film formulations of buprenorphine.. Both studies enrolled healthy volunteers, aged 18 to 55 years, who received concurrent oral naltrexone to reduce adverse events (AEs); subjects with a history or evidence of substance abuse or current use of any product affecting cytochrome P450 3A4 activity were excluded. The first study (n = 25) was a 5-period crossover trial with 4 single doses (75 and 300 and 300 and 1200 μg) of 2 formulations (F14 and F24) of buccal buprenorphine (BBUP) and a 300-μg intravenous dose of buprenorphine with a 7-day washout between periods. In the second study, each subject (n = 10) received 6 doses of 4 BBUP strengths (60, 120, 180, and 240 μg BID) in a dose-escalation design. Plasma concentrations of buprenorphine and norbuprenorphine were assayed, and pharmacokinetics were summarized with descriptive statistics and analyzed by using a linear mixed effects model (single-dose study). AEs were recorded.. In the single-dose study, the 2 formulations exhibited comparable bioavailability of 46% to 51% that was independent of dose, with a single buprenorphine peak concentration from each BBUP dose occurring at 2.5 to 3 hours. The mean buprenorphine Cmax across the doses ranged from 0.17 ng/mL for the 75-µg dose to 1.43 ng/mL for the 1200-µg dose. AUC0-∞, AUC0-last, and Cmax were proportional to the dose of BBUP administered. Cmax of norbuprenorphine after BBUP administration was approximately one tenth that of buprenorphine Cmax. In the multiple-dose study, steady state was reached within 3 days of BID dosing. There was a linear increase in exposure across the dose range from 60 to 240 μg BID. Treatment-emergent AEs in both studies were consistent with those reported with opiate administration to healthy volunteers.. The absolute bioavailability of BBUP was 46% to 51% across a 16-fold dose range, with dose-proportional increases in systemic exposure. Apparent steady-state conditions occurred within 3 days of dosing. These pharmacokinetic results suggest that therapeutic buprenorphine plasma concentrations can be obtained with BBUP across a wide dose range in a shorter time than other (eg, transdermal) dosage forms.

Topics: Adult; Analgesics, Opioid; Biological Availability; Buprenorphine; Chemistry, Pharmaceutical; Cross-Over Studies; Female; Humans; Male; Middle Aged; Pain; Young Adult

This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine.. We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4 mg (0.6 mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400 mg twice daily on the first day and 200 mg twice daily thereafter or (iii) posaconazole 400 mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18 h and pharmacological effects were measured.. Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3 A and/or P-glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance.

Topics: Administration, Sublingual; Adult; Analgesics, Opioid; Antifungal Agents; Buprenorphine; Cross-Over Studies; Cytochrome P-450 Enzyme System; Drug Interactions; Healthy Volunteers; Humans; Male; Pain; Single-Blind Method; Triazoles; Voriconazole; Young Adult

Behavioral disturbances and pain are common in nursing home (NH) patients with dementia. An association between pain and increased agitation has been suggested, and recently a significant reduction of agitation has been demonstrated by pain treatment in patients with moderate to severe dementia. We now examined which specific agitated behaviors respond to individualized pain treatment.. Cluster randomized clinical trial.. 60 clusters (i.e., clusters defined as single independent NH units) in 18 NHs within five municipalities of Western Norway.. 352 patients with moderate to severe dementia and clinically significant behavioral disturbances.. The control group received usual treatment and care. According to a predefined scheme for 8 weeks, all patients in the intervention group received individual daily pain treatment with acetaminophen, extended release morphine, buprenorphine transdermal patch, and/or pregabaline.. Cohen-Mansfield Agitation Inventory subscales and items.. Analyses demonstrated that Factor 3 (Verbally agitated behaviors) showed the largest significant difference (DF = 1204.0, t = -4.308, p <0.001), followed by Factor 2 (Physically non-aggressive behaviors) (DF = 1198.0, t = -2.672, p = 0.008), and Factor 1 (Aggressive behaviors) (DF = 1196.0, t = -2.093, p = 0.037) after 8 weeks, by a linear random intercept mixed model in two-way repeated-measures configuration with adjustment for heteroscedasticity.. We found that verbal agitation behaviors such as complaining, negativism, repetitious sentences and questions, constant request for attention, and cursing or verbal aggression responded to pain treatment. In addition, restlessness and pacing were sensible to analgesics. Such behaviors should therefore lead to an assessment of pain, and pain treatment. Further studies comparing how pain treatment should be balanced against other strategies including psychotropic drugs are needed.

Topics: Acetaminophen; Aged, 80 and over; Analgesics; Buprenorphine; Delayed-Action Preparations; Dementia; Female; gamma-Aminobutyric Acid; Humans; Male; Morphine; Norway; Nursing Homes; Pain; Pain Management; Pregabalin; Psychomotor Agitation; Transdermal Patch

To compare sedation and antinociception after oral transmucosal (OTM) and intramuscular (IM) administration of a dexmedetomidine-buprenorphine combination in healthy adult cats.. Randomized, 'blinded' crossover study, with 1 month washout between treatments.. Six healthy neutered female cats, weighing 5.3-7.5 kg.. A combination of dexmedetomidine (40 μg kg(-1) ) and buprenorphine (20 μg kg(-1) ) was administered by either the OTM (buccal cavity) or IM (quadriceps muscle) route. Sedation was measured using a numerical rating scale, at baseline and at various time points until 6 hours after treatment. At the same time points, analgesia was scored using a dynamic and interactive visual analogue scale, based on the response to an ear pinch, and by the cat's response to a mechanical stimulus exerted by a pressure rate onset device. Physiological and adverse effects were recorded, and oral pH measured. Signed rank tests were performed, with significance set at p < 0.05. Data are presented as median and range.. There were no differences in sedation or antinociception scores between OTM and IM dosing at any of the time points. Nociceptive thresholds increased after both treatments but without significant difference between groups. Buccal pH remained between 8 and 8.5. Salivation was noted after OTM administration (n = 2) and vomiting after both OTM (n = 4), and IM (n = 3) dosing.. In healthy adult cats, OTM administration of dexmedetomidine and buprenorphine resulted in comparable levels of sedation and antinociception to IM dosing. The OTM administration may offer an alternative route to administer this sedative-analgesic combination in cats.

Topics: Administration, Mucosal; Analgesics; Animals; Buprenorphine; Cat Diseases; Cats; Dexmedetomidine; Drug Therapy, Combination; Female; Hypnotics and Sedatives; Injections, Intramuscular; Pain

Pain is frequent and distressing in people with dementia, but no randomized controlled trials have evaluated the effect of analgesic treatment on pain intensity as a key outcome.. Three hundred fifty-two people with dementia and significant agitation from 60 nursing home units were included in this study. These units, representing 18 nursing homes in western Norway, were randomized to a stepwise protocol of treating pain (SPTP) or usual care. The SPTP group received acetaminophen, morphine, buprenorphine transdermal patch and pregabalin for 8 weeks, with a 4-week washout period. Medications were governed by the SPTP and each participant's existing prescriptions. We obtained pain intensity scores from 327 patients (intervention n = 164, control n = 163) at five time points assessed by the primary outcome measure, Mobilization-Observation-Behaviour-Intensity-Dementia-2 (MOBID-2) Pain Scale. The secondary outcome was activities of daily living (ADL). We used a linear intercept mixed model in a two-way repeated measures configuration to assess change over time and between groups.. The SPTP conferred significant benefit in MOBID-2 scores compared with the control group [average treatment effect (ATE) -1.388; p < 0.001] at week 8, and MOBID-2 scores worsened during the washout period (ATE = -0.701; p = 0.022). Examining different analgesic treatments, benefit was conferred to patients receiving acetaminophen compared with the controls at week 2 (ATE = -0.663; p = 0.010), continuing to increase until week 8 (ATE = -1.297; p < 0.001). Although there were no overall improvements in ADL, an increase was seen in the group receiving acetaminophen (ATE = +1.0; p = 0.022).. Pain medication significantly improved pain in the intervention group, with indications that acetaminophen also improved ADL function.

Topics: Acetaminophen; Activities of Daily Living; Aged; Aged, 80 and over; Analgesics; Buprenorphine; Clinical Protocols; Dementia; Female; gamma-Aminobutyric Acid; Humans; Male; Morphine; Norway; Nursing Homes; Pain; Pain Management; Pain Measurement; Pregabalin; Transdermal Patch; Treatment Outcome

This study reports the pharmacokinetics of buprenorphine, following i.v. and buccal administration, and the relationship between buprenorphine concentration and its effect on thermal threshold. Buprenorphine (20 μg/kg) was administered intravenously or buccally to six cats. Thermal threshold was determined, and arterial blood sampled prior to, and at various times up to 24 h following drug administration. Plasma buprenorphine concentration was determined using liquid chromatography/mass spectrometry. Compartment models were fitted to the time-concentration data. Pharmacokinetic/pharmacodynamic models were fitted to the concentration-thermal threshold data. Thermal threshold was significantly higher than baseline 44 min after buccal administration, and 7, 24, and 104 min after i.v. administration. A two- and three-compartment model best fitted the data following buccal and i.v. administration, respectively. Following i.v. administration, mean ± SD volume of distribution at steady-state (L/kg), clearance (mL·min/kg), and terminal half-life (h) were 11.6 ± 8.5, 23.8 ± 3.5, and 9.8 ± 3.5. Following buccal administration, absorption half-life was 23.7 ± 9.1 min, and terminal half-life was 8.9 ± 4.9 h. An effect-compartment model with a simple effect maximum model best predicted the time-course of the effect of buprenorphine on thermal threshold. Median (range) ke0 and EC50 were 0.003 (0.002-0.018)/min and 0.599 (0.073-1.628) ng/mL (i.v.), and 0.017 (0.002-0.023)/min and 0.429 (0.144-0.556) ng/mL (buccal).

Topics: Administration, Buccal; Analgesics, Opioid; Animals; Buprenorphine; Cats; Cross-Over Studies; Hot Temperature; Injections, Intravenous; Male; Pain

The purpose of the study was to investigate placebo and buprenorphine effects on event-related potentials (ERPs) in experimental pain and the potential benefit of population pharmacodynamic modelling in data analysis. Nineteen healthy volunteers received transdermal placebo and buprenorphine in a cross-over study. Drug plasma concentrations and ERPs after electrical stimulation at the median nerve with intensity adjusted to pain detection threshold were recorded until 144 hrs after administration. Placebo and concentration-effect models were fitted to data using non-linear mixed-effects modelling implemented in NONMEM (V7.2.0.). Pharmacodynamic models were developed to adequately describe both placebo and buprenorphine ERP data. Models predicted significant placebo effects, but did not predict significant effects related to buprenorphine concentration. Models revealed that ERPs varied both between subjects and between study occasions. ERPs were found to be reproducible within subjects and occasions as population variance was found to be eight times higher than the unexplained variances. Between-subject variance accounted for more than 75% of the population variance. In conclusion, pharmacodynamic modelling was successfully implemented to allow for placebo and variability correction in ERP of experimental pain. Improved outcome of ERP studies can be expected if variation between subjects and study occasions can be identified and described.

Topics: Administration, Cutaneous; Buprenorphine; Cross-Over Studies; Evoked Potentials; Healthy Volunteers; Humans; Male; Models, Theoretical; Pain; Pain Threshold

To compare results from analysis of averaged and single-sweep evoked brain potentials (EPs) by visual inspection and spectral analysis in order to identify an objective measure for the analgesic effect of buprenorphine and fentanyl.. Twenty-two healthy males were included in a randomized study to assess the changes in EPs after 110 sweeps of painful electrical stimulation to the median nerve following treatment with buprenorphine, fentanyl or placebo patches. Bone pressure, cutaneous heat and electrical pain ratings were assessed. EPs and pain assessments were obtained before drug administration, 24, 48, 72 and 144 h after beginning of treatment. Features from EPs were extracted by three different approaches: (i) visual inspection of amplitude and latency of the main peaks in the average EPs, (ii) spectral distribution of the average EPs and (iii) spectral distribution of the EPs from single-sweeps.. Visual inspection revealed no difference between active treatments and placebo (all P > 0.05). Spectral distribution of the averaged potentials showed a decrease in the beta (12-32 Hz) band for fentanyl (P = 0.036), which however did not correlate with pain ratings. Spectral distribution in the single-sweep EPs revealed significant increases in the theta, alpha and beta bands for buprenorphine (all P < 0.05) as well as theta band increase for fentanyl (P = 0.05). For buprenorphine, beta band activity correlated with bone pressure and cutaneous heat pain (both P = 0.04, r = 0.90).. In conclusion single-sweep spectral band analysis increases the information on the response of the brain to opioids and may be used to identify the response to analgesics.

Topics: Adult; Analgesics, Opioid; Brain; Buprenorphine; Cross-Over Studies; Data Interpretation, Statistical; Double-Blind Method; Electric Stimulation; Electroencephalography; Evoked Potentials; Fentanyl; Healthy Volunteers; Humans; Male; Pain; Pain Measurement; Transdermal Patch; Young Adult

Laboratory mice constitute an extensively used model to study the pathologic and functional outcomes of cerebral ischemic stroke. The middle cerebral artery occlusion (MCAO) model requires surgical intervention, which potentially can result in postsurgical pain and stress. In the present study, we investigated whether buprenorphine and meloxicam, at clinically relevant doses provided pain relief without altering infarct volume in male C57BL/6 mice. Common known side-effects of buprenorphine, including decreased food consumption, were noted after surgery in buprenorphine-treated mice, but these effects were brief and seen only during the treatment period. Fecal corticosterone metabolites did not differ significantly between the groups. In the present study, buprenorphine treatment did not alter infarction volume when compared with that of mice that did not receive analgesia. In contrast, meloxicam treatment significantly reduced infarct volume and may be a confounder if used as an analgesic during MCAO surgery. Furthermore, investigation of behavioral profiles by using an automated behavioral scoring system showed that rearing and sniffing behaviors decreased as infarct volume increased. This suggests that studies of exploratory behavior may aid in developing new markers of short-term stroke-related behavioral deficiencies in laboratory mice.

Topics: Analgesics; Animals; Brain Ischemia; Buprenorphine; Corticosterone; Infarction, Middle Cerebral Artery; Male; Meloxicam; Mice; Mice, Inbred C57BL; Pain; Pain Management; Research Design; Thiazines; Thiazoles

The current study investigated the efficacy, safety, tolerability, and compliance of a transdermal buprenorphine delivery system for the management of chronic cancer pain in the pediatric population.. Sixteen pediatric patients with moderate to severe cancer-related pain not satisfactorily controlled with previous non-opioid therapies were enrolled. Transdermal buprenorphine was administered following a 72 hour schedule and rescue medication (tramadol) was allowed for breakthrough pain. Pain intensity was assessed using the Wong-Baker faces pain rating scale (WBS) and other parameters related to the global quality of life were evaluated. Children's evaluations of efficacy, compliance, and tolerability were recorded using numerical scales. Adverse events were monitored during the study and the medications needed to control opioid-related nausea and constipation were recorded.. Eleven patients (68.75%) responded to transdermal buprenorphine after 2 weeks of treatment. Pain intensity measured with WBS decreased from 6.25 at baseline to 1.38 at Day +60 (P < 0.001). All outcome measures of global quality of life (quality of sleep, alimentation, play and activity, speech, and crying) significantly improved over the 60-day study period. Children's evaluations of compliance and tolerability of the drug were always positive over the entire period of treatment. No severe adverse events were recorded. Opioid-related nausea was well controlled with medication on request, and the need for laxative therapy was greater at the end of the second month of treatment.. Transdermal buprenorphine was found to represent an efficient, safe and well tolerated approach to the management of children's chronic cancer pain.

Topics: Administration, Cutaneous; Adolescent; Analgesics, Opioid; Buprenorphine; Child; Child, Preschool; Female; Humans; Male; Neoplasms; Pain

To investigate the antinociceptive effects of buprenorphine administered in combination with acepromazine in horses and to establish an effective dose for use in a clinical environment.. To evaluate the responses to thermal and mechanical stimulation following administration of 3 doses of buprenorphine compared to positive (butorphanol) and negative (glucose) controls.. Observer blinded, randomised, crossover design using 6 Thoroughbred geldings (3-10 years, 500-560 kg). Thermal and mechanical nociceptive thresholds were measured 3 times at 15 min intervals. Horses then received acepromazine 0.05 mg/kg bwt with one of 5 treatments i.v.: 5% glucose (Glu), butorphanol 100 µg/kg bwt (But) buprenorphine 5 µg/kg bwt (Bup5), buprenorphine 7.5 µg/kg bwt (Bup7.5) and buprenorphine 10 µg/kg bwt (Bup10). Thresholds were measured 15, 30, 45, 60, 90, 120, 150, 180, 230 min, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 24 h post treatment administration. The 95% confidence intervals for threshold temperature (ΔT) for each horse were calculated and an antinociceptive effect defined as ΔT, which was higher than the upper limit of the confidence interval. Duration of thermal antinociception was analysed using a within-subjects ANOVA and peak mechanical thresholds with a general linear model with post hoc Tukey tests. Significance was set at P<0.05.. Mean (± s.d.) durations of thermal antinociception following treatment administration were: Glu 0.5 (1.1), But 2.9 (2.0), Bup5 7.4 (2.3), Bup7.5 7.8 (2.7) and Bup10 9.4 (1.1) h. B5, B7.5 and B10 were significantly different from Glu and But. No serious adverse effects occurred, although determination of mechanical thresholds was confounded by locomotor stimulation.. Administration of acepromazine and all doses of buprenorphine produced antinociception to a thermal stimulus for significantly longer than acepromazine and either butorphanol or glucose.. This study suggests that buprenorphine has considerable potential as an analgesic in horses and should be examined further under clinical conditions and by investigation of the pharmacokinetic/pharmacodynamic profile.

Topics: Acepromazine; Animals; Buprenorphine; Butorphanol; Cross-Over Studies; Dose-Response Relationship, Drug; Horse Diseases; Horses; Hot Temperature; Male; Pain; Pain Measurement; Time Factors

Naloxone can enhance the antinociceptive/analgesic effects of buprenorphine in humans and rats. The antinociceptive effects of a patented 15:1 buprenorphine:naloxone combination was investigated in cats using a thermal and mechanical nociceptive model. Twelve cats received buprenorphine 10 μg/kg, naloxone 0.67 μg/kg or a buprenorphine-naloxone combination intramuscularly in a randomised cross over study. Using thermal and mechanical analgesiometry validated in the cat, pre-treatment baselines were measured. Following test drug administration, thresholds were studied for the next 24h. Naloxone did not enhance the thermal antinociceptive effect of buprenorphine. The results from this study are in agreement with previously published work showing that naloxone antagonises the effects of clinically analgesic doses of buprenorphine. Mechanical nociceptive thresholds were not affected by buprenorphine.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Cats; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hot Temperature; Male; Naloxone; Narcotic Antagonists; Pain

The descending pain inhibitory system is impaired in chronic pain and it is important to know how analgesics interact with this system. The aim of this human experimental pain, double-blind, randomized, placebo-controlled, 3 way cross-over study was to investigate the effect of 2 different opioids on descending pain inhibition using conditioning pain modulation (CPM) as a screening tool.. Twenty-two healthy male volunteers were randomized to 72 hours of treatment with transdermal patches of fentanyl (25 μg/h), buprenorphine (20 μg/h), or placebo. The CPM was induced by immersing the hand into cold (3.0 ± 0.3°C) water and the evoked pain was continuously rated on a visual analogue scale (VAS). The test stimulus [pressure pain tolerance threshold (PPTol)] was applied to the contra-lateral arm. The CPM test was performed at baseline, 24, 48, and 72 hours after application of the patches.. The opioid treatments did not significantly (F=2.249; P=0.07) modulate the PPTol over the treatment period compared with placebo. The CPM-evoked PPTol increases (percentage increase from what was obtained at the baseline before patch application) were significantly enhanced by buprenorphine (P=0.004) and fentanyl (P=0.005) compared with placebo, with no differences between the 2 active drugs. Fentanyl significantly attenuated the time to cold water-evoked VAS peak compared with placebo (P=0.005), and the same trend was observed for buprenorphine (P=0.06). The VAS pain intensity was not affected.. The opioids buprenorphine and fentanyl significantly potentiate the effect of descending pain inhibition in healthy volunteers.

Topics: Administration, Cutaneous; Adult; Analgesics, Opioid; Buprenorphine; Cross-Over Studies; Double-Blind Method; Fentanyl; Humans; Hyperalgesia; Male; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Young Adult

To evaluate the analgesic efficacy of ABT-116, a transient receptor potential cation channel vanilloid subfamily V member 1 antagonist, and compare it with that of buprenorphine by measurement of mechanical and thermal nociceptive thresholds in dogs.. Six 7- to 8-month-old dogs (3 males and 3 females).. In a crossover study design, all dogs received ABT-116 (30 mg/kg, PO) and buprenorphine (0.03 mg/kg, orotransmucosally), with each treatment separated by 1 week. Physiologic variables were recorded prior to and 1, 6, and 24 hours after drug administration. Thermal (thoracic) and mechanical (dorsolateral aspect of the radius [proximal] and dorsopalmar aspect of the forefoot [distal]) nociceptive thresholds were assessed prior to (baseline) and 15 minutes and 1, 2, 4, 6, 12, 18, and 24 hours after treatment.. Buprenorphine administration resulted in higher overall thermal and proximal mechanical nociceptive thresholds, compared with ABT-116. Distal mechanical nociceptive thresholds after treatment were higher than baseline values for both treatments, but the magnitude of change was greater for buprenorphine at 1 hour after administration. Whereas HR and RR sporadically differed from baseline values after ABT-116 administration, rectal temperature increased from a baseline value of 39 ± 0.2°C (mean ± SD) to a peak of 40.6 ± 0.2°C at 6 hours.. In dogs without inflammation or nerve injury, PO administration of ABT-116 did not consistently result in an increase in nociceptive thresholds. However, clinically relevant increases in rectal temperature were identified after ABT-116 administration.

Topics: Administration, Mucosal; Analgesics, Opioid; Animals; Buprenorphine; Cross-Over Studies; Dogs; Female; Indazoles; Male; Pain; Pain Measurement; Phenylurea Compounds; TRPV Cation Channels

Physical pain is common among individuals seeking treatment for opioid dependence. Pain may negatively impact addiction treatment. The authors prospectively studied opioid-dependent individuals initiating office-based buprenorphine treatment, comparing buprenorphine treatment outcomes (treatment retention and opioid use) among participants with and without pain (baseline pain or persistent pain). Among 82 participants, 60% reported baseline pain and 38% reported persistent pain. Overall, treatment retention was 56% and opioid use decreased from 89% to 26% over 6 months. In multivariable analyses, the authors found no association between pain and buprenorphine treatment outcomes. Opioid-dependent individuals with and without pain can achieve similar success with buprenorphine treatment.

Topics: Buprenorphine; Female; Humans; Longitudinal Studies; Male; Medication Adherence; Middle Aged; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Primary Health Care; Treatment Outcome

Despite the frequent clinical use of buprenorphine in reptiles, its antinociceptive efficacy is not known. In a randomized, complete cross-over study, the antinociceptive efficacy of buprenorphine (0.2 mg/kg s.c.) was compared with hydromorphone (0.5 mg/kg s.c.), and saline (0.9% s.c. equivalent volume) in 11 healthy red-eared slider turtles (Trachemys scripta elegans). Additionally, buprenorphine at 0.1 and 1 mg/kg was compared with saline in six turtles. Hindlimb withdrawal latencies were measured after exposure to a focal, thermal noxious stimulus before and between 3 hr and up to 96 hr after drug administration. Buprenorphine did not significantly increase hindlimb withdrawal latencies at any time point compared with saline. In contrast, hydromorphone administration at 0.5 mg/kg significantly increased hindlimb withdrawal latencies for up to 24 hr. These results show that hydromorphone, but not buprenorphine, provides thermal antinociception in red-eared slider turtles.

Topics: Animals; Buprenorphine; Cross-Over Studies; Dose-Response Relationship, Drug; Hot Temperature; Hydromorphone; Pain; Time Factors; Turtles

P-glycoprotein (P-gp) is expressed on the blood-brain barrier (BBB) and acts as a transporter regulating the analgesic effect of morphine. The P-gp is also expressed by different types of tumors. The aim of this study was to determine the potential association of the P-gp expression in malignant tumors with analgesic effects in patients.. The P-gp expression in 120 malignant tumors was examined by immunohistochemistry. The analgesic responses of individual patients to morphine and buprenorphine (BNP) were evaluated by visual analog scale (VAS). The levels of plasma morphine and BNP were determined by HPLC.. We found that there was no significant difference in the values of VAS between patients with P-gp(+) and P-gp(-) malignant tumors in responses to 0.000025 g x kg(-2) of BNP administered by patient-controlled intravenous analgesia (PCIA), accompanied by similar levels of plasma BNP in those patients. In contrast, the values of VAS in response to 0.00075 g x kg(-2) of morphine in patients with P-gp(+) tumors were significantly greater than those in the patients with P-gp(-) tumors, although similar levels of plasma morphine were detected in both groups of patients. Furthermore, treatment with a higher dose (0.0011 g x kg(-2)) of morphine effectively controlled pain in those with P-gp(+) tumors.. Our data indicated that patients with P-gp(+) tumors required a higher dose of morphine to achieve an analgesic effect and that the P-gp expression in tumors may be valuable for predicting the analgesic responses of patients with severe pain to morphine.

Topics: Aged; Analgesia, Patient-Controlled; Analgesics; ATP Binding Cassette Transporter, Subfamily B, Member 1; Buprenorphine; Chromatography, High Pressure Liquid; Female; Humans; Immunohistochemistry; Male; Middle Aged; Morphine; Neoplasms; Pain; Pain Measurement

Tail biopsy in mice is a common procedure in genetically modified mouse colonies. We evaluated the anesthetic and analgesic effects of various agents commonly used to mitigate pain after tail biopsy. We used a hot-water immersion assay to evaluate the analgesic effects of isoflurane, ice-cold ethanol, ethyl chloride, buprenorphine, and 2-point local nerve blocks before studying their effects on mice receiving tail biopsies. Mice treated with ethyl chloride spray, isoflurane and buprenorphine, and 2-point local nerve blocks demonstrated increased tail-flick latency compared with that of untreated mice. When we evaluated the behavior of adult and preweanling mice after tail biopsy, untreated mice demonstrated behavioral changes immediately after tail biopsy that lasted 30 to 60 min before returning to normal. The use of isoflurane, isoflurane and buprenorphine, buprenorphine, 2-point nerve block, or ethyl chloride spray in adult mice did not significantly improve their behavioral response to tail biopsy. Similarly, the use of buprenorphine and ethyl chloride spray in preweanling mice did not improve their behavioral response to tail biopsy compared with that of the untreated group. However, immersion in bupivacaine for 30 s after tail biopsy decreased tail grooming behavior during the first 30 min after tail biopsy. The anesthetic and analgesic regimens tested provide little benefit in adult and preweanling mice. Given that tail biopsy results in pain that lasts 30 to 60 min, investigators should carefully consider the appropriate anesthetic or analgesic regimen to incorporate into tail-biopsy procedures for mice.

Topics: Analgesics; Anesthetics; Animals; Animals, Outbred Strains; Behavior, Animal; Biopsy; Bupivacaine; Buprenorphine; Ethyl Chloride; Female; Grooming; Isoflurane; Male; Mice; Nerve Block; Pain; Tail

Previous reports have demonstrated greater antinociception following administration of a buprenorphine/naloxone combination compared to buprenorphine alone among healthy volunteers. The aim of the current investigation was to determine whether buprenorphine antinociception could be enhanced with the addition of ultra-low dose naltrexone, using a range of dose ratios. A repeated-measures, double-blind, cross-over trial was undertaken with 10 healthy participants. The effects of each buprenorphine:naltrexone ratio (100:1, 133:1, 166:1, and 200:1) on cold pressor tolerance time and respiration were compared to the effects of buprenorphine only. The 166:1 ratio was associated with significantly greater tolerance time to cold pressor pain than buprenorphine alone. Minimal respiratory depression and few adverse events were observed in all conditions. These findings suggest that, as previously described with naloxone, the addition of ultra-low dose naltrexone can enhance the antinociceptive effect of buprenorphine in humans. This potentiation is dose-ratio dependent and occurs without a concomitant increase in adverse effects.

Topics: Adolescent; Adult; Analgesia; Analgesics, Opioid; Buprenorphine; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Treatment Outcome

Pharmacokinetic/pharmacodynamic (PK/PD) modelling can be used to characterize the relationship between dose regimen of opioids, plasma concentration and effect of opioids, which in turn can lead to more rational treatment regimens of pain. The aim of this study was to investigate the concentration-effect relationship for transdermal buprenorphine and fentanyl in experimentally induced pain. Twenty-two healthy volunteers were randomized to receive transdermal patches with fentanyl (25 μg/hr, 72 hr), buprenorphine (20 μg/hr, 144 hr) or placebo. The experimental pain tests were pressure at the tibial bone, cutaneous thermal stimulation, cold pressor test (conditioning stimulus (3 ± 0.3°C cold water), nerve growth factor-induced muscle soreness and intradermal capsaicin-induced hyperalgesia and allodynia. Experiments were carried out at baseline, 24, 48, 72 and 144 hr after application of patches. Time-course of placebo was described first and was afterwards added to the description of the time-courses of buprenorphine and fentanyl. This was either described by zero (no drug effect), linear or E(max) model concentration-effect relationships. Time-dependent changes in pain measures in the placebo arm were described by linear or quadratic functions. The time-course of fentanyl and buprenorphine plasma concentrations was complex but could be represented by cubic spline interpolation in the models. Buprenorphine significantly attenuated bone-associated pain, heat pain, nerve growth factor-induced soreness and cold pressor pain. Fentanyl significantly attenuated cold pressor pain for the administered dose regimens. Although the PK/PD relationship for both drugs could be described with similar models, tissue-differentiated analgesic effects between buprenorphine and fentanyl was shown.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Capsaicin; Cold Temperature; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Fentanyl; Hot Temperature; Humans; Hyperalgesia; Male; Models, Biological; Pain; Pain Measurement; Time Factors; Transdermal Patch; Young Adult

Chronic pain increases with age, and in the elderly, comorbidities and polypharmacotherapy make the choice of treatment for pharmacological pain control a complex matter.. We conducted a multicenter, prospective, observational study to evaluate the efficacy and safety of the buprenorphine transdermal delivery system (TDS) in elderly patients with chronic noncancer pain. The aim was to assess the cognitive and behavioral status of patients during treatment.. The study included 93 patients (69 women and 24 men); the mean age was 79.7 years, and in most cases, the pain was due to osteoarthritis. Almost three-quarters (74.2%) of the patients had suffered pain for more than 12 months. The treatment was buprenorphine TDS, starting from a dose of 17.5 μg/h. Outcomes were assessed using the Mini-Mental State Examination (MMSE), the 17-item Hamilton Depression scale (HAM-D 17), the Neuropsychiatric Inventory, the Barthel Index, the Short-Form Health Survey (SF-12), a verbal numeric rating scale, and the Cumulative Illness Rating Scale (CIRS).. Buprenorphine treatment was associated with a decrease in pain severity without negative effects on the central nervous system. On the HAM-D scale, there were reductions in both the psychological and somatic scores. On the MMSE, values at the beginning and end of the study were comparable. Evaluation by SF-12 showed improvements in physical and mental status. CIRS values at baseline and at the end of the study were superimposable, indirectly confirming the tolerability and safety profile of the drug.. Our experience confirms the analgesic activity and safety of buprenorphine TDS in the elderly. There was an improvement in mood and a partial resumption of activities, with no influence on cognitive and behavioral ability.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Analgesics, Opioid; Behavior; Buprenorphine; Chronic Disease; Cognition; Female; Health Surveys; Humans; Male; Neuropsychological Tests; Osteoarthritis; Pain; Prospective Studies

Chronic pain and hyperalgesia can be difficult to treat with classical opioids acting predominately at the µ-opioid receptor. Buprenorphine and its active metabolite are believed to act through µ-, κ- and δ-receptors and may therefore possess different analgesic and anti-hyperalgesic effects compared with pure µ-receptor agonists, for example, fentanyl. Here, we have compared the analgesic and anti-hyperalgesic effects of buprenorphine and fentanyl.. Twenty-two healthy volunteers were randomized to treatment with transdermal buprenorphine (20 µg·h(-1), 144 h), fentanyl (25 µg·h(-1), 72 h) or placebo patches in a double-blind, cross-over experimental pain study. The experimental pain tests (phasic pain, sensitization) involved pressure at the tibial bone, cutaneous electrical and thermal stimulation, intramuscular nerve growth factor, UVB light burn injury model and intradermal capsaicin-induced hyperalgesia. Pain testing was carried out at baseline, 24, 48, 72 and 144 h after application of the drugs.. Compared with placebo, buprenorphine, but not fentanyl, significantly attenuated pressure at the tibial bone as well as pressure pain in the primary hyperalgesic area induced by UVB light The two drugs were equipotent and better than placebo against cutaneous thermal pain stimulation), but failed to show significant analgesic effect to cutaneous electrical stimulation, nerve growth factor-induced muscle soreness and to capsaicin-induced hyperalgesia.. Buprenorphine, but not fentanyl, showed analgesic effects against experimentally induced, bone-associated pain and primary hyperalgesia compared with placebo. These tissue- and modality-differentiated properties may reflect the variable effects of opioid drugs observed in individual patients.

Topics: Administration, Cutaneous; Analgesics; Analgesics, Opioid; Buprenorphine; Capsaicin; Cross-Over Studies; Double-Blind Method; Electric Stimulation; Fentanyl; Humans; Hyperalgesia; Male; Nerve Growth Factor; Pain; Pain Measurement; Skin; Young Adult

The objective of this study was to evaluate the benefit of a seven-day buprenorphine transdermal patch for patients with chronic musculoskeletal pain previously receiving long-term treatment with ibuprofen or diclofenac alone. Data of a subgroup of 703 patients were analysed which were part of a multicenter observational study with 3,295 patients. These patients had previously received ibuprofen or diclofenac and were characterized by older age,the presence of gastrointestinal, cardiovascular, and renal risk factors and the existence of chronic musculoskeletal pain. The switch to the seven-day buprenorphine patch resulted in a clinically significant decrease of the mean pain intensity at rest during the day from 5.3 to 2.9, on physical effort during the day from 7.1 to 3.3, and at night from 4.9 to 1.9 at the end of the study (11-point NRS scale, p

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Chronic Disease; Diclofenac; Drug Administration Schedule; Drug Substitution; Female; Humans; Ibuprofen; Long-Term Care; Male; Middle Aged; Pain; Pain Measurement; Prospective Studies

This study evaluated the analgesia effects of the epidural administration of 0.1 mg/kg bodyweight (BW) of morphine or 5 μg/kg BW of buprenorphine in ponies with radiocarpal joint synovitis. Six ponies were submitted to 3 epidural treatments: the control group (C) received 0.15 mL/kg BW of a 0.9% sodium chloride (NaCl) solution; group M was administered 0.1 mg/kg BW of morphine; and group B was administered 5 μg/kg BW of buprenorphine, both diluted in 0.9% NaCl to a total volume of 0.15 mL/kg BW administered epidurally at 10 s/mL. The synovitis model was induced by injecting 0.5 ng of lipopolysaccharide (LPS) in the left or right radiocarpal joint. An epidural catheter was later introduced in the lumbosacral space and advanced up to the thoracolumbar level. The treatment started 6 h after synovitis induction. Lameness, maximum angle of carpal flexion, heart rate, systolic arterial pressure, respiratory rate, temperature, and intestinal motility were evaluated before LPS injection (baseline), 6 h after LPS injection (time 0), and 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 h after treatments. Although the model of synovitis produced clear clinical signs of inflammation, the lameness scores in group C were different from the baseline for only up to 12 h. Both morphine and buprenorphine showed a reduction in the degree of lameness starting at 0.5 and 6 h, respectively. Reduced intestinal motility was observed at 0.5 h in group M and at 0.5 to 1 h in group B. Epidural morphine was a more effective analgesic that lasted for more than 12 h and without side effects. It was concluded that morphine would be a valuable analgesic option to alleviate joint pain in the thoracic limbs in ponies.

Topics: Analgesia, Epidural; Analgesics, Opioid; Animals; Buprenorphine; Carpal Joints; Female; Horse Diseases; Horses; Lameness, Animal; Lipopolysaccharides; Male; Morphine; Pain; Pain Measurement; Synovitis

This was a multicenter, non-interventional, post-marketing study that aimed to evaluate the analgesic activity, safety of use, safety profile and adverse drug reactions of transdermal buprenorphine (Transtec 35, 52.5 and 70 μg/h) during the treatment of moderate to severe chronic cancer and non-cancer pain. The study was performed in Poland by 339 doctors. The study involved 4,030 general practice outpatients (managed by primary care physicians), pain therapy center patients, specialist outpatient clinic patients as well as patients treated in inpatients units. The recruitment process began in September of 2007, and the study was completed in October of 2008. The study has been reported to the Central Register of Clinical Trials in Poland; it was also in accordance with the requirements of the Polish Pharmaceutical Law in force. The objective of the study was to evaluate the efficacy, safety of use and application of transdermal buprenorphine in patients with moderate to severe cancer pain and in patients with severe, non-malignant pain in the course of other diseases. Patients were enrolled if their pain was not well-controlled after using non-opioid analgesics. Another objective of the study was to monitor adverse drug reactions of transdermal buprenorphine reported by patients or noted by the doctors during the study visits. This first such multicenter study in Poland has confirmed high efficacy and good tolerability of buprenorphine and, therefore, confirmed its usefulness in the treatment of moderate to severe cancer pain as well as in the treatment of severe pain in patients with non-cancer pain that cannot be effectively treated with non-opioid analgesics.

Topics: Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Pain; Poland; Prospective Studies; Severity of Illness Index; Transdermal Patch

This pilot study tested the effectiveness of transcutaneous electric acupoint stimulation (TEAS) as an adjunctive treatment for inpatients receiving opioid detoxification with buprenorphine-naloxone at a private psychiatric hospital. Participants (N = 48) were randomly assigned to active or sham TEAS and received three 30-minute treatments daily for 3 to 4 days. In active TEAS, current was set to maximal tolerable intensity (8-15 mA); in sham TEAS, it was set to 1 mA. By 2 weeks postdischarge, participants in active TEAS were less likely to have used any drugs (35% vs. 77%, p < .05). They also reported greater improvements in pain interference (F = 4.52, p < .05) and physical health (F = 4.84, p < .01) over time. TEAS is an acceptable, inexpensive adjunctive treatment that is feasible to implement on an inpatient unit and may be a beneficial adjunct to pharmacological treatments for opioid detoxification.

Topics: Acupuncture Points; Adolescent; Adult; Analgesics, Opioid; Analysis of Variance; Buprenorphine; Chi-Square Distribution; Combined Modality Therapy; Drug Administration Schedule; Female; Health Status; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Patient Selection; Substance Withdrawal Syndrome; Survival Analysis; Time Factors; Transcutaneous Electric Nerve Stimulation

The present investigation examines baseline patient characteristics to predict dosing of buprenorphine-naloxone, a promising treatment for opioid addiction in youths.. This study of 69 opioid-dependent youths is a secondary analysis of data collected during a National Institute on Drug Abuse (NIDA) Clinical Trials Network study. Outpatients aged 15-21 were randomized to a 12-week buprenorphine-naloxone dosing condition (including 4 weeks of taper). Predictors of dosing included sociodemographic characteristics (gender, race, age, and education), substance use (alcohol, cannabis, cocaine, and nicotine use), and clinical characteristics (pain and withdrawal severity).. Most (75.4%) reported having either "some" (n=40, 58.0%) or "extreme" (n=12, 17.4%) pain on enrollment. Maximum daily dose of buprenorphine-naloxone (19.7 mg) received by patients reporting "extreme" pain at baseline was significantly higher than the dose received by patients reporting "some" pain (15.0mg) and those without pain (12.8 mg). In the adjusted analysis, only severity of pain and withdrawal significantly predicted dose. During the dosing period, there were no significant differences in opioid use, as measured by urinalysis, by level of pain.. These data suggest that the presence of pain predicts buprenorphine-naloxone dose levels in opioid-dependent youth, and that patients with pain have comparable opioid use outcomes to those without pain, but require higher buprenorphine-naloxone doses.

Topics: Adolescent; Age Factors; Buprenorphine; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Male; Naloxone; Narcotic Antagonists; Narcotics; National Institute on Drug Abuse (U.S.); Opioid-Related Disorders; Outpatients; Pain; Pain Measurement; Socioeconomic Factors; Substance Withdrawal Syndrome; Time Factors; Treatment Outcome; United States; Young Adult

For individuals dependent on opioids, recovery efforts begin with a period of withdrawal that typically includes discomfort from symptoms, possibly precipitating a return to drug use. The study described here investigated whether the provision of ancillary medications for opioid withdrawal symptoms affected treatment outcomes in 139 participants receiving buprenorphine in a 13-day detoxification trial. Outcome measures include the number of opioid-free urine samples collected and retention in treatment. Ancillary medications were provided to 70% of participants: 59% received medication for insomnia, 45% for anxiety, 40% for bone pain, 35% for nausea, and 28% for diarrhea. Findings indicate no difference in the number of opioid-free urine samples between the group receiving ancillary medication and the group who did not, although tests of specific ancillary medications indicate that those who received diarrhea medication had fewer opioid-free urines than those who did not (P = .004). Results also indicate that participants attended fewer days of treatment if they received anxiety, nausea, or diarrhea medication compared to no medication (all P values < .05).

Topics: Adult; Analgesics, Opioid; Anxiety; Buprenorphine; Diarrhea; Female; Humans; Inactivation, Metabolic; Male; Middle Aged; Narcotics; Nausea; Opioid-Related Disorders; Pain; Receptors, Opioid, delta; Sleep Initiation and Maintenance Disorders; Substance Withdrawal Syndrome; Treatment Outcome

Osteoarthritis (OA) is a common cause of chronic pain, particularly in the older population. Modern approaches to the management of OA pain recommend tailoring treatment to the individual. This study examines treatment options for OA pain in the form of low-dose transdermal and sublingual opioid analgesia.. The aims of this trial were to compare the efficacy and tolerability of seven-day, low-dose transdermal buprenorphine patches (BuTrans, Napp Pharmaceuticals Limited UK) with sublingual buprenorphine (Temgesic, Schering-Plough Limited UK) in patients with moderate to severe pain caused by OA of the hip(s) and/or knee(s), and to establish analgesic equivalence of the two products.. Two hundred forty-six patients with OA pain in the hip(s) and/or knee(s) were enrolled in this randomized, double-blind, parallel-group study; 110 completed the study. Patients were randomized to receive transdermal buprenorphine patches (5, 10, and 20 microg/hour) or sublingual buprenorphine (200 and 400 microg tablets). Their medication was titrated to pain control and they were treated for up to seven weeks. The main outcome measures were pain intensity (primary outcome), sleep disturbance, quality of life, and safety assessments.. Patients' Box Scale-11 pain scores decreased between entry and assessment in both treatment groups. During the 28-day assessment period, the estimated mean treatment differences (95% confidence intervals) were 0.00 (-0.68,0.69), -0.11 (-0.85,0.63), and -0.13 (-0.95,0.68), for the morning, midday, and evening scores, respectively. All the confidence intervals were within the prespecified limits for equivalence (-1.5, 1.5). Use of escape medication was low. In both treatment groups, sleep disturbance caused by pain decreased between entry and assessment. Patients' quality of life improved during the study. Significantly fewer patients receiving the transdermal buprenorphine patches reported nausea (P=0.035), dizziness (P=0.026), and vomiting (P=0.039).. In conclusion, seven-day, low-dose transdermal buprenorphine patches are as effective as sublingual buprenorphine, with a better tolerability profile.

Topics: Administration, Cutaneous; Administration, Sublingual; Analgesics, Opioid; Buprenorphine; Double-Blind Method; Female; Humans; Male; Osteoarthritis, Hip; Osteoarthritis, Knee; Pain; Pain Measurement; Quality of Life; Treatment Outcome

Musculoskeletal pathologies are among the most frequent causes of long-term non-oncological severe pain and consequent physical impairment. Aims of pharmacological and physical therapy are to reduce pain, promote functional recovery and improve overall quality of life. Pharmacological therapy may include the use of opioids.. To evaluate the efficacy and tolerability of transdermal buprenorphine (TDS) in the long-term management of non-oncological, chronic, moderate-to-severe musculoskeletal pain.. An open-label, prospective, single-centre, 6-month study.. A 'real world' outpatient setting.. Adult patients with chronic moderate-to-severe musculoskeletal pain were enrolled consecutively.. Patients initially received buprenorphine TDS 11.7 microg/h (one-third of 35 microg/h patch) every 72 hours. If required, patients could be up-titrated to 17.5 microg/h (one-half of 35 microg/h patch), 23.4 microg/h (two-thirds of 35 microg/h patch) or 35 microg/h. Concomitant antiemetics were allowed.. The primary endpoint was percentage mean reduction in static and dynamic pain visual analogue scale (VAS) scores at study end (10 being worst pain, 0 being no pain). Quality of life and tolerability were also assessed.. We enrolled 146 patients aged 41-94 years; their baseline mean +/- SD static and dynamic pain VAS scores were 6.87 +/- 1.89 and 7.70 +/- 1.74, respectively. Buprenorphine TDS initial dosages were 11.7 microg/h (n = 139), 17.5 microg/h (n = 4), 23.4 microg/h (n = 1) and 35 microg/h (n = 2). At 6 months, 89 patients were under treatment; 11% (n = 10) were receiving 11.7 microg/h, 30% (n = 27) 17.5 microg/h, 6% (n = 5) 23.4 microg/h and 53% (n = 47) 35 microg/h. Patients achieved a nonsignificant reduction in pain at rest and in movement; mean +/- SD static and dynamic pain VAS scores decreased to 1.56 +/- 2.05 and 3.54 +/- 2.02, respectively. The quality of life improved as shown by significant (p < 0.01) increases from baseline in all items relating to physical and mental health on the Short-Form 36 health survey. Patients experienced recovery of daily and social activities according to the significant (p < 0.01) increase in Karnofsky Performance Status sub-item scores. Twenty-three patients discontinued treatment because of adverse events, which were mainly gastrointestinal or CNS-related.. Low-dose buprenorphine TDS had good analgesic efficacy, and quality of life improved as early as 1 month after treatment initiation. Our results suggest that buprenorphine TDS is a well tolerated long-term analgesic for patients experiencing chronic musculoskeletal pain of moderate-to-severe intensity.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Chronic Disease; Female; Humans; Italy; Male; Middle Aged; Musculoskeletal Diseases; Pain; Prospective Studies; Quality of Life; Severity of Illness Index; Time Factors; Treatment Outcome

To compare the analgesic efficacy of buprenorphine plus detomidine with that of morphine plus detomidine when administered epidurally in horses undergoing bilateral stifle arthroscopy.. Prospective, randomized, blinded clinical trial.. Twelve healthy adult horses participating in an orthopedic research study. Group M (n = 6) received morphine (0.2 mg kg(-1)) and detomidine (0.15 mg kg(-1)) epidurally; group B (n = 6) received buprenorphine (0.005 mg kg(-1)) and detomidine (0.15 mg kg(-1)) epidurally.. Horses received one of two epidural treatments following induction of general anesthesia for bilateral stifle arthroscopy. Heart rate (HR), mean arterial blood pressure (MAP), end-tidal CO(2) (Pe'CO(2)), and end-tidal isoflurane concentrations (E'Iso%) were recorded every 15 minutes following epidural administration. Post-operative assessment was performed at 1, 2, 3, 6, 9, 12, and 24 hours after standing; variables recorded included HR, respiratory rate (f(R)), abdominal borborygmi, defecation, and the presence of undesirable side effects. At the same times post-operatively, each horse was videotaped at a walk and subsequently assigned a lameness score (0-4) by three ACVS diplomates blinded to treatment and who followed previously published guidelines. Nonparametric data were analyzed using Wilcoxon's rank-sum test. Inter- and intra-rater agreement were determined using weighted kappa coefficients. Statistical significance was set at p

Topics: Analgesia, Epidural; Analgesics; Analgesics, Opioid; Animals; Buprenorphine; Drug Therapy, Combination; Female; Horse Diseases; Horses; Imidazoles; Injections, Epidural; Male; Morphine; Pain

We assessed the efficacy of using an alpha-1A-specific blocker for improving the success rate in shock wave lithotripsy (SWL) for lower ureteral stones.. This prospective study was conducted from June 2005 to December 2006 and involved 107 patients. All the patients underwent SWL with the PCK Stonelith. The patients were randomly divided into 3 groups: group 1 (34 patients) received tamsulosin, group 2 (35 patients) received terazosin, and group 3 (38 patients) received placebo. All patients were diagnosed by kidney-ureter-bladder X-ray, abdominal ultrasonography and intravenous urography. The number of colic episodes, lower urinary tract symptoms, analgesic dosage and days for spontaneous passage of the stones through the ureter were recorded by diary. Statistical analyses were performed using ANOVA, the chi(2) test, Fisher's exact test and the non-parametric Wilcoxon 2-sample t test.. There were no differences between the groups regarding age, stone size, expulsion time and expulsion rate. The number of colic episodes and the analgesic dosage were significantly lower in group 1 compared with groups 2 and 3. A statistically significant difference was observed in lower urinary tract symptoms: lower urinary tract symptoms were observed in 4 of 34 patients in group 1 (12%), in 8 of 35 in group 2 (23%), and in 13 of 38 in group 3 (34%). Adverse effects were noted in 5 of 32 patients in group 2 (16%), which was significantly different in comparison with group 3.. Administration of an alpha-1A-specific blocker reduced analgesic dosage and colic episodes after SWL of lower ureteral stones. There was no benefit with regard to increasing stone expulsion rate or decreasing expulsion time.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Adult; Analgesics, Opioid; Buprenorphine; Colic; Combined Modality Therapy; Female; Humans; Lithotripsy; Male; Middle Aged; Pain; Pain Measurement; Pilot Projects; Prazosin; Prospective Studies; Receptors, Adrenergic, alpha-1; Sulfonamides; Tamsulosin; Treatment Outcome; Ureteral Calculi

This study compared the efficacy and safety of low-dose 7-day buprenorphine patches and prolonged-release tramadol tablets in patients with chronic, moderate to severe osteoarthritis (OA) pain of the hip and/or knee.. Eligible patients were adults with a clinical and radiologic diagnosis of OA of the hip and/or knee and moderate to severe pain, as confirmed by a mean Box Scale 11 (BS-11) score >or=4 while using paracetamol 4000 mg/d for pain during the screening week. Patients were randomized in a 1:1 ratio to receive either low-dose 7-day buprenorphine patches (patch strengths of 5, 10, and 20 microg/h, with a maximum dosage of 20 microg/h) or twice-daily prolonged-release tramadol tablets (tablet strengths of 75, 100, 150, and 200 mg, with a maximum dosage of 400 mg/d) over a 12-week open-label treatment period. Supplementary paracetamol was available as rescue medication throughout the study. The primary end point was the difference in BS-11 scores from baseline to the completion of treatment. Noninferiority was assumed if the treatment difference on the BS-11 scale was -1.5 boxes, indicating a clinically meaningful result. Secondary efficacy variables were rescue medication use, sleep disturbance and quality of sleep, and patients' and investigators' global assessments of pain relief. In addition, patient preference was assessed at the completion visit by asking patients whether, given equal pain relief, they would prefer basic treatment for OA pain with a patch applied once weekly or a tablet taken twice daily. Exploratory variables included investigators' assessments of patients' pain, stiffness, and ability to perform daily activities (Western Ontario and McMaster Universities Osteoarthritis Index); patients' quality of life (EuroQol EQ-5D health states index and EuroQol visual analog scale); and abuse and diversion of study drug.. One hundred thirty-four patients (69 receiving 7-day buprenorphine patches and 65 receiving tramadol tablets) were randomized and received >or=1 dose of study medication. A respective 98.6% and 100% of the 2 treatment groups were white, with mean (SD) ages of 64.4 (11.1) and 64.2 (9.3) years. Both treatments were associated with a clinically meaningful reduction in pain from baseline to study completion. The least squares mean change from baseline in BS-11 scores in the 7-day buprenorphine patch and tramadol tablet groups was -2.26 (95% CI, -2.76 to -1.76) and -2.09 (95% CI, -2.61 to -1.58). The efficacy of 7-day buprenorphine patches was noninferior to that of prolonged-release tramadol tablets. The incidence of adverse events (AEs) was comparable in the 2 treatment groups: 226 AEs were reported in 61 patients (88.4%) in the 7-day buprenorphine patch group, and 152 AEs were reported in 51 patients (78.5%) in the tramadol group. Ten patients (14.5%) in the 7-day buprenorphine patch group and 19 (29.2%) in the tramadol tablet group withdrew from the study due to AEs. The most common AEs in the 7-day buprenorphine patch group were nausea (30.4%), constipation (18.8%), and dizziness (15.9%); the most common AEs in the tramadol tablet group were nausea (24.6%), fatigue (18.5%), and pain (12.3%). Most patients (47/67 [70.1%] in the 7-day buprenorphine patch group and 43/61 [70.5%] in the tramadol tablet group) reported that they would prefer a 7-day patch to a twice-daily tablet for future pain treatment.. In these patients with chronic, moderate to severe OA pain of the hip and/or knee, 7-day low-dose buprenorphine patches were an effective and well-tolerated analgesic. The buprenorphine patches were noninferior to prolonged-release tramadol tablets. European Union Drug Regulating Authorities Clinical Trials number: 2006-003233-32.

Topics: Acetaminophen; Administration, Cutaneous; Administration, Oral; Adult; Aged; Aged, 80 and over; Analgesics, Non-Narcotic; Analgesics, Opioid; Buprenorphine; Chronic Disease; Delayed-Action Preparations; Drug Administration Schedule; Humans; Middle Aged; Osteoarthritis, Hip; Osteoarthritis, Knee; Pain; Pain Measurement; Patient Satisfaction; Radiography; Sleep; Sweden; Tablets; Time Factors; Tramadol; Treatment Outcome

Due to tolerance development and adverse side effects, chronic pain patients frequently need to be switched to alternative opioid therapy. To assess the efficacy and tolerability of an alternative transdermally applied (TDS) opioid in patients with chronic cancer pain receiving insufficient analgesia using their present treatment.. A total of 32 patients received alternative opioid therapy, 16 were switched from buprenorphine to fentanyl and 16 were switched from fentanyl to buprenorphine. The dosage used was 50% of that indicated in equipotency conversion tables. Pain relief was assessed at weekly intervals for the next 3 weeks. Pain relief as assessed by VAS, PPI, and PRI significantly improved (p < 0.0001) in all patients at all 3 follow up visits. After 3 weeks of treatment, the reduction in the mean VAS, PPI, and PRI scores in the fentanyl and buprenorphine groups was 68, 77, 74, and 69, 79, and 62%, respectively. Over the same time period the use of oral morphine as rescue medication was reduced from 27.5 +/- 20.5 (mean +/- SD) to 3.75 +/- 8.06, and 33.8 +/- 18.9 to 3.75 +/- 10.9 mg/day in the fentanyl and buprenorphine groups, respectively. There was no significant difference in either pain relief or rescue medication use between the two patient groups The number of patient with adverse events fell during the study. After the third week of the treatment the number of patients with constipation was reduced from 11 to 5, and 10 to 4 patients in the fentanyl and buprenorphine groups, respectively. There was a similar reduction in the incidence of nausea and vomiting. No sedation was seen in any patient after one week of treatment.. Opioid switching at 50% of the calculated equianalgesic dose produced a significant reduction in pain levels and rescue medication. The incidence of side effects decreased and no new side effects were noted. Further studies are required to provide individualized treatment for patients according to their different types of cancer.

Topics: Adult; Aged; Analgesia; Analgesics, Opioid; Buprenorphine; Chronic Disease; Female; Fentanyl; Humans; Male; Middle Aged; Neoplasms; Pain; Palliative Care

Pharmacokinetic analysis of buprenorphine administered to six healthy dogs via the oral transmucosal (OTM) route at doses of 20 and 120 microg/kg was conducted using liquid chromatography-electrospray ionization-tandem mass spectroscopy (LC-ESI-MS/MS). Bioavailability was 38% plus or minus 12% for the 20 microg/kg dose and 47%+/-16% for the 120 microg/kg dose. Maximum plasma concentrations were similar for buprenorphine doses of 20 microg/kg IV and 120 microg/kg OTM. Sedation and salivation were common side effects, but no bradycardia, apnea, or cardiorespiratory depressive effects were seen. When the two OTM dosing rates were normalized to dose, LC-ESI-MS/MS analysis of buprenorphine and its metabolites detected no significant difference (P>.05), indicating dose proportionality. The results of this study suggest that OTM buprenorphine may be an alternative for pain management in dogs.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Area Under Curve; Biological Availability; Buprenorphine; Chromatography, Gas; Chromatography, High Pressure Liquid; Cross-Over Studies; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Injections, Intravenous; Intestinal Absorption; Mass Spectrometry; Pain; Treatment Outcome

Strong opioids are recommended for treating severe cancer pain in the advanced stages of the disease. Few data are available concerning the efficacy of buprenorphine in cancer pain. We compared transdermal buprenorphine 70 microg/h (BUP TDS) to placebo in an enriched design study. Opioid-tolerant patients with cancer pain requiring strong opioids in the dose range of 90-150 mg/d oral morphine equivalents entered a two-week run-in phase, during which they were converted to BUP TDS. Patients who could be stabilized on BUP TDS were randomized to BUP TDS or placebo patch for a two-week maintenance phase. Rescue medication (buprenorphine sublingual tablets 0.2mg) was allowed as required. Response was defined as a mean pain intensity of <5 (0-10 scale) and a mean daily buprenorphine sublingual tablet intake of < or =2 tablets during the maintenance phase. Of 289 patients who entered the run-in phase, 100 discontinued treatment due to lack of efficacy or adverse events; 189 patients continued treatment in the maintenance phase (94 BUP TDS, 95 placebo), of whom 31 discontinued treatment (7 BUP TDS, 24 placebo). A significant difference in the number of treatment responders was observed: 70 BUP TDS (74.5%, 65.7-83.3) vs. 47 placebo (50%, 39.9-60.1) (P=0.0003). This result was supported by a lower daily pain intensity, lower intake of buprenorphine sublingual tablets and fewer dropouts in the BUP TDS group. The incidence of adverse events was slightly higher for BUP TDS. In conclusion, BUP TDS 70 microg/h is an efficacious and safe treatment for patients with severe cancer pain.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Comorbidity; Double-Blind Method; Europe; Female; Humans; Male; Middle Aged; Neoplasms; Pain; Placebo Effect; Treatment Outcome

The aim of this placebo-controlled double-blinded cross-over study was to investigate the antihyperalgesic effect of topical morphine and buprenorphine in the sunburn pain model.. The study was designed as a double-blind, placebo-controlled cross-over trial, separated into 2 parts each with 16 volunteers. In part A morphine dissolved in Ultrabas-ultrasic ointment at 3 concentrations (0.1, 0.2, 0.4%) and placebo ointment were applied to 4 UVB-induced erythemas on the thighs. In part B buprenorphine at 3 concentrations (0.01, 0.02 and 0.1%) and placebo dissolved in a gel for transcutaneous application, was applied to 4 erythemas on the thighs. Thermal and mechanical hyperalgesia were assessed in the respective erythema by standardized quantitative sensory testing and opioids were compared to the placebo.. Neither morphine nor buprenorphine showed any significant reduction of hyperalgesia in comparison to the placebo.. The topical application of opioids in this form has no effect on inflamed skin.

Topics: Administration, Topical; Adult; Analgesics, Opioid; Buprenorphine; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gels; Humans; Male; Morphine; Pain; Sunburn

The aim of this randomized open-label prospective study was to evaluate the analgesic activity of buprenorphine in a transdermal formulation for cancer chronic pain control versus sustained-release morphine, in all cases combined with oral tramadol. A transdermal system with 35 microg/h buprenorphine was applied to the first group of patients (BT); the second group received 60 mg/day of sustained-release morphine (MT). In both groups oral tramadol was administered to a maximum of 200 mg daily, in case of need. The administration of transdermal buprenorphine versus morphine resulted in significant differences in the physical pain (P = 0.01), mental health (P = 0.03) and vitality (P = 0.001). These data indicated that the BT group showed an improvement of pain and a positive effect on the quality life.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Delayed-Action Preparations; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Morphine; Neoplasms; Pain; Quality of Life; Tramadol

To investigate spontaneous locomotor activity (SLA) and antinociceptive effects of buprenorphine in horses.. 6 healthy adult horses.. Horses received each of 3 treatments (10 mL of saline [0.9% NaCl] solution, 5 microg of buprenorphine/kg, or 10 microg of buprenorphine/kg). Treatments were administered IV. Order of treatments was randomized, and there was a 10-day interval between subsequent treatments. Spontaneous locomotor activity was investigated in a behavioral box by use of infrared photoelectric sensors connected to a computer, which detected movement of each horse. Antinociceptive effect was investigated by hoof-withdrawal reflex latency (HWRL) and skin-twitching reflex latency (STRL) after painful stimulation with a heat lamp.. Moderate excitement was observed in all horses from 5 to 10 minutes after the administration of both dosages of buprenorphine. The SLA increased significantly for 6 and 14 hours after IV administration of 5 and 10 microg of buprenorphine/kg, respectively. Values for HWRL increased significantly only at 30 minutes after injection of 5 microg of buprenorphine/kg, whereas STRL and HWRL each increased significantly from 1 to 6 hours (except at 2 and 4 hours) and 11 hours, respectively, after injection of 10 microg of buprenorphine/kg.. IV injection of buprenorphine caused a dose-dependent increase in SLA, but only the dose of 10 microg/kg induced analgesia on the basis of results for the experimental method used.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Horses; Male; Motor Activity; Pain; Pain Measurement; Time Factors

A number of subjects aged over 65 suffer from some kind of chronic pain. The constant growth of this demographic group makes research of new and efficacious treatment strategies necessary. Transdermal buprenorphine has shown to be a safe and efficacious pharmacotherapy for patients with moderate to severe chronic pain in clinical trials. This paper provides the outcome of this drug in routine clinical practice.. A prospective, uncontrolled observational study that included a 3-month follow-up of patients starting transdermal buprenorphine was performed. Information was collected systematically on pain relief, quality of life (EuroQol-5D questionnaire), comfort of patch use and adverse events. Missing data were imputed by the <>.. Out of 1,188 patients with known age, 564 were under 65, 337 were between 65 and 75, and 287 were over 75 years. Within these respective age groups, 63.9%, 66.3% and 67.7% of patients showed <> or <> pain relief; 60.4%, 60.7% and 65.2% showed improvement of sleep quality; and the mean increases of the score of the EuroQol-5D visual analogue scale were 16.0 mm, 15.8 mm and 16.8 mm. Drug-related adverse events were reported in 39.6%, 35.4% and 31.9% of patients, respectively.. This study performed in the routine-care setting supports the findings from previous randomised controlled clinical trials of transdermal buprenorphine.

Topics: Administration, Cutaneous; Aged; Analgesics, Opioid; Buprenorphine; Chronic Disease; Female; Humans; Male; Middle Aged; Pain; Prospective Studies

A model of nociceptive threshold determination was developed for evaluation of NSAID analgesia in cats. In a crossover study, eight cats received carprofen (4 mg/kg), buprenorphine (0.01 mg/kg) or saline (0.3 ml) subcutaneously before intradermal kaolin injection on the antebrachium to induce mild inflammation. Pressure thresholds were measured at the injected site using blunt-ended pins advanced by manual inflation of a bladder within a bracelet. Bladder pressure was recorded as threshold (PT) at the behavioural end point. Baseline PT were recorded before kaolin injection (time 0). PT was measured at 2-10 h intervals for 52 h. PT below the lower 95% confidence interval (CI) of baseline values indicated hyperalgesia. After saline, hyperalgesia was detected from 2-6 h, 22-26 h, and at 30 and 36 h. After carprofen, PT remained within the 95% CI. After buprenorphine, PT remained within the 95% CI except at 2h. Carprofen and to some extent buprenorphine, prevented inflammatory hyperalgesia.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Carbazoles; Cat Diseases; Cats; Cross-Over Studies; Female; Hyperalgesia; Inflammation; Male; Pain

Postoperative pain management in laboratory animals is important for animal welfare and required under law in many countries. Frequent injection of analgesics to rodents after surgery is stressful for the animals and labour-intensive for animal care personnel. An alternative dosing scheme such as administration of analgesics in the drinking water would be desirable. However, the efficacy of a chronic oral analgesic treatment via this route has not yet been documented. This study investigated the antinociceptive efficacy of buprenorphine administered ad libitum via the drinking water of laboratory rats. The antinociceptive efficacy of buprenorphine in drinking water was compared with repeated subcutaneous injections. A comparison was also made between buprenorphine in drinking water and the combination of one single subcutaneous injection of buprenorphine followed by buprenorphine in drinking water. Antinociception was assessed by use of an analgesiometric model measuring the rats' latency time to withdrawal from a noxious heat stimulus applied to the plantar surface of the paw. Results revealed that buprenorphine in drinking water (0.056 mg/mL) induced significant increases in paw withdrawal latency times during a three-day period of administration with a maximal effect at 39 h after the start of buprenorphine administration. One single injection of buprenorphine (0.1 mg/kg s.c.) followed by buprenorphine in the drinking water (0.056 mg/mL) induced an earlier onset of antinociception than buprenorphine in drinking water alone. In contrast, buprenorphine (0.1 mg/kg s.c.) injected every 8 h over a period of three days did not result in significant increases in paw withdrawal latency times. In conclusion, our results suggest that one single subcutaneous injection of buprenorphine followed by buprenorphine in drinking water may be a viable treatment option for the relief of pain in laboratory rats, but at the doses used in this study in pain-free rats it was associated with a decrease in water intake and some behavioural changes.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Buprenorphine; Male; Pain; Rats; Rats, Wistar; Time Factors; Water

Six domestic shorthair cats, aged three to four years and weighing 5.1 to 7.4 kg, were used to assess the thermal antinociceptive effect of a transdermal buprenorphine patch, designed to supply 35 mug buprenorphine/hour, which was applied to the shaved thorax. The cats' thermal thresholds were tested before the patch was applied and two, four, six, eight, 10, 12, 14 and 16 hours after it had been applied, and then every six hours until it was removed after 72 hours, and for a further 24 hours afterwards. Blood was collected at each time to measure the plasma concentration of buprenorphine. The patches did not produce a significant change in the thermal thresholds of the cats throughout the testing period. The mean (sd) peak plasma buprenorphine concentration was 10 (0.81) ng/ml.

Topics: Administration, Cutaneous; Analgesics, Opioid; Animals; Buprenorphine; Cat Diseases; Cats; Female; Male; Pain; Time Factors

Opioid rotation is increasingly becoming an option to improve pain management especially in long-term treatment. Because of insufficient analgesia and intolerable side effects, a total of 42 patients (23 male, 19 female; mean age 64.1 years) suffering from severe musculoskeletal (64%), cancer (21%) or neuropathic (19%) pain were converted from high-dose morphine (120 to >240 mg/day) to transdermal buprenorphine. The dose of buprenorphine necessary for conversion (at least 52.5 microg/h) was titrated individually by the treating physician. No conversion recommendations were given and the treating physician used his or her own judgment for dose adjustment. Pain relief, overall satisfaction and quality of sleep (very good, good, satisfactory, poor, or very poor), and the incidence and severity of adverse drug reactions over a period of at least 10 weeks and up to 1 year was assessed. Following rotation, patients experiencing good/very good pain relief increased from 5% to 76% (P < 0.001). Only 5% reported insufficient relief. Relief was achieved with buprenorphine alone in 77.4%, while 17% needed an additional opioid for breakthrough pain. Sleep quality (good/very good) increased from 14% to 74% (P < 0.005). Adverse effects were reported in 11.9%, mostly because of local irritation, did not result in termination of therapy. Neither tolerance nor refractory effect following rotation from morphine to buprenorphine was noted. Conversion tables with a fixed conversion ratio are of limited value in patients treated with high-dose morphine.

Topics: Administration, Cutaneous; Aged; Analgesics, Opioid; Buprenorphine; Chronic Disease; Clinical Protocols; Dose-Response Relationship, Drug; Drug Tolerance; Female; Humans; Male; Middle Aged; Morphine; Pain; Pain Measurement; Palliative Care; Patient Satisfaction; Product Surveillance, Postmarketing; Prospective Studies; Sleep

In 2001, a transdermal matrix patch formulation of buprenorphine was approved for the treatment of moderate to severe cancer pain and severe pain that is unresponsive to nonopioid analgesics. The primary recommendation contained in the prescribing information was that transdermal patches be worn for a 3-day period before application of a new patch.. This study was conducted to evaluate the potential for extending the time the buprenorphine patch is worn from 3 to 4 days.. This single-center, randomized, open-label, crossover Phase III study compared the efficacy and tolerability of the buprenorphine transdermal patch applied for different durations, with patch changes every 3 days versus every 4 days (12 days each), in patients with chronic moderate or severe pain of malignant or nonmalignant origin. Study participants were aged >18 years, had already responded to at least 4 weeks of transdermal buprenorphine, and had achieved steady-state conditions for at least 2 weeks before enrollment. The primary end point was patients' rating of the quality of treatment (analgesic efficacy and tolerability, rated on a 5-point scale: very good, good, satisfactory, poor, and inadequate) at the completion of each treatment regimen. Also recorded were physicians' ratings of the quality of treatment; pain intensity, rated on an 11-point numerical rating scale (from 0 = no pain to 10 = worst pain imaginable) and on the McGill Pain Questionnaire (MPQ) (maximum pain = 3.0); health status, assessed using the 36-item Short Form Health Survey (SF-36), expressed as a percentage of the best health condition (100%); and pain relief (5-point scale: complete, good, satisfactory, slight, and none). Local skin tolerability was evaluated for objective and subjective dermatologic symptoms at the patch application sites. Patients recorded daily pain intensities at specified times of day and night, pain relief (5-point verbal rating scale), and sleep duration (2-3 hours, >3-<6 hours, or >or=6 hours) in a diary. The safety profile was evaluated based on standard monitoring of adverse events, vital signs, and routine laboratory tests.. Forty-nine white patients (25 women, 24 men) were enrolled; their mean (SD) age was 61.6 (11.5) years, and their mean weight was 74.7 (16.7) kg. The most common source of pain was musculoskeletal disorders (40 patients), followed by nervous system disorders (10), neoplasms (9), injuries (5), and other causes (6). Forty-one patients completed the study; 2 patients discontinued because of adverse events, 1 because of lack of efficacy, and 5 for nonmedical reasons. Thirty-three patients provided data per protocol. Patients in the perprotocol population received a mean (SD) transdermal buprenorphine dose of 49.9 (38.9) microg/h. The proportion of patients in the per-protocol population rating the quality of treatment as adequate (combined ratings of very good, good, and satisfactory) was 93.9% (31/33) for both regimens. The physicians' ratings indicated adequate quality of treatment in 93.8% (30/32) of patients applying 4 patches for 3 days each and 97.0% (32/33) of patients applying 3 patches for 4 days each. Mean (SD) pain intensity scores on the numerical rating scale were similar after completion of the 3- and 4-day regimens (3.73 [1.88] and 3.88 [1.75] points, respectively), as were MPQ scores (0.79 [0.67] and 0.79 [0.78]). The mean (SD) proportion of days with at least satisfactory pain relief was 83.9% (26.1%) and 85.6% (24.4%) for the 3- and 4-day regimens; the corresponding proportions of nights with at least satisfactory pain relief were 85.2% (26.6%) and 88.1% (21.4%). Continuously assessed pain intensities at specified times of day and night (numerical rating scale) did not differ significantly between regimens. Mean SF-36 health status scores did not differ significantly between regimens (total score: 37.7% [17.0%] and 37.7% [17.3%]). Mean rates of nights with good sleep quality were 28.5% (39.9%) for the 3-day regimen and 36.0% (42.6%) for the 4-day regimen. Local skin tolerability was comparable for the 3- and 4-day regimens, with objective findings (mainly erythema) at the patch-application sites in 17 of 32 and 11 of 33 patients, respectively, and subjective symptoms (mainly itching) in 16 of 32 and 13 of 33 patients. The most common adverse events in the safety population were nausea, dizziness/giddiness, and malaise/fatigue (3/49 [6.1%] each).. Analgesic efficacy, patients' satisfaction with the quality of treatment, and skin tolerability did not differ significantly between 3 and 4 days of patch application in these patients with chronic pain who had been previously stabilized on transdermal buprenorphine.

Topics: Administration, Cutaneous; Aged; Analgesics, Opioid; Buprenorphine; Cross-Over Studies; Drug Administration Schedule; Erythema; Female; Humans; Male; Middle Aged; Pain; Pain Measurement; Patient Satisfaction; Quality of Health Care; Severity of Illness Index; Treatment Outcome

This study compared the efficacy and safety profile of buprenorphine transdermal delivery system (BTDS) and placebo in subjects with persistent noncancer-related pain who required opioid analgesics.. This was a multicenter, double-blind, parallel-group study in adult subjects (age >/=18 years) with at least a 2-month history of noncancer-related pain for which they received oral opioid combination agents. The study employed a maintenance-of-analgesia, or randomized-withdrawal, design. During a 7- to 21-day open-label run-in phase, all subjects received BTDS, titrated as needed. Subjects who achieved stable pain control and were able to tolerate BTDS in the run-in phase were randomly assigned to continue BTDS at the dose achieved during the run-in phase or to receive placebo for up to 14 days. Acetaminophen 500-mg tablets were provided as escape (rescue) medication. Subjects completed the study on day 14 or when they met predefined criteria for ineffective treatment: requiring >1 g of acetaminophen as escape medication on any day of the double-blind evaluation phase, requiring a change in study drug dose, having difficulty keeping the patch affixed, or discontinuing because of ineffective treatment without meeting any of the first 3 criteria. The primary efficacy variable was the proportion of subjects with ineffective treatment. Secondary efficacy variables were the time to ineffective treatment; the proportion of subjects who reached ineffective treatment or discontinued for any reason other than ineffective treatment; and the amount of escape medication used. Assessment of the safety profile was based on adverse events and changes in vital signs and physical and laboratory findings.. Five hundred eighty-eight subjects entered the open-label run-in phase, and 267 (129 BTDS, 138 placebo) were subsequently randomized to doubleblind treatment. Demographic characteristics were similar between the double-blind BTDS and placebo groups (61.2% and 63.8% female, respectively; 99.2% and 98.6% white; mean [SD] age, 56.2 [13.3] and 59.2 [11.5] years). In the primary efficacy analysis, the proportion of subjects with ineffective treatment was lower with BTDS than with placebo (51.2% vs 65.0%; 95% CI, 1.09-2.95); the odds of ineffective treatment were 1.79 times greater for placebo relative to BTDS (P = 0.022). In the secondary efficacy analyses, the median time from the first dose of double-blind study drug to ineffective treatment was significantly longer with BTDS than with placebo (median, 10 vs 3 days; P = 0.011). The proportion of subjects who reached ineffective treatment or discontinued for reasons other than ineffective treatment was lower in the BTDS group compared with the placebo group (55.0% vs 67.9%); the odds of ineffective treatment or discontinuation for a reason other than ineffective treatment was 1.76 times greater with placebo compared with BTDS (P = 0.028). The mean amount of escape medication used was significantly lower in the BTDS group than in the placebo group (1.7 vs 2.2 acetaminophen tablets per day; P = 0.015). The most common adverse events in the open-label run-in or double-blind phase occurring at a higher incidence with BTDS than with placebo were pruritus at the patch application site (9.3% vs 5.1%, respectively), headache (3.9% vs 2.2%), and somnolence (2.3% vs 0.7%).. In this population of adult subjects with persistent noncancer-related pain who required opioid therapy, BTDS use was associated with analgesic efficacy and was generally well tolerated. Results of this study were presented in part at the annual meeting of the American Pain Society, March 30-April 2, 2005, Boston, Massachusetts.

Topics: Acetaminophen; Administration, Cutaneous; Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Non-Narcotic; Analgesics, Opioid; Buprenorphine; Chronic Disease; Double-Blind Method; Drug Delivery Systems; Female; Humans; Male; Middle Aged; Pain; Treatment Failure

To evaluate the effects of subarachnoidally administered hyperbaric morphine, buprenorphine, and methadone on avoidance threshold to noxious electrical stimulation of the perineal, sacral, lumbar, and thoracic regions in horses.. 6 healthy adult horses.. Horses were assigned to receive subarachnoid administration of hyperbaric morphine (0.01 mg/kg), buprenorphine (0.001 mg/kg), methadone (0.01 mg/kg), or 10% dextrose solution in equal volumes (5 mL). Electrical stimulation was applied every 10 minutes for 60 minutes and every 30 minutes for 120 minutes after subarachnoid injection over the dermatomes of the perineal, sacral, lumbar, and thoracic regions, and the avoidance threshold voltage was recorded. Heart and respiratory rate, blood gas tensions, serum electrolyte concentrations, and sedative effects were also evaluated.. Administration of 10% dextrose solution did not change the avoidance threshold. Morphine and methadone significantly increased the avoidance threshold by 10 minutes after injection, which lasted until 120 minutes after subarachnoid administration in the perineal, sacral, lumbar, and thoracic regions. Profound analgesia (avoidance threshold > 40 V) was achieved in all regions. Buprenorphine also significantly increased the avoidance threshold by 10 minutes (36 V) after injection, which lasted 60 minutes and was considered moderate. Heart rate, blood pressure, respiratory rate, and blood gas tensions stayed within reference range. No ataxia, signs of sedation, or CNS excitement were observed.. Subarachnoid administration of hyperbaric morphine or methadone produces intense analgesia for 120 minutes over the dermatomes of the perineal, sacral, lumbar, and thoracic areas without cardiorespiratory depression, ataxia, or CNS excitement in horses.

Topics: Analgesia; Analgesics, Opioid; Animals; Buprenorphine; Cross-Over Studies; Female; Horse Diseases; Horses; Injections, Spinal; Male; Methadone; Morphine; Pain

When selecting the appropriate long-acting opioid to treat cancer pain, both analgesic efficacy and safety need consideration. Generally, opioids are well tolerated. However, of opioid-typical adverse events, respiratory depression is especially important because of the risk of a fatal outcome. Although all potent opioid analgesics act via the micro-opioid receptor system, they differ in how they affect respiratory control. Recently, the respiratory effects of fentanyl (1 7 microg/kg) and buprenorphine (0.7-9 microg g/kg) were compared in healthy opioid-naïve volunteers. Fentanyl produced dose-dependent depression of respiration with apnoea at doses > or = 3 microg/kg, while buprenorphine caused depression that levelled at approximately 50% of baseline with doses > or = 2 microg/kg. These findings indicate the occurrence of a ceiling in the respiratory depression induced by buprenorphine but not by fentanyl. Surprisingly few studies have addressed the clinically important ability to reverse the respiratory effects of opioids. A recent assessment of the naloxone dose required to reverse 0.2 mg intravenous buprenorphine-induced respiratory depression in healthy opioid-naïve volunteers, found that the accumulated naloxone dose causing 50% reversal of respiratory depression was 1.20 +/- 0.32 mg/70 kg (given in 30 min); 80% reversal was observed at 2.50 +/- 0.60 mg/70 kg (given in 30 min). At greater buprenorphine doses, full reversal is observed when the duration of naloxone infusion is increased. These findings indicate the need for a continuous rather than bolus administration of naloxone to reverse the respiratory effects of buprenorphine. In conclusion, buprenorphine is more favourable compared with fentanyl in respect to ventilatory control. Buprenorphine causes limited respiratory depression with a ceiling effect at higher doses, while fentanyl causes dose-dependent respiratory depression with apnoea at high dose levels. In the rare instance of respiratory depression, reversal is possible with a sufficient and continuous infusion of naloxone.

Topics: Analgesics, Opioid; Apnea; Buprenorphine; Dose-Response Relationship, Drug; Double-Blind Method; Fentanyl; Humans; Naloxone; Narcotic Antagonists; Neoplasms; Pain; Respiratory Insufficiency

Supplemental dosing of an opioid is the main treatment suggested to manage breakthrough pain in cancer patients. The intravenous route has been proven to be safe and effective, providing rapid analgesia in patients receiving oral morphine. Transdermal buprenorphine (TTS-BUP) is increasingly used in cancer pain management, but this drug has been labeled as a difficult drug to use in combination with other opioids. The aim of this open-label study was to verify the safety and effectiveness of intravenous morphine (IV-MO) for the treatment of episodic pain in cancer patients receiving TTS-BUP. A consecutive sample of 29 cancer patients, who were treated with TTS-BUP, reported an acceptable basal analgesia, and presented with episodic pains were selected for the study. The IV-MO dose was one-fifth of the morphine equivalent oral daily dose calculated using a ratio of TTS-BUP/oral morphine of 1:75, and a morphine IV/oral ratio of 1:3. For each episode, pain intensity and opioid-related adverse effects were recorded when severe pain occurred (T0), and 15 minutes after. One hundred six breakthrough events in the 29 patients (3.7 episodes per patient, on average) were recorded during admission. The mean pain intensity decreased from an initial value of 7.3 (confidence interval [CI] 95% 7.0-7.5) to 2.9 (CI 95% 2.5-3.3) 15 minutes after IV-MO. Ninety-eight episodes (92.4%) were considered treated successfully, defined as a reduction of more than 33% within 15 minutes; 88 of these episodes (83.0%) had more than 50% pain intensity decrease. No differences in age, gender, pain mechanism, and time of events were found. Eight episodes (7.5%) did not respond effectively within 15 minutes, and required further doses. The occurrence of adverse effects for each episode treated was not frequent and intensity was not relevant. IV-MO was effective and safe in most cancer patients receiving TTS-BUP who experienced pain exacerbation.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Drug Combinations; Female; Humans; Injections, Intravenous; Male; Middle Aged; Morphine; Neoplasms; Pain; Pain Measurement; Palliative Care; Secondary Prevention; Treatment Outcome

This is the first randomized controlled trial that tests the analgesic efficacy of transdermally delivered opioids in healthy volunteers and that assesses the sensitivity of different experimental pain tests to detect analgesia in this setting. Transdermal application of the full agonist fentanyl (TDF: 12.5 or 25 microg/h) and the partial agonist buprenorphine (TDB: 35 microg/h) was compared in three experimental models of acute pain (heat pain, painful electrical stimulation, cold pressor) in a double-blind, randomized, placebo-controlled, 4-arm crossover study with 20 healthy subjects (15 men, 5 women). Patches were administered for 72 h and pain levels measured at baseline and 24 and 72 h, with an 11-day wash-out. The cold pressor test was most sensitive to analgesic effects, with significant reductions in area under the pain intensity curve for all active compounds at 24 h (average reductions: 14% TDF 12.5 microg/h, 35% TDF 25 microg/h, 43% TDB 35 microg/h). There were significant increases in heat pain threshold for TDF 25 microg/h and TDB 35 microg/h. Painful electrical stimulation failed to demonstrate an analgesic effect. The magnitude of analgesia in the cold pressor model showed some correlation with TDF dosage and comparable effects for the full agonist fentanyl and the partial agonist buprenorphine. We conclude that the cold pressor test was most sensitive to analgesic effects in healthy subjects and that a transdermal dose of 12.5 microg/h fentanyl achieved significant pain reduction compared with placebo. Subjects experienced opioid-typical AEs including dizziness, nausea and vomiting. No serious AEs occurred.

Topics: Administration, Cutaneous; Adult; Analgesics, Opioid; Buprenorphine; Cold Temperature; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Electric Stimulation; Female; Fentanyl; Hot Temperature; Humans; Immersion; Male; Pain; Pain Measurement; Sensitivity and Specificity

Different mechanisms were proposed for opioid-induced analgesia and antihyperalgesia, which might result in different pharmacodynamics. To address this issue, the time course of analgesic and antihyperalgesic effects of intravenous (i.v.) and sublingual (s.l.) buprenorphine was assessed in an experimental human pain model. Fifteen volunteers were enrolled in this randomized, double-blind, and placebo controlled cross-over study. The magnitude of pain and the area of secondary hyperalgesia following transcutaneous stimulation were repetitively assessed before and up to 150 min after administration of (1) 0.15 mg buprenorphine i.v. and placebo pill s.l., (2) 0.2 mg buprenorphine s.l. and saline 0.9% i.v. or (3) saline 0.9% i.v. and placebo pill s.l. as a control. The sessions were separated by 2 week wash-out periods. For both applications of buprenorphine the antihyperalgesic effects were more pronounced as compared to the analgesic effects (66+/-9 vs. 26+/-5% and 43+/-10 vs. 10+/-6%, for i.v. and s.l. application, respectively). This contrasts the pattern for the intravenous administration of pure mu-receptor agonists in the same model in which the antihyperalgesic effects are weaker. The apparent bioavailability of buprenorphine s.l. as compared to buprenorphine i.v. was 58% with a 15.8 min later onset of antinociceptive effects. The half-life of buprenorphine-induced analgesic and antihyperalgesic effects were 171 and 288 min, respectively. In contrast to pure mu-receptor agonists, buprenorphine exerts a lasting antihyperalgesic effect in our model. It will be of major clinical interest whether this difference will translate into improved treatment of pain states dominated by central sensitization.

Topics: Administration, Sublingual; Adult; Algorithms; Analgesics, Opioid; Biological Availability; Buprenorphine; Cross-Over Studies; Double-Blind Method; Female; Humans; Hyperalgesia; Injections, Intravenous; Male; Middle Aged; Models, Statistical; Pain; Pain Measurement; Placebos; Receptors, Opioid, mu; Transcutaneous Electric Nerve Stimulation; Treatment Outcome

Buprenorphine, a potent opioid analgesic, has been available in parenteral and oral or sublingual(SL) formulations for >25 years. In 2001, the buprenorphine transdermal delivery system (TES) was introduced at 3 release rates (35, 52.5, and 70 microg/h) for the treatment of chronic cancer and noncancer pain.. This study compared the analgesic efficacy and tolerability of buprenorphine TES at a release rate of 35 microg/h with those of buprenorphine SL and placebo in patients with severe or very severe chronic cancer or noncancer pain.. This multicenter, double-blind, placebo-controlled, parallel-group trial was 1 of 3 Phase III studies involved in the clinical development of buprenorphine TDS. It comprised a 6-day open-label run-in phase in which patients received buprenorphine SL 0.8 to 1.6 mg/d as needed and a double-blind phase in which patients were randomized to receive 3 sequential patches containing buprenorphine TES 35 microg/h or placebo, each lasting 72 hours. Rescue analgesia consisting of buprenorphine SL 02-mg tablets was available as needed throughout the double-blind phase. The main outcome measures were (1) the number of buprenorphine SL tablets required in addition to buprenorphine TES during the double-blind phase compared with the placebo group and compared with the buprenorphine SL requirement during the run-in phase, and (2) patients' assessments of pain intensity, pain relief, and duration of sleep uninterrupted by pain in the double-blind phase compared with the run-in phase. Adverse events were documented throughout the study.. One hundred thirty-seven patients were included in the double-blind phase (90 buprenorphine TES, 47 placebo). The buprenorphine TES group included 47 men and 43 women (mean [SD] age, 56.0 [12.1] years), and the placebo group included 23 men and 24 women (mean age, 55.7 [12.9] years). Forty-five patients had cancer-related pain and 92 had noncancer-related pain. The 2 treatment groups were comparable with respect to sex distribution, age, height, and body weight Patients receiving buprenorphine TES significantly reduced their consumption of buprenorphine SL tablets in the double-blind phase compared with patients receiving placebo (reduction of 0.6 [0.4] mg vs 0.4 [0.4] mg; P = 0.03). The relationship between the buprenorphine SL dose in the run-in phase and the number of buprenorphine SL tablets required in the double-blind phase was dose dependent in the active-treatment group only. Patients' assessments of pain intensity and pain relief suggested better analgesia with buprenorphine TES than with placebo, although the differences did not reach statistical significance. The proportion of patients who reported sleeping for >6 hours uninterrupted by pain in the double-blind phase compared with the run-in phase increased by 6.4% in the buprenorphine TDS group (35.6% vs 292%, respectively), compared with a decrease of 5.9% in the placebo group (40.4% vs 463%); no statistical analysis of sleep duration data was performed. Buprenorphine TDS was well tolerated, with adverse events generally similar to those associated with other opioids. The incidence of systemic adverse events in the double-blind phase was similar in the 2 treatment groups (28.9% buprenorphine TDS, 27.6% placebo), with the most common adverse events being nausea, dizziness, and vomiting. After patch removal, skin reactions (mainly mild or moderate pruritus and erythema) were seen in 35.6% of the buprenorphine TDS group and 25.5% of the placebo group.. In the population studied, buprenorphine TDS provided adequate pain relief, as well as improvements in pain intensity and duration of pain-free sleep. It may be considered a therapeutic option for the treatment of moderate to severe chronic pain.

Topics: Administration, Cutaneous; Administration, Sublingual; Analgesics, Opioid; Buprenorphine; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Neoplasms; Pain; Pain Measurement; Tablets

Buprenorphine is a potent opioid analgesic that is available in sublingual and parenteral formulations. A new formulation, buprenorphine transdermal delivery system (TDS), has been developed.. The aim of this study was to compare the analgesic efficacy and tolerability of the 3 available dosages of buprenorphine TDS (35.0, 52.5, and 70.0 microg/h) with placebo.. This was a randomized, double-blind, placebo-controlled, multicenter study. Patients with chronic, severe pain related to cancer or other diseases and inadequately controlled with weak opioids were randomized to receive buprenorphine TDS 35.0, 52.5, or 70.0 microg/h or placebo patch for up to 15 days. A new patch was applied every 72 hours, for a total of 5 patches. All patients were permitted rescue analgesia with sublingual buprenorphine tablets (0.2 mg) as required for breakthrough pain.. A total of 157 patients (86 women, 71 men; mean [SD] age, 58.7 [11.8] years) were initially enrolled in the study. Buprenorphine TDS was associated with significantly higher response rates than was placebo at the 35.0- and 52.5-microg/h dosages (36.6% and 47.5%, respectively, vs 16.2%; P=0.032 and P=0.003, respectively) and a numerically higher response rate at 70.0 microg/h (33.3%), although this difference did not reach statistical significance. Patients treated with buprenorphine TDS experienced a 56.7% reduction in use of sublingual rescue analgesic during the study compared with an 8% reduction with the placebo patch. A total of 43.5% of patients treated with buprenorphine TDS reported good or complete pain relief compared with 32.4% in the placebo group. Pain intensity decreased in a dose-dependent manner with buprenorphine TDS, and the duration of sleep uninterrupted by pain was improved by the end of the study. More than three fourths (78.8%) of patients in the placebo and buprenorphine TDS groups reported at least 1 adverse event (AE) during the study. The most common AEs were central nervous system and gastrointestinal symptoms. The majority of treatment-related AEs were mild or moderate in intensity and were typical of those occurring at the beginning of therapy with a strong opioid.. Buprenorphine TDS was shown to be an effective analgesic against chronic, severe pain in this study population. Patients treated with this new formulation of buprenorphine showed improved duration of sleep and reduced need for additional oral analgesics.

Topics: Administration, Cutaneous; Administration, Sublingual; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Chronic Disease; Dosage Forms; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Neoplasms; Pain; Pain Measurement; Sleep

Advanced patch technology has yielded a novel transdermal therapeutic system (TDS) for the rate-controlled systemic delivery of buprenorphine. Buprenorphine TDS is available in three strengths with release rates of 35, 52.5 and 70 microg/h over 72 h, corresponding to daily doses of 0.8, 1.2 and 1.6 mg, respectively. In total, 445 patients with chronic pain of malignant or non-malignant origin requiring long-term treatment with potent opioid analgesics were enrolled in the clinical trial programme. The patients were treated with buprenorphine TDS in one of three dosage strengths or with placebo TDS in a randomised double-blind setting. Greater pain relief was documented in patients treated with buprenorphine TDS than in those treated with placebo. The benefit of buprenorphine TDS was further reflected in the larger number of patients who slept for longer than 6 h per night. Patients switching from Step 2 or Step 3 opioids to buprenorphine TDS encountered no problems with the conversion. Typical opioid-related adverse events were reported with a low incidence and mild intensity. In an open follow-up study 239 patients elected to continue treatment with buprenorphine TDS. The confirmation of clinical benefit, coupled with a high level of patient compliance and improved quality of life, substantiate the usefulness of buprenorphine TDS in a practical setting.

Topics: Administration, Cutaneous; Administration, Sublingual; Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Pain; Pain Measurement; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

Pain from multiple rib fractures may affect pulmonary function, morbidity, and length of stay in the intensive care units. This study describes some clinical characteristics of epidural buprenorphine, a lipophilic and partial opiate agonist with a higher micro receptor affinity than morphine, in combating the pain in multiple rib fractures.. The study was conducted prospectively over a 15-month period. A total of 27 patients admitted to the hospital with multiple rib fractures were studied. Buprenorphine at a concentration of 0.3 mg in 5-10 ml normal saline was administered epidurally, twice daily the first 24 h, thereafter once daily. Ventilatory function tests (including vital capacity, tidal volume, respiratory rate, and minute volume) and assessment of pain intensity using a simple, categorical, verbal rating scale were obtained before and after institution of analgesia. Any nausea, vomiting, hypotension, urinary retention, respiratory depression or pruritus were recorded.. We found a significant improvement in ventilatory function tests during the 1st, 2nd, and 3rd day after epidural analgesia when compared with the preanalgesia levels (P < 0.001). Changes in the verbal rating scale demonstrated that epidural buprenorphine was associated with marked improvement in pain at rest and pain during coughing and deep breathing. None of our patients developed hypotension (<10% of the baseline), urinary retention or respiratory depression. Nausea, vomiting, and mild pruritus were the only reported complications.. Epidurally introduced narcotic, like buprenorphine in saline, has been found to be effective in our study to achieve adequate analgesia in treatment of patients with multiple rib fractures. In addition, this methodology of pain relief eliminates the costly delivery system and early discharge, and allows walking epidurals and follow-up on outpatient basis.

Topics: Analgesia, Epidural; Analgesics, Opioid; Buprenorphine; Female; Humans; Male; Middle Aged; Pain; Pain Measurement; Prospective Studies; Pulmonary Ventilation; Respiratory Function Tests; Rib Fractures; Tidal Volume; Time Factors; Vital Capacity

To assess the analgesic efficacy and side effects of buprenorphine and procaine in patients with acute pancreatitis.. Forty patients (average age, 50 years; 23 male) with acute pancreatitis or an acute bout of a chronic pancreatitis were prospectively randomized to receive buprenorphine or procaine for pain relief. Both analgesics were administered as constant intravenous (i.v.) infusions and additional analgesics were given on demand. Pain scores were assessed on a visual analogue scale. Close clinical control and laboratory checks were performed during the three-day study period.. Patients receiving buprenorphine were significantly less likely to demand additional analgesics (1 versus 14 patients; P < 0.0001). The pain scores for patients in the buprenorphine group were significantly lower over the treatment period in comparison to procaine (P < 0.05). The reduction of pain score was significantly greater during the initial two treatment days using buprenorphine (day 1: 55 versus 25, P < 0.0001; day 2: 62 versus 40, P = 0.005). Side effects were comparable for both groups with the exception of a slightly higher sedation rate under buprenorphine.. Constant i.v. application of buprenorphine is more effective than the recommended procaine for pain relief in acute pancreatitis.

Topics: Acute Disease; Adult; Aged; Analgesics; Analgesics, Opioid; Buprenorphine; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pain; Pain Measurement; Pancreatitis; Procaine; Prospective Studies

In many cases, the treatment of neuropathic pain by intrathecal opioids fails to meet expectations. In a trial involving 10 patients, the intrathecal administration of clonidine combined with opioids in the treatment of chronic pain was introduced in our department for the first time. Eight patients with neuropathic pain syndromes were subjected to a continuous intrathecal clonidine application in addition to intrathecal morphine. At an average dose of 44 microg clonidine/day, a 70-100% reduction in pain was achieved. Residual non-neuropathic pain in 4 of 8 patients was successfully treated with clonidine and low doses of opioids. On the basis of the results achieved so far, we recommend that clonidine should be routinely tested for intrathecal drug administration, especially in patients with a prominent neuropathic pain component.

Topics: Adrenergic alpha-Agonists; Adult; Aged; Analgesics; Analgesics, Opioid; Buprenorphine; Chronic Disease; Clonidine; Drug Therapy, Combination; Female; Humans; Infusion Pumps, Implantable; Injections, Spinal; Male; Middle Aged; Morphine; Pain; Pain Measurement

The effectiveness of a balanced analgesia with buprenorphine ketoprofen-propacetamol for pain control during extracorporeal shock wave lithotripsy (ESWL) was evaluated in order to reduce the requirements for general anaesthesia. Two hundred and ninety-one consecutive patients were included in a randomized, placebo-controlled, double-blind study. Patients in each group received midazolam 5 mg pre-operatively as premedication. The subjects then received either placebo (group 1), buprenorphine 0.3 mg (group 2) or the combination buprenorphine 0.3 mg plus ketoprofen 100 mg and propacetamol 2 g (group 3) intravenously (i.v.) at a constant rate. The treatment was started 45 min prior to ESWL. Pain was assessed using a three-point verbal scale: (0)no pain; (1) moderate pain; and (2) intense pain needing general anaesthesia. The patients assessed their pain intensity on a 0-100 mm visual analogue scale. Only 69% of group 1 patients received ESWL with midazolam premedication. Buprenorphine provided good analgesia in 87% of group 2 patients, while the combination buprenorphine-ketoprofen-propacetamol was effective in 99% of group 3 patients (P < 0.05). The incidence of nausea and vomiting was similar in the buprenorphine groups. No respiratory depression was reported. In conclusion, the buprenorphine-ketoprofen-propacetamol combination provided effective analgesia, allowing ESWL to be performed without the need for general anaesthesia.

Topics: Acetaminophen; Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Non-Narcotic; Analgesics, Opioid; Anesthesia, General; Buprenorphine; Double-Blind Method; Female; Humans; Ketoprofen; Kidney Calculi; Lithotripsy; Male; Middle Aged; Pain; Pain Measurement; Premedication

Clinical recommendations for analgesics in laboratory rodents are usually derived from basic research. However, animal models of pain often involve withdrawal reflexes evoked by threshold-level stimuli, whereas pain associated with surgery or disease involves injury and inflammation. Moreover, the analgesics used in research tend to be chosen as exemplars of a drug class, without regard for whether the route of administration is practical, whether the drug has useful kinetics or whether the side effects are tolerable. This paper provides data on the efficacy of drugs from four classes, using the formalin test as a model of injury-induced pain. Formalin (50 microliters, 2.5 per cent) was injected subcutaneously into a rat's paw and the behavioural response (lifting or licking of the paw) was recorded. Buprenorphine at 0.1 mg/kg and dipyrone at 200 mg/kg completely suppressed the pain responses. When formalin was injected six hours after buprenorphine or dipyrone, pain scores were 30 per cent of control scores. In the absence of pain and handling, 0.6 mg/kg buprenorphine was lethal to 25 per cent of rats. Locomotor activity was slightly depressed by 300 mg/kg dipyrone. Xylazine at 2 mg/kg suppressed pain responses, but the analgesia had decreased to less than 50 per cent after two hours and the effects were variable thereafter; at 8 mg/kg rats were unresponsive to a strong pinch. Acepromazine at 2.5 mg/kg reduced pain to 20 per cent of control scores and this level of analgesia was maintained for six hours; neuroleptic effects were prominent at 5 mg/kg.

Topics: Acepromazine; Adjuvants, Anesthesia; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Dipyrone; Dose-Response Relationship, Drug; Formaldehyde; Male; Motor Activity; Narcotic Antagonists; Pain; Pain Measurement; Rats; Xylazine

Opioid analgesics represent one of the most important tools in a sequential pharmacological approach to oncological pain relief. They are recommended by the WHO when nonsteroidal anti-inflammatory drugs (NSAIDs) no longer provide adequate analgesia. However, the use of opioids is limited because of their numerous and often severe adverse effects. This aspect of opioids has motivated continuous research projects aimed at discovering drugs that can provide maximum pain relief but with improved tolerability. Tramadol is a new, centrally acting analgesic with a dual mechanism of action. It shows a selective interaction with mu receptors, which are responsible for nociception, and has weak pharmacodynamic activity on other opioid receptors. At the same time, it acts synergistically on neuroamine transmission by inhibiting synaptic noradrenaline (norepinephrine) reuptake and inducing intrasynaptic serotonin (5-hydroxytryptamine; 5-HT) release. From a pharmacokinetic standpoint, tramadol offers high bioavailability, with similar patterns after oral or parenteral administration (half-life 5 to 7 hours, time to peak plasma concentration 3.1 hours, and approximately 20% plasma protein binding). Although the efficacy of tramadol is comparable to that of other drugs with similar modes of action, the incidence of side effects such as constipation and respiratory depression is lower. The frequency of euphoria and dysphoria is negligible, resulting in little risk of abuse or dependence. It therefore seemed appropriate to further investigate the efficacy and tolerability of tramadol, defined as having only weak potency, in comparison with a widely used opioid, in oncological pain. Buprenorphine was selected as an opioid with a potency equivalent to half that of morphine, but with tolerability that is partially limited by the fact that it frequently gives rise to adverse reactions considered typical of stronger opioids. To compare the analgesic effect and tolerability of tramadol and buprenorphine, 60 patients (44 men, 16 women; average age 61.4 years), all presenting with advanced tumours, were treated orally in a controlled crossover trial with randomised sequences. Patients took both drugs, each for a week, with a 24-hour washout period between treatments. Tramadol was prescribed at the daily dose of 300mg, orally, and buprenorphine at 0.6 mg/day, as a sublingual preparation. Assessments were made of Karnofsky performance status and severity of pain before and during t

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; Analysis of Variance; Buprenorphine; Female; Humans; Male; Middle Aged; Neoplasms; Pain; Tramadol

In this multicentre trial tramadol and buprenorphine were compared for the treatment of neoplastic pain no longer responsive to non-steroidal antiinflammatory drugs. A total of 131 adults (86 M, 45F) were treated with tramadol (one 100-mg slow-release tablet every 8-12 h), or buprenorphine (one sublingual 0.2-mg tablet every 6-8 h). The trial was to continue for up to six months. Most patients started treatment with 2-3 tablets/day in both groups, and the mean treatment period was 58 days for tramadol and 51 for buprenorphine. Almost all dose changes needed were made in the first fortnight in both treatment groups, and the largest number of patients dropped out because of inadequate pain relief or progression of the underlying disease. The results achieved in the first two weeks persisted throughout the rest of the trial, and the investigator's assessments on each patient's clinical chart corresponded closely with those that patients made in their own daily diaries. In the four hours after the first dose both drugs virtually halved the severity of pain (measured using a visual analogue scale), and this relief lasted throughout treatment. By the end of the first week the proportion of patients with strong/unbearable pain in the tramadol group had fallen significantly (from 98.4% to 48.1%, p < 0.05), as compared to a drop from 92% to 66.7% for buprenorphine. The quality of sleep also tended to improve in the tramadol group, with the proportion of patients enjoying good or deep sleep rising from 37% to 50%, as compared to 33% to 40-44% with buprenorphine. Karnofsky's and Spitzer's indices reflecting the quality of life did not change in the tramadol group; in the buprenorphine group the Karnofsky index dropped slightly after a fortnight (p < 0.05 between treatments). In the first two months of the trial the number of patients with no/moderate pain rose continuously in the tramadol group (71% and 80% after one and two months); the rise was less marked in the buprenorphine group (number of patients with mild/moderate pain, 45% and 65%). In both the short term and in the longer term, it was found that the levels of efficacy and acceptability were always significantly better in the tramadol group than in the buprenorphine group. General and biological safety in both drugs was good. The most typical side-effects were those characteristic of opioids (nausea and/or vomiting, drowsiness). Adverse reactions were reported in 17 patients taking tramadol (25%) and in 16

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Female; Humans; Karnofsky Performance Status; Male; Middle Aged; Neoplasms; Pain; Pain Measurement; Patient Compliance; Patient Satisfaction; Tablets; Tramadol

The time has come to evaluate critically our practice of cancer pain management and the assumptions on which it is based. We owe it to our patients to maximize the quality of their lives and to provide evidence for them that is based on a scientific approach rather than anecdotal experience. From the information available, opioids do have effects on cognitive and psychomotor function, and although many of these effects diminish once the patient is on a stable dose, the evidence suggests that baseline pretreatment levels are not achieved. In addition, the relationship between measurable effects and the performance of everyday tasks such as driving is unclear. The challenge we now face is to continue the improvements in cancer pain control achieved over the last 25 years. The management of the central adverse effects of opioids must be focused on accurate assessment and careful titration of opioids against pain. Adjuvant analgesic drugs and non-drug measures should be used whenever possible, and drugs should be chosen that will not contribute to existing difficulties. The appropriate use of psychostimulants has yet to be established as has the relative benefit of one opioid over another in cancer pain.

Topics: Adult; Amphetamines; Analgesics, Opioid; Buprenorphine; Central Nervous System Stimulants; Chronic Disease; Cocaine; Codeine; Cognition; Dextropropoxyphene; Dopamine Uptake Inhibitors; Humans; Methylphenidate; Morphine; Neoplasms; Pain; Psychomotor Performance; Randomized Controlled Trials as Topic; Reaction Time; Thiazoles

Topics: Administration, Oral; Administration, Sublingual; Adult; Aged; Aged, 80 and over; Buprenorphine; Drug Therapy, Combination; Drug Tolerance; Female; Humans; Male; Middle Aged; Morphine; Neoplasms; Pain; Pain Measurement; Prospective Studies

The efficacy of phenytoin (PHT), buprenorphine (Bu), and Bu+PHT for the relief of cancer pain of various etiologies was evaluated in a randomized, double-blind study of 3 groups, each comprised of 25 patients. Treatment duration was 1 month. PHT (100 mg by mouth twice daily) provided greater than 50% pain relief to 18 patients (72%) and greater than 75% relief to 4 (16%). Bu (0.2 mg sublingually twice daily) gave 21 patients (84%) greater than 50% relief and 15 patients (60%) greater than 75% relief. Of the Bu-treated patients, 8 had major side effects, while none of the PHT-treated patients experienced significant untoward reactions. Combined therapy (PHT, 50 mg PO+Bu 0.1 mg SL twice daily) provided greater than 50% pain relief to 22 patients (88%) and greater than 75% to 18 (72%); only 3 patients experienced a significant side effect. This study suggests that phenytoin has mild-to-moderate pain-relieving properties of its own and can significantly enhance buprenorphine analgesia. By permitting a lower opioid dose, it may reduce the occurrence of opioid-related side effects. PHT's lack of serious side effects, as well as its documented anxiolytic and antidepressant actions, may add to its comparative usefulness. Further clinical trials of PHT as a coanalgesic and/or adjuvant agent in cancer pain are warranted.

Topics: Adult; Buprenorphine; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Neoplasms; Pain; Phenytoin

The aim of the present study has been to assess the responsiveness of various types of chronic pain to opioids given i.v. and tested against placebo in a double-blind, randomized fashion. Pain classified as primary nociceptive was effectively alleviated (P greater than 0.001) while neuropathic deafferentation pain was not significantly influenced by morphine or equivalent doses of other opioids. Also 'idiopathic' pain, defined as chronic pain with no or little demonstrable pathology, failed to respond. The results were not related to whether the patients were regular users of narcotic analgesics or not. The outcome of our double-blind opioid test has proved useful to justify a continued, or discontinued, use of narcotic medication in individual patients. It may also support the indication and choice of invasive stimulation procedures (spinal cord or brain). The results of the study illustrate the misconception of chronic pain as an entity and highlight the importance of recognizing different neurobiological mechanisms and differences in responsiveness to analgesic drugs as well as to non-pharmacological modes of treatment. The opioid test has thus become a valuable tool in pain analysis and helpful as a guide for further treatment.

Topics: Analgesics; Buprenorphine; Chronic Disease; Endorphins; Female; Humans; Male; Morphine; Nervous System Diseases; Nociceptors; Pain; Pain Measurement; Pain, Intractable; Palliative Care; Transcutaneous Electric Nerve Stimulation

Topics: Adrenocorticotropic Hormone; Adult; Aldosterone; Anesthesia, General; Buprenorphine; Enflurane; Female; Humans; Hydrocortisone; Isoflurane; Male; Middle Aged; Pain; Prolactin; Radioimmunoassay

In a randomized cross-study analgesic activity and side effects of two narcotics, buprenorphine and pentazocine, administered orally in 91 advanced cancer patients whose pain intensity varied from moderate to severe, have been compared. The number of hours of sleep and hours standing after administration of both the drugs were also assessed and in 16 patients life activity was taken into consideration. The analysis of data showed: a better pain control with buprenorphine, than with pentazocine, with a statistically significant difference of P less than 0.001; an increase in the number of hours of sleep with buprenorphine, in comparison with pentazocine, with P less than 0.001; an increase in the number of hours standing with buprenorphine, in comparison with pentazocine; as for side effects, many more patients had to stop treatment with pentazocine than with buprenorphine.

Topics: Administration, Oral; Buprenorphine; Clinical Trials as Topic; Humans; Neoplasms; Pain; Pentazocine; Random Allocation; Time Factors

We have tested the usefulness of the critical flicker fusion threshold-test (CFF), Maddox wing readings (MW), and visual analogue scale scores (VAS) in a double-blind, random-order study designed to evaluate the clinical effects of two different kinds of opiates, buprenorphine and fentanyl in comparison with those of placebo. The results were compared with the so-called postanaesthetic recovery score (PARS). In 7 healthy volunteers MW and VAS differentiated the effects of buprenorphine 7.5 micrograms/kg i.v. from those of fentanyl 2.5 micrograms/kg i.v. and placebo. CFF was very insensitive in this respect and PARS completely useless. Our results show that, in addition to the known usefulness of VAS, MW is also able to differentiate the effects of these opiates.

Topics: Adult; Blood Pressure; Buprenorphine; Female; Fentanyl; Flicker Fusion; Heart Rate; Humans; Hypnotics and Sedatives; Male; Pain; Psychomotor Performance

Twelve patients with intense or very intense pain of the non-incident type, secondary to neoplasia, were divided at random into two groups and treated with an epidural dose of 3 mg of morphine in 10 ml of glucose solution (6 patients = group M) or with 0.3 mg of buprenorphine in the same vehicle (6 patients = group B). None of the patients had previously been treated with opioids by any route. After first determining basal values, the following assessments were carried out: (1) evaluation of the analgesic effect of the drugs with checks at 30 min and at 1, 2, 3, 4, 6 and 18 h after administration, using a visual analogue scale, a numerical rating scale and a simple descriptive scale; and (2) evaluation of effects on respiration by means of checks at 30 and 90 min and at 6 and 18 h, on control of breathing indices (P0.1; VE; VA; Ti/Ttot; VT/Ti; RR), gas exchange indices (delta(A-a)O2; VD/VT; pAO2; R) and blood gas and acid-base indices (paO2; paCO2; pH; HCO3-). The data obtained were analyzed statistically using analysis of variance and Student's t test. The study results showed very similar analgesic efficacy for both treatments at a single dosage level of morphine (3 mg) compared to buprenorphine (0.3 mg), which was approximately 3 times greater than an equivalent parenteral dose of morphine (10 mg). Analysis of the results revealed statistically, though not clinically, significant changes in respiratory function indices, only in the buprenorphine-treated group. The effects of buprenorphine on respiratory function, when administered epidurally at the above dosage, are less favourable than those of morphine in the early measurements, probably because of its greater systemic absorption; nevertheless, the risk of delayed respiratory depression appears to be less after buprenorphine than after morphine.

Topics: Aged; Buprenorphine; Double-Blind Method; Female; Humans; Injections, Epidural; Male; Middle Aged; Morphine; Neoplasms; Pain; Prospective Studies; Pulmonary Gas Exchange; Random Allocation; Respiration

Topics: Buprenorphine; Clinical Trials as Topic; Double-Blind Method; Humans; Morphinans; Pain; Pain, Postoperative

Sixty patients suffering from moderate to severe pain following either orthopaedic or gynaecological surgery were treated with intramuscular buprenorphine (0.3 mg) or an intramuscular combination of buprenorphine (0.3 mg)/naloxone (0.2 mg) and the analgesic efficacy and safety of the two treatments was compared. The evaluation of efficacy showed that both treatments provided good analgesia which was apparent at the first assessment time (10 minutes) and continued for approximately 10 hours. Only seven patients suffered from unwanted side-effects with only drowsiness/sleepiness and nausea being reported by more than one patient. Over-all analysis of the results showed that there were no significant differences between the two treatments with regard to efficacy and safety.

Topics: Adolescent; Adult; Aged; Analgesia; Buprenorphine; Drug Therapy, Combination; Female; Humans; Kinetics; Male; Middle Aged; Morphinans; Naloxone; Pain; Postoperative Complications

Buprenorphine appears to have an analgesic effect (evaluated after a week of treatment) statistically superior to that of the comparative drug. On the whole, during buprenorphine treatment the normal activities of life of the individual patient improved. The percentage incidence of the side-effects is similar for the two drugs. Buprenorphine, however, caused less intense side-effects than pentazocine.

Topics: Adult; Aged; Buprenorphine; Humans; Middle Aged; Morphinans; Neoplasms; Pain; Pentazocine; Time Factors

Topics: Buprenorphine; Clinical Trials as Topic; Epidural Space; Humans; Injections; Morphinans; Morphine; Narcotics; Pain; Time Factors

Morphine chlorhydrate and buprenorphine chlorhydrate are given intramuscularly at increasing doses to patients suffering from intense pain in the facial or trigeminal nerves territory. No other drugs are used. The diverses groups of ten patients received respectively: --morphine: 0.100, 0.150, 0.200 mg/kg; --buprenorphine: 0.0015, 0.003, 0.006 mg/kg. On the whole, the analgesia is induced after a short time and is more durable, more intense as the dose is increased. Yet, concerning buprenorphine, the analgesia is not more intense with the 0.006 mg/kg dose, than with the 0.003 mg/kg dose. This phenomenon, if confirmed, would be an important limitation for the clinical use of this drug. For equianalgesic doses buprenorphine and morphine give an analgesia similar in time of initiation and in duration.

Topics: Aged; Buprenorphine; Female; Humans; Male; Middle Aged; Morphinans; Morphine; Pain

1 Buprenorphine is a new antagonist analgesic which was offered sublingually to 141 patients with moderate cancer pain as an alternative to their current analgesic. These patients were not on regular strong morphine-like analgesics. 2 Forty-seven patients used the drug on demand in unit doses ranging from 0.15-0.8 mg for an average of 12 weeks. A full-time nurse-observer was used throughout the studies. 3 Good analgesic results were obtained. Certain difficult chronic dull aching pains in the head and neck were especially helped by the drug. There was no indication of dependence or tolerance in this study. 4 The main side-effect was drowsiness which lessened with usage of the drug. A major advantage of the drug was the absence of constipation as a side-effect. 5 This sublingual preparation seems worthy of addition to the commercially available range of analgesics in clinical practice.

Topics: Buprenorphine; Clinical Trials as Topic; Humans; Morphinans; Neoplasms; Pain

This study explored the effect of transdermal buprenorphine on quality of life and six symptoms in cancer patients with pain.. Transdermal opioids offer advantages over traditional routes of administration. The impact of transdermal buprenorphine on quality of life for patients with cancer in Asian populations is unknown.. This study employed a single-arm observational repeated measures design. Cancer patients with pain were evaluated prior to treatment (baseline). Over a 4-week treatment period, quality of life and symptoms were assessed at 2 and 4 weeks. This study adhered to the recommendations of STROBE guidelines.. This multi-site study was conducted in six hospitals located across northern, middle and southern Taiwan. Adult cancer patients whose pain was previously stable with opioid analgesics and, based on clinical judgement, were able to convert to transdermal buprenorphine treatment were invited to participate. Quality of life was measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30).. Generalised estimating equations showed participants who completed at least one follow-up measurement (N = 80) over 4-weeks had a significant improvement in overall quality of life. Functional status only improved for social functioning. However, symptom severity decreased significantly for nausea/vomiting, pain, insomnia and constipation.. The study provides initial evidence supporting transdermal buprenorphine for providing beneficial effects of improving quality of life and reducing severity of symptoms in Asian patients with cancer.. The findings of this study can inform the clinical practice that the use of transdermal buprenorphine in cancer patients with pain may also reduce the severity of other symptoms and improve overall quality of life.. This study was registered in ClinicalTrials.gov. Identifier: NCT04315831.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Humans; Neoplasms; Pain; Quality of Life

Buprenorphine is one of the strongest opioids used for the relief of cancer pain. This study aims to evaluate the real-world clinical experiences of transdermal buprenorphine used in moderate to severe cancer pain in the Asian population.. This is an open-labeled, multicenter, 4-week observational study. Stable cancer pain patients who decided to switch the previous opioid to transdermal buprenorphine will be enrolled in this study. The safety and effectiveness were observed and collected. Pain assessment was performed using a numerical rating scale by the investigators and the Brief Pain Inventory Short Form (BPI-SF) by the patient. The safety profiles included concomitant medications and adverse events (AEs).. A total of 83 patients were enrolled in this study. The global pain scores in the BPI, as well as the four individual pain parameters (worst, least, average, and right now), showed a continued decrease (p < .05) from week 2 to week 4. Significant improvements were observed in normal work activities, relations with other people, sleep, enjoyment of life, and global BPI pain interference score on week 4. Pain assessments conducted by investigators demonstrated significant, continuous improvements during the study periods. In addition, transdermal buprenorphine demonstrated good safety/tolerability with limited drug-related AEs in the Asian population with cancer pain.. This study demonstrated that transdermal buprenorphine in the Asian population has good safety profiles and continued improvements in pain relief, sleep, and pain interferences. Transdermal buprenorphine can be an effective and convenient option as a transdermal opioid for patients with moderate to severe cancer pain in Taiwan. (NCT Number: NCT04315831).

Topics: Analgesics, Opioid; Buprenorphine; Cancer Pain; Humans; Neoplasms; Pain; Taiwan

Buprenorphine is a frequently used medication for opioid use disorder and misunderstanding buprenorphine's unique pharmacology has historically complicated perioperative analgesia. The purpose of this study was to evaluate the association of perioperative buprenorphine continuation in patients with substance use disorder on perioperative opioid use.. This was a single-center retrospective study at a level 1 trauma academic medical center. Adult patients using outpatient buprenorphine for medication for opioid use disorder admitted with an operating room booking were included. Patients were grouped (continuation, withheld) retrospectively based upon the decision to continue or omit buprenorphine therapy while admitted. The primary outcome of the study was any use of full mu-opioid agonists during days 1-7 of admission. Secondary outcomes included length of stay and average pain scores during days 1-7 of admission.. 43.4% of patients in the continuation cohort used no full mu-opioid agonists during days 1-7 compared to 3.1% of patients in the withheld cohort (P < 0.001). No significant difference in median length of stay was noted (4.7 d [2.8-6.6] versus 6.1 d [4.0-8.2], P = 0.36). There was no statistical difference in average pain scores on postoperative days 1 (5.2 versus 6.9, P = 0.82) and 7 (0 versus 0, P = 0.41).. Perioperative continuation of buprenorphine is associated with reduced use of alternative full mu-opioid agents while admitted without impacting pain scores.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Humans; Opioid-Related Disorders; Pain; Retrospective Studies

Prior research suggests a potential relationship between the nonmedical use of gabapentin and use of opioid agonist medications (OAMs), buprenorphine and methadone. However, this research has been limited in scope and understanding despite increases in gabapentin prescribing in opioid use disorder (OUD) treatment settings and increased detection in opioid overdose fatalities.. Data were analyzed for 346 participants of a follow-up program to an ongoing national opioid surveillance program of new entrants to treatment for opioid use disorder. Data were sourced from a cross-sectional online survey distributed in July/August 2021.. Lifetime exposure to gabapentin was reported by 60.0 % of the sample, while lifetime history of nonmedical use was reported by 43.2 %. Of those nonmedically using gabapentin, 50.0 % did so while also on a dosage of either buprenorphine or methadone, with 28.4 % engaged in concurrent nonmedical use of both gabapentin and OATs. Motivations for concurrent nonmedical use included high-seeking (38.6 %), self-management of pain/physical symptoms (33.3 %), and self-management of OUD (22.2 %).. Gabapentin exposure in treatment-seeking persons with OUD appears to be quite common, and use, both medically and nonmedically, frequently occurs alongside OAMs. Motivations for concurrent nonmedical use of gabapentin and OATs mirrors motivations for off-label prescribing by healthcare providers, but may also serve as a form of self-management of OUD when OAM regimens are interrupted, insufficiently prescribed or prescribed at insufficient dosages. Further research should seek to understand the risks versus benefits of gabapentin in OAM treatment settings.

Topics: Analgesics, Opioid; Buprenorphine; Cross-Sectional Studies; Gabapentin; Humans; Methadone; Motivation; Opiate Substitution Treatment; Opioid-Related Disorders; Pain

A mindfulness-based intervention that reduces comorbid pain, anxiety, and substance use during office-based opioid treatment (OBOT) could enhance retention and prevent overdose. We conducted a pilot study of the Mindful Recovery OUD Care Continuum (M-ROCC), a 24-week trauma-informed program with a motivationally-sensitive curriculum.. Patients prescribed buprenorphine (N = 18) enrolled in M-ROCC. We collected urine toxicology biweekly. At 0, 4, and 24 weeks, participants completed PROMIS-Pain, PROMIS-Anxiety, Mindfulness (FFMQ), Experiential Avoidance (BEAQ), Interoceptive Awareness (MAIA), and Self-Compassion (SCS-SF) scales. We estimated changes over time using mixed models. Participants completed qualitative interviews at 4 and 24 weeks.. Positive urine toxicology decreased over time for cocaine (β = -.266, p = .008) and benzodiazepines (β = -.208, p = .028). M-ROCC reduced PROMIS-Pain (Z = -2.29; p = .022), BEAQ (Z = -2.83; p = .0005), and increased FFMQ (Z = 3.51; p < .001), MAIA (Z = 3.40; p = .001), and SCS-SF (Z = 2.29; p = .022). Participants with co-morbid anxiety had decreased PROMIS-Anxiety (Z = -2.53; p = .012). Interviewed participants commonly used mindfulness practices for stress and anxiety (12/12, 100%), and to reduce pain catastrophizing and rumination (7/12, 58%).. This is the first study to report the effects of a 24-week mindfulness program during buprenorphine treatment on common comorbidities, including pain interference, anxiety, cocaine, and benzodiazepine use. The findings that M-ROCC is associated with reduced experiential avoidance, as well as increased interoceptive awareness and self-compassion, align with proposed mechanisms that are now extended to OUD treatment. Future larger randomized controlled trials are needed before effectiveness can be established and the role of these mechanisms can be confirmed.

Topics: Anxiety; Buprenorphine; Cocaine; Humans; Mindfulness; Pain; Pilot Projects; Primary Health Care; Substance-Related Disorders

Limited information exists regarding individual subgroups of recovery from opioid use disorder (OUD) following treatment and how these subgroups may relate to recovery trajectories. We used multi-dimensional criteria to identify OUD recovery subgroups and longitudinal transitions across subgroups.. In a national longitudinal observational study in the United States, individuals who previously participated in a clinical trial for subcutaneous buprenorphine injections for treatment of OUD were enrolled and followed for an average of 4.2 years after participation in the clinical trial.. We identified recovery subgroups based on psychosocial outcomes including depression, opioid withdrawal and pain. We compared opioid use, treatment utilization and quality of life among these subgroups.. Three dimensions of the recovery process were identified: depression, opioid withdrawal and pain. Using these three dimensions, participants were classified into four recovery subgroups: high-functioning (minimal depression, mild withdrawal and no/mild pain), pain/physical health (minimal depression, mild withdrawal and moderate pain), depression (moderate depression, mild withdrawal and mild/moderate pain) and low-functioning (moderate/severe withdrawal, moderate depression and moderate/severe pain). Significant differences among subgroups were observed for DSM-5 criteria (P < 0.001) and remission status (P < 0.001), as well as with opioid use (P < 0.001), treatment utilization (P < 0.001) and quality of life domains (physical health, psychological, environment and social relationships; Ps < 0.001, Cohen's fs ≥ 0.62). Recovery subgroup assignments were dynamic, with individuals transitioning across subgroups during the observational period. Moreover, the initial recovery subgroup assignment was minimally predictive of long-term outcomes.. There appear to be four distinct subgroups among individuals in recovery from OUD. Recovery subgroup assignments are dynamic and predictive of contemporaneous, but not long-term, substance use, substance use treatment utilization or quality of life outcomes.

Topics: Analgesics, Opioid; Buprenorphine; Humans; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Quality of Life; Substance Withdrawal Syndrome; United States

Patients with opioid use disorder (OUD) may experience inadequate pain management especially during childbirth. This study assessed and compared patient and provider perspectives on analgesia during and after delivery in women with OUD.. Prospective cohort, mixed method design including semi-structured interviews and structured surveys with pregnant or recently pregnant patients (n = 17) and provider (n = 15) groups.. Prenatal clinics and hospital postpartum units.. Patients were pregnant women with OUD currently treated with methadone (n = 1) or buprenorphine (n = 16). Providers were obstetricians (n = 5), obstetric nurses (n = 5) and anesthesiologists (n = 5).. Validated questionnaires were completed by both groups; patient interviews were conducted during the third trimester and at 5 days post-delivery. Patient topics included pain management preferences, analgesia satisfaction and attitudes toward pain. Provider topics included labor and postpartum pain management perspectives. Interviews were independently coded and qualitatively analyzed for major themes.. Five major themes emerged from patient interviews: (1) neuraxial blockade was endorsed for labor pain; (2) otherwise, limited pain control options were perceived; (3) no consensus around use of opioids for pain; (4) non-opioid options should be available; and (5) provider communication and health-care system issues act as barriers to adequate pain management. Provider perspective themes included the following: (1) unique challenges in pain management for patients with OUD; (2) confusion on how to plan for and make perinatal adjustments to medication for OUD; (3) discrepant views on use of opioids for pain management; (4) endorsement of non-pharmacological and non-opioid options; and (5) need for improved provider collaboration in developing pain management plans.. Patients with opioid use disorder and health-care providers prioritize pain management during and after childbirth, but have discrepant views on use of opioids and other pain management options. Inadequate care coordination and discrepancies in opinions need to be addressed both within care teams and between patients and providers. Clinicians would benefit from better evidence to guide clinical care of patients with OUD for patient-centered pain management.

Topics: Analgesics, Opioid; Buprenorphine; Female; Humans; Opioid-Related Disorders; Pain; Pain Management; Pregnancy; Pregnant Women; Prospective Studies

Medications for opioid use disorder (MOUD) are a life-saving intervention; thus, it is important to address barriers to successful initiation. Spasticity affects many patients with spinal cord injury and can be painful and physically debilitating. Chronic painful conditions can lead to the illicit use of non-prescribed opioids, but fear of pain is a barrier to the initiation of MOUD. In this case report, we describe the novel use of botulinum toxin A injections to treat abdominal spasticity and facilitate Acute Pain Service-led buprenorphine/naloxone initiation in a patient with opioid use disorder and severe abdominal spasticity due to spinal cord injury.. A patient with C4 incomplete tetraplegia and opioid use disorder complicated by abdominal spasticity refractory to oral antispasmodics and self-treating with intravenous heroin was referred to the Acute Pain Service for inpatient buprenorphine/naloxone initiation. The patient began to fail initiation of buprenorphine/naloxone secondary to increased pain from abdominal spasms. The patient was offered ultrasound-guided abdominal muscle chemodenervation with botulinum toxin A, which resulted in the resolution of abdominal spasticity and facilitated successful buprenorphine/naloxone initiation. At 6 months post-initiation, the patient remained abstinent from non-prescribed opioids and compliant with buprenorphine/naloxone 8 mg/2 mg three times a day.. This case report demonstrates that inpatient buprenorphine/naloxone initiation by an Acute Pain Service can improve the success of treatment by addressing barriers to initiation. Acute Pain Service clinicians possess unique skills and knowledge, including ultrasound-guided interventions, that enable them to provide innovative and personalized approaches to care in the complex opioid use disorder population.

Topics: Analgesics, Opioid; Anesthesia, Conduction; Botulinum Toxins, Type A; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Humans; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Pain Clinics

Long-acting injectable buprenorphine (LAIB) is a new treatment for opioid use disorder that is generating positive outcomes. Negative effects are typically mild and transient, but can occasionally be serious, resulting in treatment discontinuation/non-adherence. This paper aims to analyse patients' accounts of how they felt during the first 72 h after initiating LAIB.. Semi-structured interviews were conducted (June 2021-March 2022) with 26 people (18 males and 8 females) who had started LAIB within the previous 72 h. Participants were recruited from treatment services in England and Wales and were interviewed by telephone using a topic guide. Interviews were audio-recorded, transcribed and coded. The concepts of embodiment and embodied cognition framed the analyses. Data on participants' substance use, initiation onto LAIB and feelings were tabulated. Next, participants' accounts of how they felt were analysed following the stages of Iterative Categorization.. Participants reported complex combinations of changing negative and positive feelings. Bodily experiences included withdrawal symptoms, poor sleep, injection-site pain/soreness, lethargy and heightened senses inducing nausea ('distressed bodies'), but also enhanced somatic wellbeing, improved sleep, better skin, increased appetite, reduced constipation and heightened senses inducing pleasure ('returning body functions'). Cognitive responses included anxiety, uncertainties and low mood/depression ('the mind in crisis') and improved mood, greater positivity and reduced craving ('feeling psychologically better'). Whereas most negative effects reported are widely recognized, the early benefits of treatment described are less well-documented and may be an overlooked distinctive feature of LAIB.. During the first 72 h after initiating long-acting injectable buprenorphine, new patients report experiencing a range of interconnected positive and negative short-term effects. Providing new patients with information about the range and nature of these effects can prepare them for what to expect and help them manage feelings and reduce anxiety. In turn, this may increase medication adherence.

Topics: Analgesics, Opioid; Buprenorphine; Emotions; Female; Humans; Male; Medication Adherence; Opiate Substitution Treatment; Opioid-Related Disorders; Pain

Patients with opioid use disorder (OUD) frequently leave the hospital as patient directed discharges (PDDs) because of untreated withdrawal and pain. Short-acting opioids can complement methadone, buprenorphine, and non-opioid adjuvants for withdrawal and pain, however little evidence exists for this approach. We described the safety and preliminary outcomes of short-acting opioid agonist treatment (sOAT) for hospitalized patients with OUD at an academic hospital in Philadelphia, PA.. From August 2021 to March 2022, a pharmacist guided implementation of a pilot sOAT protocol consisting of escalating doses of oxycodone or oral hydromorphone scheduled every four hours, intravenous hydromorphone as needed, and non-opioid adjuvants for withdrawal and pain. All patients were encouraged to start methadone or buprenorphine treatment for OUD. We abstracted data from the electronic health record into a secure platform. The primary outcome was safety: administration of naloxone, over-sedation, or a fall. Secondary outcomes were PDDs and respective length of stay (LOS), discharges on methadone or buprenorphine, and discharges with naloxone. We compared secondary outcomes to hospitalizations in the 12 months prior to the index hospitalization among the same cohort.. Of the 23 cases, 13 (56.5%) were female, 19 (82.6%) were 40 years or younger, and 22 (95.7%) identified as White. Twenty-one (91.3%) regularly injected opioids and four (17.3%) were enrolled in methadone or buprenorphine prior to hospitalization. sOAT was administered at median doses of 200-320 morphine milligram equivalents per 24-h period. Naloxone administration was documented once in the operating room, over-sedation was documented once after unsanctioned opioid use, and there were no falls. The PDD rate was 44% with median LOS 5 days (compared to PDD rate 69% with median LOS 3 days for prior admissions), 65% of sOAT cases were discharged on buprenorphine or methadone (compared to 33% for prior admissions), and 65% of sOAT cases were discharged with naloxone (compared to 19% for prior admissions).. Pilot implementation of sOAT was safe. Compared to prior admissions in the same cohort, the PDD rate was lower, LOS for PDDs was longer, and more patients were discharged on buprenorphine or methadone and with naloxone, however efficacy for these secondary outcomes remains to be established.

Topics: Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Female; Humans; Hydromorphone; Male; Methadone; Naloxone; Opiate Substitution Treatment; Opioid-Related Disorders; Pain

Patients with opioid use disorder may be asked by their clinicians to discontinue maintenance buprenorphine treatment before surgical operations due to concerns that buprenorphine will interfere with acute pain management. However, discontinuation of buprenorphine may not be well tolerated or safe for all patients. We, therefore, administered a survey to better understand the experiences of patients on buprenorphine treatment who had previously undergone painful procedures and had their buprenorphine maintenance treatment either continued or discontinued before the procedure.. After this study received institutional review board approval, patients were invited to participate if they were being prescribed sublingual buprenorphine for treatment of opioid use disorder and had also previously undergone a painful procedure requiring treatment with full agonist opioids. Patients who were eligible and agreed to participate (n = 32) then completed a survey of basic demographics; medical, psychiatric, and substance use histories; and their experience and satisfaction with the treatment of pain and substance use in the perioperative period, including whether buprenorphine was continued or discontinued before their procedure.. Compared with patients whose home dose of buprenorphine was continued (n = 15), patients whose buprenorphine was discontinued preoperatively (n = 17) reported less satisfaction with pain management and were more likely to be prescribed full agonist opioids upon discharge.. Consistent with prior studies, these survey findings suggest that discontinuation of buprenorphine before painful surgeries may be associated with poorer clinical outcomes.. This survey study adds patients' perspective to a growing body of scientific literature suggesting that discontinuation of maintenance buprenorphine treatment before painful procedures may decrease patient satisfaction and increase clinical risk.

Topics: Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Humans; Opioid-Related Disorders; Pain

Adequate pain management is essential for ethical and scientific reasons in animal experiments and should completely cover the period of expected pain without the need for frequent re-application. However, current depot formulations of Buprenorphine are only available in the USA and have limited duration of action. Recently, a new microparticulate Buprenorphine formulation (BUP-Depot) for sustained release has been developed as a potential future alternative to standard formulations available in Europe. Pharmacokinetics indicate a possible effectiveness for about 72 h. Here, we investigated whether the administration of the BUP-Depot ensures continuous and sufficient analgesia in two mouse fracture models (femoral osteotomy) and could, therefore, serve as a potent alternative to the application of Tramadol via the drinking water. Both protocols were examined for analgesic effectiveness, side effects on experimental readout, and effects on fracture healing outcomes in male and female C57BL/6N mice. The BUP-Depot provided effective analgesia for 72 h, comparable to the effectiveness of Tramadol in the drinking water. Fracture healing outcome was not different between analgesic regimes. The availability of a Buprenorphine depot formulation for rodents in Europe would be a beneficial addition for extended pain relief in mice, thereby increasing animal welfare.

Topics: Agnosia; Analgesia; Animals; Buprenorphine; Disease Models, Animal; Drinking Water; Female; Femoral Fractures; Male; Mice; Mice, Inbred C57BL; Pain; Pain Management; Tramadol

Acute pain management is challenging in trauma patients undergoing outpatient buprenorphine therapy at the time of injury due to the high binding affinity of this partial agonist. The purpose of this study was to evaluate acute pain management in admitted trauma patients with discontinued versus continued outpatient buprenorphine therapy.. This retrospective study included adult trauma patients admitted to a level-1 trauma center between January 2017 and August 2020 who were receiving buprenorphine prior to admission. Groups were defined as buprenorphine discontinued (BD) or continued (BC) during hospitalization. The primary outcome compared median daily morphine milligram equivalents between groups. Secondary outcomes utilized patient-reported numeric rating scale (NRS) scores to compare incidences of no pain (NRS 0), mild (NRS 1-3), moderate (NRS 4-6), and severe (NRS 7-10) pain.. A total of 57 patients were included (BD 37 [64.9%] and BC 20 [35.1%]). The median (interquartile range) outpatient daily buprenorphine dose was similar between groups (8 [8-16] mg versus 16 [8-16], P = 0.25). Median daily morphine milligram equivalents was significantly higher during admission in the BD group (103.7 [80.7-166] versus 67 [30.8-97.4], P = 0.002). Incidence of no pain (7.1% versus 5.7%, P = 0.283), mild (5.5% versus 4.3%, P = 0.295), moderate (20.2%, 19.8%, P = 0.855), or severe (67.2% versus 70.2%, P = 0.185) pain was similar between BD and BC groups, respectively.. Continuation of outpatient buprenorphine therapy in acute trauma patients is associated with decreased daily opioid requirements and similar analgesic efficacy compared to patients with BD. Based on our findings, trauma patients receiving outpatient buprenorphine and not requiring ventilator support may benefit from buprenorphine continuation within 48 h of initial presentation.

Topics: Adult; Buprenorphine; Humans; Morphine Derivatives; Outpatients; Pain; Pain Management; Retrospective Studies

Most people with opioid use disorder (OUD) have co-occurring substance use, which is associated with lower receipt of OUD medications (MOUD). Expanding MOUD provision and care linkage outside of substance use disorder (SUD) specialty settings is a key strategy to increase access. Therefore, it is important to understand how MOUD providers in these settings approach care for patients with co-occurring substance use. This qualitative study of Veterans Health Administration (VA) clinicians providing buprenorphine care in primary care, mental health, and pain settings aimed to understand (1) their approach to addressing OUD in patients with co-occurring substance use, (2) perspectives on barriers/facilitators to MOUD receipt for this population, and (3) support needed to increase MOUD receipt for this population.. We interviewed a purposive sample of 27 clinicians (12 primary care, 7 mental health, 4 pain, 4 pharmacists) in the VA northwest network. The interview guide assessed domains of the Tailored Implementation for Chronic Diseases Checklist. Interviews were transcribed and qualitatively analyzed using inductive content analysis.. Participants reported varied approaches to identifying co-occurring substance use and addressing OUD in this patient population. Although they reported that this topic was not clearly addressed in clinical guidelines or training, participants generally felt that patients with co-occurring substance use should receive MOUD. Some viewed their primary role as providing this care, others as facilitating linkage to OUD care in SUD specialty settings. Participants reported multiple barriers and facilitators to providing buprenorphine care to patients with co-occurring substance use and linking them to SUD specialty care, including provider, patient, organizational, and external factors.. Efforts are needed to support clinicians outside of SUD specialty settings in providing buprenorphine care to patients with co-occurring substance use. These could include clearer guidelines and policies, more specific training, and increased care integration or cross-disciplinary collaboration. Simultaneously, efforts are needed to improve linkage to specialty SUD care for patients who would benefit from and are willing to receive this care, which could include increased service availability and improved referral/hand-off processes. These efforts may increase MOUD receipt and improve OUD care quality for patients with co-occurring substance use.

Topics: Analgesics, Opioid; Buprenorphine; Humans; Mental Health; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Primary Health Care; Veterans

Medications for opioid use disorder (MOUD; methadone, buprenorphine, naltrexone) are the most effective treatments for OUD, and MOUD is protective against fatal overdoses. However, continued illegal drug use can increase the risk of treatment discontinuation. Given the widespread presence of fentanyl in the drug supply, research is needed to understand who is at greatest risk for concurrent MOUD and drug use and the contexts shaping use and treatment discontinuation.. From 2017 to 2020, Massachusetts residents with past-30-day illegal drug use completed surveys (N = 284) and interviews (N = 99) about MOUD and drug use. An age-adjusted multinomial logistic regression model tested associations between past-30-day drug use and MOUD use (current/past/never). Among those on methadone or buprenorphine (N = 108), multivariable logistic regression models examined the association between socio-demographics, MOUD type; and past-30-day use of heroin/fentanyl; crack; benzodiazepines; and pain medications. Qualitative interviews explored drivers of concurrent drug and MOUD use.. Most (79.9%) participants had used MOUD (38.7% currently; 41.2% past), and past 30-day drug use was high: 74.4% heroin/fentanyl; 51.4% crack cocaine; 31.3% benzodiazepines, and 18% pain medications. In exploring drug use by MOUD history, multinomial regression analyses found that crack use was positively associated with past and current MOUD use (outcome referent: never used MOUD); whereas benzodiazepine use was not associated with past MOUD use but was positively associated with current use. Conversely, pain medication use was associated with reduced odds of past and current MOUD use. Among those on methadone or buprenorphine, separate multivariable logistic regression models found that benzodiazepine and methadone use were positively associated with heroin/fentanyl use; living in a medium-sized city and sex work were positively associated with crack use; heroin/fentanyl use was positively associated with benzodiazepine use; and witnessing an overdose was inversely associated with pain medication use. Many participants qualitatively reported reducing illegal opioid use while on MOUD, yet inadequate dosage, trauma, psychological cravings, and environmental triggers drove their continued drug use, which increased their risk of treatment discontinuation and overdose.. Findings highlight variations in continued drug use by MOUD use history, reasons for concurrent use, and implications for MOUD treatment delivery and continuity.

Topics: Analgesics, Opioid; Benzodiazepines; Buprenorphine; Crack Cocaine; Drug Overdose; Fentanyl; Heroin; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Pharmaceutical Preparations

Hospitalizations are a vital opportunity for the initiation of life-saving opioid agonist therapy (OAT) for patients with opioid use disorder. A novel approach to OAT initiation is the use of IV buprenorphine for low dose induction, which allows patients to immediately start buprenorphine at any point in a hospitalization without stopping full agonist opioids or experiencing significant withdrawal.. This is a retrospective case series of 33 patients with opioid use disorder concurrently treated with full agonist opioids for pain who voluntarily underwent low dose induction at a tertiary academic medical center. Low dose induction is the process of initiating very low doses of buprenorphine at fixed intervals with gradual dose increases in patients who recently received or are simultaneously treated with full opioid agonists. Our study reports one primary outcome: successful completion of the low dose induction (i.e. transitioned from low dose IV buprenorphine to sublingual buprenorphine-naloxone) and three secondary outcomes: discharge from the hospital with buprenorphine-naloxone prescription, self-reported pain scores, and nursing-assessed clinical opiate withdrawal scale (COWS) scores over a 6-day period, using descriptive statistics. COWS and pain scores were obtained from day 0 (prior to starting the low dose induction) to day 5 to assess the effect on withdrawal symptoms and pain control.. Thirty patients completed the low dose induction (30/33, 90.9%). Thirty patients (30/33, 90.9%) were discharged with a buprenorphine prescription. Pain and COWS scores remained stable over the course of the study period. Mean COWS scores for all patients were 2.6 (SD 2.8) on day 0 and 1.6 (SD 2.6) on day 5. Mean pain scores for all patients were 4.4 (SD 2.1) on day 0 and 3.5 on day 5 (SD 2.1).. This study found that an IV buprenorphine low dose induction protocol was well-tolerated by a group of 33 hospitalized patients with opioid use disorder with co-occurring pain requiring full agonist opioid therapy. COWS and pain scores improved for the majority of patients. This is the first case series to report mean daily COWS and pain scores over an extended period throughout a low dose induction process.

Topics: Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Humans; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Retrospective Studies

Opioid and local anaesthetic receptors are abundantly concentrated in different layers of the skin. Therefore, simultaneous targeting of these receptors can produce more potent dermal anaesthesia. Herein, we developed lipid-based nanovesicles for the co-delivery of buprenorphine and bupivacaine to efficiently target skin-concentrated pain receptors. Invasomes incorporating two drugs were prepared by ethanol injection method. Subsequently, the size, zeta potential, encapsulation efficiency, morphology, and in-vitro drug release of vesicles were characterized. Ex-vivo penetration features of vesicles were then investigated by the franz diffusion cell on the full-thickness human skin. Wherein, it was demonstrated that invasomes penetrated the skin deeper and delivered bupivacaine more effectively than buprenorphine to the target site. The superiority of invasome penetration was further evidenced by the results of ex-vivo fluorescent dye tracking. Estimation of in-vivo pain responses by the tail-flick test revealed that compared with the liposomal group, the group receiving invasomal formulation and drug-free invasomal formulation (only containing menthol) displayed increased analgesia in the initial times of 5 and 10 min. Also, no signs of oedema or erythema were observed in the Daze test in any of the rats receiving the invasome formulation. Finally, ex-vivo and in-vivo assays demonstrated efficiency in delivering both drugs into deeper layers of skin and exposing them to the located pain receptors, which improves the time of onset and the analgesic effects. Hence, this formulation appears to be a promising candidate for tremendous development in the clinical setting.

Topics: Analgesia; Animals; Bupivacaine; Buprenorphine; Humans; Liposomes; Pain; Rats; Skin

Opioid-induced deficits in maternal behaviors are well-characterized in rodent models. Amid the current epidemic of opioid use disorder (OUD), prevalence among pregnant women has risen sharply. Yet, the roles of buprenorphine replacement treatment for OUD (BT/OUD) in the brain functions of postpartum mothers are unclear. Using functional magnetic resonance imaging (fMRI), we have developed an evolutionarily conserved maternal behavior neurocircuit (MBN) model to study human maternal care versus defensive/aggressive behaviors critical to mother-child bonding. The anterior cingulate gyrus (ACC) is not only involved in the MBN for mother-child bonding and attachment, but also part of an opioid sensitive "pain-matrix". The literature suggests that prescription opioids produce physical and emotional "analgesic" effects by disrupting specific resting-state functional connectivity (rs-FC) of ACC to regions related to MBN. Thus, in this longitudinal study, we report findings of overlapping MBN and pain matrix circuits, for mothers with chronic exposure of BT/OUD. A total of 32 mothers were studied with 6 min rs-FC at 1 month (T1) and 4 months postpartum (T2), including seven on BT/OUD and 25 non-BT/OUD mothers as a comparison group. We analyzed rs-FC between the insula, putamen, and the dorsal anterior cingulate cortex (DACC) and rostral ACC (RACC), as the regions of interest that mediate opioid analgesia. BT/OUD mothers, as compared to non-BT/OUD mothers, showed less left insula-RACC rs-FC but greater right putamen-DACC rs-FC at T1, with these between-group differences diminished at T2. Some of these rs-FC results were correlated with the scores of postpartum parental bonding questionnaire. We found time-by-treatment interaction effects on DACC and RACC-dependent rs-FC, potentially identifying brain mechanisms for beneficial effects of BT, normalizing dysfunction of maternal brain and behavior over the first four months postpartum. This study complements recent studies to ascertain how BT/OUD affects maternal behaviors, mother-child bonding, and intersubjectivity and reveals potential MBN/pain-matrix targets for novel interventions.

Topics: Analgesics, Opioid; Brain; Buprenorphine; Female; Gyrus Cinguli; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Mothers; Opioid-Related Disorders; Pain; Pregnancy

Kratom has been used for different reasons such as pain, opioid withdrawal, and relaxation. Kratom can cause dependence and overdose, and it's classified under 'drugs of concern' by the US Drug Enforcement Administration. Despite these concerns, kratom is legal in most of the United States and many countries around the world with easy accessibility. Literature searches reveal recommendations to use buprenorphine (or buprenorphine-naloxone), which are medications to treat opioid use disorder, in order to treat patients with kratom use disorder; however, there are no formal guidelines available. Buprenorphine (or buprenorphine-naloxone) induction is recommended to be conducted under observation (i.e. in the clinic) in the United States, but COVID-19 has resulted in shifts toward telehealth.. Describe case series of successful management of kratom use disorder using telehealth followed by unobserved buprenorphine-naloxone home induction and highlight implications for future management, including maintenance dosage and induction method.. We present 2 very similar kratom use disorder patients who reported taking 35 g of kratom per day who underwent unobserved buprenorphine-naloxone home induction.. Both were seen via telehealth initially. They reported no adverse effects before, during, or after the unobserved home induction on buprenorphine-naloxone but stabilized on significantly different dosages.. Telehealth followed by unobserved buprenorphine-naloxone induction at home may be an alternative to traditional buprenorphine-naloxone induction where treatment accessibility is limited. In addition to daily doses of kratom use, other factors, such as duration of kratom use and individual psychological factors may determine the most comfortable dose of buprenorphine-naloxone.

Topics: Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Humans; Mitragyna; Opioid-Related Disorders; Pain; United States

The objective of this study was to compare pain control and opioid consumption in critically ill patients who were treated with buprenorphine sublingual or oxycodone oral/enteral during ICU admission.. This was a retrospective, parallel, cohort study.. General medical or surgical ICUs of a quaternary, urban hospital in Sydney, NSW, Australia.. Data were obtained for all patients admitted to two general medical or surgical ICU from January 2019 to January 2023. Patients were grouped as those who received buprenorphine sublingual versus oxycodone oral/enteral.. None.. Pain control was compared between a propensity score matched cohort of patients who received buprenorphine versus oxycodone. The primary outcome was the probability of significant pain. A significant pain score was defined as greater than or equal to 4 on the 0-10 Numeric Rating Scale or greater than or equal to 6 on the Behavioral Pain Scale. The study cohort included 1,070 patients (288 buprenorphine and 782 oxycodone). After propensity score matching, there were 288 patients in each group. The mean age of the matched cohort was 64 ± 16 years, 295 (51%) were male, and 359 (62%) had a surgical admission. The median probability of significant pain was 0.16 with buprenorphine and 0.17 with oxycodone (median difference, 0.01; 95% CI, -0.02 to 0.04; p = 0.50). Median opioid consumption in oral morphine milligram equivalents (MMEs) was 65 with buprenorphine and 70 with oxycodone (median difference, -1 mg; 95% CI, -10 to 10 mg; p = 0.73). Median MME per ICU day was 22 with buprenorphine and 22 with oxycodone (median difference, 1 mg; 95% CI, -2 to 5 mg; p = 0.38).. Buprenorphine sublingual is as effective as oxycodone oral/enteral with regard to pain control and opioid consumption in the ICU. Buprenorphine sublingual is an appropriate option for patients in the ICU who are unable to take oral/enteral medications.

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Cohort Studies; Female; Humans; Male; Middle Aged; Oxycodone; Pain; Retrospective Studies

Topics: Analgesics, Opioid; Buprenorphine; Chronic Pain; COVID-19; Humans; Opioid-Related Disorders; Pain; Quality Improvement

Buprenorphine (BUP) can be a safe and effective alternative to traditional opioids for many patients with chronic pain. For patients on higher doses of opioids, rotation to BUP is complicated by the requirement of an opioid-free interval or withdrawal during the transition. Microdosing inductions, in which BUP is gradually titrated, while full agonist opioids are continued, are a viable alternative to traditional inductions. The objective of this article is to review the current literature on BUP microdosing induction, with a focus on patients using opioids for pain. A literature review of the PubMed database was performed in the United States on articles published from inception to May 2021. A total of 34 publications were included. The most commonly utilized microdosing strategy involved administering divided doses of sublingual (SL) products marketed for opioid use disorder treatment, with 25 (73.5%) articles reporting use of partial SL tablets or films (ranging from 1/8 to 1/2 of a 2 mg product) at some point during the induction. Transdermal patches, low-dose SL BUP available in Europe, intravenous BUP, and buccal BUP have also been used. Beyond the products used, the speed of the microinduction, setting, final BUP dosing, and management of concomitant full agonists vary widely in the literature. Microdosing regimens should be individualized based on local guidelines and patient-specific factors. Further studies comparing the safety and efficacy of different protocols are warranted.

Topics: Analgesics, Opioid; Buprenorphine; Hospice and Palliative Care Nursing; Humans; Opioid-Related Disorders; Pain; Palliative Care

Sustained-release formulations of controlled substances are commonly used to provide analgesia in research animals. These formulations represent refinements that offer the advantage of prolonged, multiday pain relief with a single injection, thereby decreasing handling stress in animals and saving time for scientists. Compounding pharmacies produce sustainedrelease buprenorphine for veterinary use (i. e., buprenorphine SR-LAB); one of these pharmacies has shortened the original 6-mo shelf-life to 28 d to comply with United States Pharmacopeia standards for ensuring sterility. This limitation risks increasing the waste of controlled substances, which require an expensive destruction process that is legally enforced in our state. To assess whether the sterility of buprenorphine SR-LAB is preserved for at least 6 mo in a general laboratory setting, we tested 5 bottles for the presence of endotoxin and bacterial and fungal contamination monthly for 6 mo. Overall, results of the study showed that the bottles remained sterile over the 6-mo duration as no endotoxin was detected and the bottles did not become contaminated with bacteria or fungi. In conclusion, when stored securely and used with aseptic handling techniques, buprenorphine SR-LAB can be maintained in a sterile state for 6 mo in a general laboratory setting.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Delayed-Action Preparations; Infertility; Pain

Medication treatment for opioid use disorder (OUD) (MOUD; buprenorphine and methadone) reduces opioid use and overdose. Discontinuation of MOUD can quickly lead to relapse, overdose and death. Few persons who initiate MOUD are retained on treatment, thus it is critical to identify factors associated with retention.. Evaluated data was from an ongoing prospective cohort study of adults aged 18 or older with DSM-5 moderate to severe OUD seeking MOUD in the community and followed for 6 months. Participants were considered retained on MOUD through 6 months if they reported taking MOUD at every study interview without discontinuation. A high dose of MOUD was defined as a methadone dose > 85 mg or buprenorphine dose ≥ 16 mg. Multivariable logistic regression was conducted to assess factors associated with 6-month MOUD retention.. A total of 118 participants (73% male, 58% white, 36% with HIV) were included. Buprenorphine was initiated by 58% and 42% started methadone. MOUD retention was 49% and 58% among buprenorphine and methadone, respectively, at 6-months. In adjusted models, a high MOUD dose (OR = 4.71, 95% CI 2.05-10.84) and higher pain interference (OR = 1.59, 95% CI 1.15-2.19) was associated with MOUD retention.. Adequate dosing of MOUD leads to improved retention on MOUD. Further, persons with high pain interference at baseline had higher odds of retention on MOUD. Both methadone and buprenorphine have analgesic effects, thus those with high pain interference could have dual benefits of MOUD for treating OUD and pain. Interventions should be tailored to improve adequate MOUD dosing to improve retention on MOUD.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Drug Overdose; Female; Humans; Male; Methadone; Naltrexone; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Prospective Studies

The aim of this study is to ascertain the analgesic efficacy and total oral morphine equivalent daily dose (OMEDD) effect of a buprenorphine-based analgesic protocol in the treatment of severe Oral Mucositis (OM).. This is a retrospective cohort study.. This study was done in a single Quaternary Referral Centre, Haematology Unit.. Fifty-four stem cell transplant patients suffering at least grade 3 oral mucositis (OM), 24 prior to [Pr-I] and 30 subsequent to [Po-I] a buprenorphine-based OM analgesic protocol.. We analysed data from the above subjects with the primary outcome measure of difference in total OMEDDs from all opioid types and administration routes, and secondary outcome measures of area under the curve (AUC) of 11-point Numerical Rating Scale (NRS-11) pain assessments, sedation scores and respiratory rate.. Use of Buprenorphine via transdermal, sublingual and intravenous Patient Controlled Analgesia (PCA) delivery as part of an analgesic protocol for severe post stem cell transplant oral mucositis in adult patients appears to significantly reduce opioid requirements and pain on swallowing. Further randomised prospective work is required to confirm these associations.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Deglutition; Humans; Morphine; Pain; Pain Management; Prospective Studies; Retrospective Studies; Stomatitis

Hospice and palliative care (HPC) clinicians increasingly care for patients with concurrent painful serious illness and opioid use disorder (OUD) or opioid misuse; however, only a minority of HPC clinicians have an X-waiver license or actively use it to prescribe buprenorphine as medication treatment for OUD.. To understand barriers for HPC clinicians to obtaining an X-waiver and prescribing buprenorphine as medication treatment for OUD.. We performed content analysis on 100 survey responses from members of the national Buprenorphine Peer Support Network, a group of HPC clinicians interested in buprenorphine, on X-waiver status, barriers to obtaining an X-waiver, and barriers to active prescribing.. Of 100 HPC clinicians surveyed, only 26 of 57 HPC clinicians with X-waivers had ever prescribed. Prominent barriers included discomfort managing concurrent pain, buprenorphine, and OUD; concerns about impacts on practice; unsupportive practice culture; insufficient practice support; patient facing challenges; and cumbersome regulatory policies.. Despite HPC clinicians' interest in buprenorphine prescribing for OUD, several steps are needed to facilitate the practice, including clinician education tailored to pain and to clinical challenges faced by HPC clinicians, mentorship on buprenorphine use, and cultural and practice changes to dismantle systemic stigma towards addiction. We propose evidence-based steps derived from our survey findings that individual clinicians, HPC leaders, and national HPC organizations can take to improve care for patients with painful serious illness and OUD.

Topics: Buprenorphine; Hospices; Humans; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Palliative Care; Practice Patterns, Physicians'

Buprenorphine, a novel opioid with complex pharmacology, is effective for treating pain and is qualitatively safer than high-dose full agonist opioid therapy; but transitioning to buprenorphine can be technically complex and carries some risk of precipitated withdrawal. We report our clinic's experience converting 36 patients with sickle cell disease (SCD) from full agonist opioids to buprenorphine using a method developed in the past 10 years. Thirty of these patients were induced using a standard outpatient protocol and six were induced during medical admissions. Typically, patients were on high-dose chronic opioid therapy (COT) with inadequate response, and often with very high acute care utilization. Unlike prior case series, the method of induction, dosing, and management of withdrawal are detailed, as are post-induction adverse events. There were seven adverse events in the first 3 days following standard induction, and two of which were judged to be definitely related to the induction but none with any lasting sequelae. At 6 months follow-up, five participants had discontinued buprenorphine (16.67%), and overall acute care visits dropped from a mean of 10.50 (SD 11.35) in the 6 months pre-induction to 2.89 (SD 3.40) in the 6 months post-induction. In an appropriately interdisciplinary care setting, buprenorphine shows promise as a safe alternative to COT with early evidence of benefit for high-utilizing patients with SCD.

Topics: Adult; Analgesics, Opioid; Anemia, Sickle Cell; Buprenorphine; Hospitalization; Humans; Pain

This cross-sectional study of US adults examines the prevalence of and characteristics associated with prescribed buprenorphine use among US adults with pain-motivated nonmedical use of prescription opioids.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Humans; Pain; Prescriptions; Self Report

Methadone is an evidence-based treatment for opioid use disorder (OUD) and pain management. Methadone for OUD may be difficult for some patients to access, particularly those in rural areas.. The purpose of this study was to characterize methadone distribution patterns between 2017 and 2019 across the United States.. The US Drug Enforcement Administration's Automated Reports and Consolidated Ordering System was used to acquire the number of opioid treatment programs (OTPs) per state and methadone distribution weight in grams. Methadone distributions by weight, corrected for state population and number of OTPs, were compared from 2017 to 2019 between states, within regions, and nationally.. The national distribution of methadone increased +12.3% for OTPs but decreased -34.6% for pain. Whereas all states saw a decrease in pain distribution, the Northeast showed a significantly smaller decrease than all other regions. Additionally, the majority of states experienced an increase in distribution for OTPs, and most states demonstrated a relatively stable or increasing number of OTPs, with an +11.5% increase nationally. The number of OTPs per 100K state population ranged from 2.1 in Rhode Island to 0.0 in Wyoming.. Although methadone distribution for OUD was increasing in the United States, the pronounced regional disparities identified warrant further consideration to improve patient access to this evidence-based pharmacotherapy, particularly in the Midwest and West regions. Greater implementation of telehealth and involvement of primary care into opioid treatment practice offer possible solutions to eliminating geographical treatment barriers.

Topics: Analgesics, Opioid; Buprenorphine; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Telemedicine; United States

Opioid abuse represents a public health crisis that has significant associated morbidity and mortality. Since beginning in the early 1990's, the opioid abuse epidemic has been difficult to control due to regulatory, economic, and psychosocial factors that have perpetuated its existence. This era of opioid abuse has been punctuated by three distinct rises in mortality, precipitated by unique public health problems that needed to be addressed. Patients affected by opioid abuse have been historically treated with either methadone or naltrexone. While these agents have clinical utility supported by robust literature, we the authors posit that buprenorphine is a superior therapy for both opioid use disorder (OUD) as well as pain. This primacy is due to the pharmacological properties of buprenorphine which render it unique among other opioid medications. One such property is buprenorphine's ceiling effect of respiratory depression, a common side effect and complicating factor in the administration of many classical opioid medications. This profile renders buprenorphine safer, while simultaneously retaining therapeutic utility in the medical practitioner's pharmacopeia for the treatment of opioid use disorder and pain.

Topics: Analgesics, Opioid; Buprenorphine; Humans; Methadone; Naltrexone; Opiate Substitution Treatment; Opioid-Related Disorders; Pain

We report a case in which sublingual buprenorphine was used to help transition a patient off intravenous (IV) opioid analgesics medications post-multiple abdominal procedures. Intravenous opioids are commonly used in inpatient surgical pain management for patients with severe pain who are unable to take oral medications. Typically, a short course of IV analgesics is used, followed by transition to oral analgesic regimen. However, in patients with poor gastrointestinal absorption, pain control can be challenging. We present this case to highlight how sublingual buprenorphine can be a useful agent for acute pain management, especially when conventional strategies provide suboptimal responses.

Topics: Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Humans; Pain; Pain Management

This case report demonstrates using buprenorphine 32 mg to achieve adequate pain control after a total knee replacement. The patient stopped buprenorphine 48 hours before surgery. He was prescribed 150 tablets of oxycodone 5 mg. After finishing oxycodone, he experienced significant pain that was relieved by 32 mg of buprenorphine daily. Urine drug screens were negative perioperatively. Patients with opioid use disorder require careful discharge planning to avoid opioid relapses or misuses of pain medications. Buprenorphine offers many unique advantages in acute pain control, including lower risk of respiratory depression, abuse potential, and lower risk of nephrotoxicity.

Topics: Analgesics, Opioid; Arthroplasty, Replacement, Knee; Buprenorphine; Humans; Male; Oxycodone; Pain

Buprenorphine (Bup) is an opioid analgesic that is commonly used in laboratory rodents to provide postoperative analgesia. However, dosing every 4 to 6 h is necessary to maintain an analgesic plasma concentration of the drug. A long lasting, highly concentrated veterinary formulation of Bup (LHC-Bup) has been used to provide prolonged analgesia in cats and nonhuman primates. In the current study, we evaluated the duration of efficacy of LHC-Bup to determine if this formulation would provide a similarly prolonged analgesia in rats. Drug concentrations were measured after subcutaneous injection of 0.5 mg/kg LHC-Bup in both male and female rats. Plasma levels were measured at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, and 72 h. Male and female rats had peak plasma levels of LHC-Bup at 90 ng/mL and 34 ng/mL, respectively, at 15 min after administration, with a steady decrease by 24 h to 0.7 ng/mL in males and 1.3 ng/mL in females. Mechanical pain tolerance was evaluated after LHC-Bup administration using a Randall-Selitto analgesiometer to assess paw withdrawal. Male rats had a significantly longer paw withdrawal time for up to 12 h after administration, and females had longer paw withdrawal times for up to 24 h. An experimental laparotomy model was then used to assess the clinical efficacy of LHC-Bup at 0.5 mg/kg. LHC-Bup treatment was associated with a greater total distance traveled, reduced time to retrieve a food treat, and reduced grooming from 3 to 12 h after surgery as compared with saline controls. Groups receiving LHC-Bup showed coprophagy whereas other rats did not. These results suggest that administering LHC-Bup at 0.5 mg/kg provides therapeutic plasma concentrations for 12 to 24 h after administration and analgesic efficacy for at least 12 h after dosing. As such, LHC-Bup is a suitable alternative to Bup-HCl.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Cats; Delayed-Action Preparations; Female; Male; Pain; Pain Measurement; Rats

Buprenorphine is a commonly used opioid for mitigating pain in laboratory mice after surgical procedures; however, the dosing interval necessary for standard buprenorphine may require treatment every 4 to 6 h to maintain an adequate plane of analgesia. An alternative formulation that provides prolonged plasma concentration with long-lasting effects would be beneficial in achieving steady-state analgesia. We evaluated a long-lasting and highly concentrated formulation of buprenorphine (Bup-LHC) in mice. Pharmacokinetic analysis was performed to assess plasma concentrations in male C57BL/6J (B6) and female CD1 mice after subcutaneous injection of 0.9 mg/kg. The Bup-LHC formulation provided plasma drug levels that exceeded the therapeutic level for at least 12 h in male B6 mice and was below therapeutic levels by 8 h in female CD1 mice. An experimental laparotomy model was used to assess analgesic efficacy. Female CD1 mice were treated with either Bup-LHC (0.9 mg/kg) or saline at 1 h before undergoing an ovariectomy via a ventral laparotomy. At 3, 6, 12, 24, and 48 h after surgery, pain was assessed based on the following behaviors: orbital tightness, grooming, wound licking, rearing, arched posture, ataxia, piloerection, nest building, and general activity. At 3 and 6 h after surgery, Bup-LHC-treated mice had significantly less wound licking and orbital tightness and considerably higher activity levels than did saline-treated mice. At 12 h, wound licking, orbital tightness and activity in Bup-LHC-treated mice were no longer significantly different from those of saline-treated mice. The results of this study suggest that Bup-LHC at 0.9 mg/kg provides sufficient plasma concentrations for analgesia in mice for 6 to 12 h after administration, as demonstrated behaviorally for at least 6 h after surgery.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Female; Male; Mice; Mice, Inbred C57BL; Pain; Pain Measurement

Regulations for new drug approvals require stringent safety testing and efficacy trial programs. The approval process for generic drugs, however, is significantly streamlined. Bioavailability data can substitute for new rounds of efficacy trials, thereby both decreasing time to approval and reducing the costs required for new studies. This regulatory choice has not been available when generic drugs are offered in a controlled release format such as a subcutaneous depot, transdermal patch or implant. The purpose of this review is to suggest that the approval of generic drugs in inert controlled release envelopes should be eligible for similar regulatory relief. Proof for this concept is provided by the example of the numerous controlled release buprenorphine products. Buprenorphine is a generic opioid used since the 1980s in tablet form to treat pain and to treat opioid addiction. Long-acting, inert delivery vehicles for the drug have become available for the same indications. Safety and bioavailability profiles of the long-acting products are the same or improved over the parent product. A review of the long-acting drugs provides compelling evidence to recommend that generic drug-controlled release products may be eligible for alternative regulatory programs.

Topics: Analgesics, Opioid; Biological Availability; Buprenorphine; Delayed-Action Preparations; Drug Approval; Drug Implants; Humans; Opioid-Related Disorders; Pain

To determine the pharmacokinetics and pharmacodynamics of high-concentration formulation of buprenorphine (1.8 mg mL. Prospective, randomized, crossover trial.. A group of six healthy adult horses weighing 521-602 kg.. On three occasions, Simbadol (0.005 mg kg. Buprenorphine was quantifiable in all horses from 15 minutes after administration up to 8-12 hours. ENT was significantly increased in treatment S2.5 compared with treatment SAL at 0.75-6 hours after treatment. Increase in locomotor activity and compulsive behavior were recorded in all horses after Simbadol, and degree of restlessness was significantly higher in treatment S5 than SAL for a sustained time. Gastrointestinal motility significantly decreased in all horses after Simbadol and returned to baseline by 16 hours after treatment.. In horses, SC Simbadol was rapidly absorbed and C

Topics: Analgesics, Opioid; Animals; Buprenorphine; Horses; Pain; Pain Measurement; Prospective Studies

In animal research, obtaining efficient and constant pain control is regulatory but challenging. The gold standard pain management consists of opioid analgesic administration, such as buprenorphine or fentanyl extended-release patches. However, as in all drugs with a short half-life time, repeated buprenorphine administrations are needed, leading to multiple injections that affect the research protocol. On the other hand, fentanyl patch efficacy is discussed in some species. These elements highlight the need of an optimal formulation of analgesic drugs for laboratory animals. In this study, we investigated how Recuvyra®, a fentanyl transdermal solution (FTS), validated in dog perioperative pain management, could provide sustained analgesia after a single topical administration in pigs in a surgical context.. A total of 11 minipigs were used in this study. As a preliminary experiment, two different doses were tested as a single application on five pigs: two pigs at full dose (2.6 mg/kg) and three pigs at half dose (1.3 mg/kg). Plasma fentanyl dosages were performed during 4 consecutive days, using liquid chromatography with tandem mass spectrometry detection. The efficacy of FTS was then evaluated in a perioperative period. Six minipigs benefited from a surgical intervention comprising a laparotomy. The FTS was blotted on the skin in a single application 20 min before the surgical incision and plasma fentanyl dosages, clinical examination (body weight, food intake, heart rate, and body temperature) and pain assessment were performed for 7 consecutive days.. During the preliminary experiment, all fentanyl concentrations reached the minimum effective concentration (MEC) extrapolated in pigs (fentanylemia ≥0.2 ng/mL) throughout the 4 days. The half dose was chosen for the next step of the study. After the surgical intervention, all plasma fentanyl concentrations remained above the MEC up to 7 days post administration. Pig clinical examinations and pain evaluations showed efficient and constant pain control at the half dose, and few adverse events were observed.. This study confirms the pharmacological and clinical efficacy of FTS at 1.3 mg/kg in pigs throughout at least 7 postoperative days following laparotomy. The clinical analgesic effect of FTS appears more efficient and well-tolerated than the one observed with repeated injections of buprenorphine. This analgesic drug formulation could be universally used in animal research to provide optimal perioperative pain management and long-term analgesia.

Topics: Administration, Cutaneous; Analgesia; Analgesics, Opioid; Animals; Buprenorphine; Dogs; Fentanyl; Pain; Pain Management; Swine; Swine, Miniature

Extended-release buprenorphine (XR) is indicated for pain management in rodents, but little is known about its use in mice. This study aimed to investigate whether high dose XR effectively attenuates post-operative hypersensitivity better than low dose XR in a mouse model of incisional pain.. Mice (n = 44) were randomly assigned to 1 of 4 treatment groups: (a) saline (1 ml/kg SC, once); (b) sustained release buprenorphine (Bup-SR, 1 mg/kg SC, once); (c) low dose extended-release buprenorphine (XR-lo, 3.25 mg/kg SC, once); (d) high dose extended-release buprenorphine (XR-hi, 6.5 mg/kg SC, once). On days -1, 0 (4 hours), 1, 2, and 3, mechanical and thermal hypersensitivities were evaluated, and plasma buprenorphine concentrations were measured.. Mechanical (days 0-2) and thermal (days 0-1) hypersensitivities were observed in the saline group. Bup-SR, XR-lo, and XR-hi attenuated mechanical hypersensitivity on days 0, 1, and 2. None of the treatment groups, except XR-Lo on day 0, attenuated thermal hypersensitivity on days 0 or 1. Plasma buprenorphine concentration peaked at 4 hours (day 0) in all treatment groups and remained greater than 1 ng/mL on days 0-2. No abnormal clinical observations or gross pathologic findings were seen in any groups.. The results indicate XR-hi did not effectively attenuate post-operative hypersensitivity better than XR-lo. Thus both 3.25 and 6.5 mg/kg XR are recommended for attenuating post-operative hypersensitivity for at least up to 48 hours in mice.

Topics: Animals; Buprenorphine; Delayed-Action Preparations; Hypersensitivity; Lipids; Mice; Pain

Topics: Analgesics, Opioid; Animals; Brain; Buprenorphine; Locomotion; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Pain; Pain Measurement; Pilot Projects; Polymorphism, Single Nucleotide; Receptors, Opioid, mu; Species Specificity; Treatment Outcome

Topics: Analgesics, Opioid; Buprenorphine; Humans; Hyperalgesia; Morphine; Pain

Topics: Analgesics, Opioid; Buprenorphine; Female; Humans; Methadone; Opioid-Related Disorders; Pain; Pregnancy

Topics: Analgesics, Opioid; Buprenorphine; Humans; Opioid Epidemic; Opioid-Related Disorders; Pain; Prescriptions

Opioids are commonly used analgesics for moderate to severe pain, but levels of drug effect vary among individuals. As for the mechanisms underlying these individual differences, there have been reports suggesting effects of polymorphisms in the gene encoding μ-opioid receptor (. Nociceptive thresholds were significantly increased in the AA as compared to the GG group after buprenorphine administration (p = 0.025), while the DSST scores were significantly lower in the AA group (p < 0.001). The VAS scores for drowsiness (p < 0.001), malaise (p < 0.001), nausea (p < 0.001), and euphoria (p = 0.004) were higher in the AA than in the GG group.. Levels of pharmacological actions of a μ-opioid receptor partial agonist vary in accordance with a polymorphism in the

Topics: Analgesics; Analgesics, Opioid; Buprenorphine; Humans; Male; Pain; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptors, Opioid, mu

Thienorphine hydrochloride is a new anti-relapse drug for opioid abusers that is currently in phase II clinical trial. In the present study, the antinociception, dependence, and signal transduction induced by thienorphine were examined. Thienorphine showed a potent antinociception effect in acetic acid-induced writhing test and formalin test. In the hot plate test and tail-flick test, thienorphine presented the typical partial opioid agonist character with a ceiling dose-response curve in addition to a bell-shaped curve. The hot plate test revealed that thienorphine induced approximately 50% of antinociception in μ receptor knockout (μ-KO) mice compared to wild-type controls (P < 0.05). The κ, δ selective antagonist nor-binaltorphimine (nor-BNI), and naltrindole decreased approximately 50-60% of theinorphine antinociception in μ-KO mice, respectively. The ORL1 receptor-selective antagonist J113397 did not affect theinorphine antinociception in μ-KO mice. Chronic treatment with thienorphine (1.5 mg/kg) induced some tolerance that was lower compared to buprenorphine or morphine addition. In contrast to buprenorphine or morphine, thienorphine did not lead to psychological dependence by conditioned place preference (CPP). The maximum inhibition of thienorphine on protein kinase A (PKA) activity was about 36%, 100%, 100%, and 12% in CHO-μ/κ/δ/ORL1-PKAcatEGFP cells, respectively. Similar results were observed in cyclic adenosine monophosphate (cAMP) accumulation inhibited by thienorphine in cells. Thienorphine significantly increased pERK1/2 in CHO-κ/δ-PKAcatEGFP cells. These results indicated that thienorphine induced analgesia through activation of κ- and δ-, partial activation of μ- opioid receptor without a bias between G-protein- and β-arrestin-mediated pathways. Thienorphine might be used for antinociception with minimal adverse effects.

Topics: Analgesics, Opioid; Animals; Brain; Buprenorphine; Cell Line, Tumor; Cyclic AMP; Female; Humans; Male; Mice; Mice, Knockout; Neurons; Nociception; Pain; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

This review evaluates current recommendations for pain management in chronic kidney disease (CKD) and end-stage kidney disease (ESKD) with a specific focus on evidence for opioid analgesia, including the partial agonist, buprenorphine.. Recent evidence supports the use of physical activity and other nonpharmacologic therapies, either alone or with pharmacological therapies, for pain management. Nonopioid analgesics, including acetaminophen, topical analgesics, gabapentinoids, serotonin-norepinephrine reuptake inhibitors, and TCA may be considered based on pain cause and type, with careful dose considerations in kidney disease. NSAIDs may be used in CKD and ESKD for short durations with careful monitoring. Opioid use should be minimized and reserved for patients who have failed other therapies. Opioids have been associated with increased adverse events in this population, and thus should be used cautiously after risk/benefit discussion with the patient. Opioids that are safer to use in kidney disease include oxycodone, hydromorphone, fentanyl, methadone, and buprenorphine. Buprenorphine appears to be a promising and safer option due to its partial agonism at the mu opioid receptor.. Pain is poorly managed in patients with kidney disease. Nonpharmacological and nonopioid analgesics should be first-line approaches for pain management. Opioid use should be minimized with careful monitoring and dose adjustment.

Topics: Analgesics, Opioid; Buprenorphine; Fentanyl; Humans; Hydromorphone; Kidney Failure, Chronic; Oxycodone; Pain; Pain Management; Receptors, Opioid, mu; Renal Insufficiency, Chronic

Topics: Analgesics, Opioid; Buprenorphine; Depression; Humans; Opioid-Related Disorders; Pain; Pramipexole

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Humans; Ischemia; Pain; Pain Management; Transdermal Patch

In the development of cancer therapeutics, no suitable replacements for the use of animals that are capable of modeling such complex disease processes are currently available. In orthotopic models, surgery is often required to access the target organ for tumor cell inoculation. Historically analgesics have been withheld in such models in light of potential effects on tumor development. The current study evaluated the effect of the opioid buprenorphine on tumor growth of a human ovarian cancer cell line (OVCAR5 OT luc2 mCherry). Female CB17 SCID mice (

Topics: Analgesia; Analgesics, Opioid; Animals; Buprenorphine; Female; Humans; Laboratory Animal Science; Mice; Mice, SCID; Ovarian Neoplasms; Pain; Pain Management; Pain, Postoperative

Countries worldwide are developing a variety of strategies to combat the opioid epidemic, such as restricting access to high-strength opioid formulations. We aimed to examine the dispensing patterns of strong opioids by dose units (DUs), age, and sex.. We used Australian population-level dispensing data from January 2003 to December 2015 and categorised strong opioids by DU: very low, low, moderate, and high, corresponding to total daily doses of less than or equal to 25, 26 to 50, 51 to 100, and greater than 100 morphine milligramme equivalents, respectively. We measured trends in strong opioid use as dispensings/1000 population/year and stratified dispensing in 2015 by patient age and sex.. From 2003 to 2015, strong opioid dispensing of very low, low, moderate, and high DU increased 6.7-, 6.2-, 2.2-, and 1.8-fold, respectively. The increase in very low and low DU dispensing was driven primarily by oxycodone (5, 10, and 15 mg tablets and capsules) and buprenorphine transdermal patches. In 2015, the number of dispensings/1000 population for very low, low, moderate, and high DU were 180.3, 77.0, 52.7, and 34.8, respectively. Females aged greater than or equal to 85 years had the highest opioid use, ranging from 157.1 dispensings/1000 population for high DU to 2104.5 dispensings/1000 population for very low DU. In contrast, the high DU dispensings in males aged 25 to 64 years exceeded their female counterparts by approximately 1.3-fold.. Relative to moderate and high DU strong opioids, dispensing of very low and low DU strong opioids increased dramatically during the study period in Australia. Future studies investigating opioids use and harms in elderly females and males between 25 to 64 years are warranted.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Analgesics, Opioid; Australia; Buprenorphine; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Prescriptions; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Opioid Epidemic; Opioid-Related Disorders; Oxycodone; Pain; Policy Making; Practice Patterns, Physicians'; Sex Factors; Transdermal Patch; Young Adult

A novel nano-formulations of biocompatible, biodegradable and thermo-responsive graphene quantum dots (GQDs) loaded dextran/poly(N-isopropylacrylamide) (Dex/PNIPAM) copolymeric matrix was synthesized and analyzed the materials characterization, sustained drug delivery system, tissue feasibility in the tissue implantation site. This research report was aimed to grafting and functionalizing thermo-responsive (Dex/PNIPAM) copolymeric composite with presence of graphene quantum dots to achieve thermal responsive drug delivery (TrDD) with no harm effect in the implantation site. The synthesized GQD by using ionic liquid were evaluated by spectroscopic (DLS, PL, XRD and Raman spectroscopy) and Transmission electron microscopic analysis (TEM). The ultra-small GQDs loaded Dex/PNIPAM and was appeared to be asymmetric and open uniform porous structure, which can be significantly favorable for cell uptake and greatly influenced to be an effective drug carrier into the cellular compartment with good fluid flow. The PNIPAM polymeric composite were exhibited sustained and enhanced drug release percentages with increasing temperature at above low critical solution temperature (LCST) is 39 °C comparable to the cumulative drug release profile of below LCST (32 °C), which demonstrated that thermo-responsive polymer was played a significant role in the delivery system. The treated group of GQDs-Dex/PNIPAM was observed that no inflammation and shows noteworthy stromal cell infiltration, demonstrating that the synthesized drug carriers did not harm to the nerves and tissues and only was responsible for the pain management.

Topics: Acrylic Resins; Animals; Buprenorphine; Cell Line; Cell Survival; Dextrans; Drug Carriers; Female; Fluorescent Dyes; Glycols; Graphite; Hydrogels; Mice; Muscle, Skeletal; Pain; Pain Management; Quantum Dots; Rats; Rats, Sprague-Dawley

The κ receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time.. To determine the opioid pharmacology of BU10119 (0.3-3 mg·kg. BU10119 alone was without any antinociceptive activity. BU10119 (1 mg·kg. BU10119 is a mixed κ/μ receptor antagonist with relatively short-duration κ antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential for the treatment of depression and other stress-induced conditions.. This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

Topics: Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Buprenorphine; Depression; Exploratory Behavior; Locomotion; Male; Mice; Pain; Receptors, Opioid, kappa; Receptors, Opioid, mu

Murine orthotopic cancer models often require surgery, potentially causing pain or distress. However, analgesics are often withheld because they may alter tumour development. Two orthotopically implanted cancers were investigated in mice pre-treated with meloxicam (10 mg/kg), buprenorphine (0.2 mg/kg) or saline (1 ml/kg). Tumours were imaged and welfare was assessed using body weight, behaviour and nociceptive responses. In study 1, BALB/c mice were inoculated with 4T1 mammary carcinoma or saline during surgery or anaesthesia. As pre-treatment with a single buprenorphine dose appeared beneficial to cancer growth consistency, a second cohort of mice additionally received saline or buprenorphine at 12 and 24 h. Surgery resulted in increased mammary tumour growth and lung metastases. These unwanted effects were lessened by buprenorphine pre-treatment, especially when given repeatedly. Mammary tumour-bearing mice became less active and nociceptive thresholds declined over time, indicating some discomfort as tumours grew. In study 2, C57BL/6 mice received B16 melanoma. This non-surgical model was used to determine whether meloxicam or buprenorphine affected cancer seeding of the lungs. While meloxicam reduced B16 lung seeding, buprenorphine did not. Mechanical thresholds decreased as cancer developed in mice bearing melanoma, but the magnitude of this was insufficient to conclude that there were any significant welfare concerns. This study highlights the scientific value in utilising non-surgical models, where possible. When surgery must be performed at the time of tumour inoculation, the effects of this should be controlled with appropriate analgesics to enhance the value and possibly translation of the research.

Topics: Analgesics; Animal Welfare; Animals; Breast Neoplasms; Buprenorphine; Cell Line, Tumor; Disease Models, Animal; Female; Lung Neoplasms; Mammary Neoplasms, Experimental; Melanoma, Experimental; Meloxicam; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Pain; Thiazines; Thiazoles; Xenograft Model Antitumor Assays

Many patients with opioid use disorder report symptoms similar to restless legs syndrome (RLS) during withdrawal. However, whether these symptoms are true RLS, their predictors and effect of treatment with pregabalin are still unknown.. A total of 19 consecutive patients with opioid use disorder who were admitted for detoxification were included in this study after obtaining informed consent. Information regarding addiction was noted, and they were screened for RLS every morning and evening. Patients were also asked to provide information regarding their sleep quality during the previous night. To control opioid withdrawal, they were prescribed buprenorphine. Pregabalin was prescribed to patients who developed RLS. For analysis, patients were divided in two groups: those with RLS and those without RLS.. The average age of the subjects included in this study was 30.2 (±10.4) years. Mean duration of substance abuse was 56.8 (±38.4) months. Ten patients developed symptoms of RLS. Groups with RLS and without RLS were comparable with reference to demographics, laboratory parameters, and dose of buprenorphine that was required to control withdrawal symptoms. On average, RLS appeared after 1.7 days of abstinence. Patients described their symptoms such as crawling, creeping sensation in the muscles or "just pain". Eight out of 10 subjects reported symptoms limited to legs; however, two described similar problems in their upper limbs as well. A change in sleep pattern was observed with delayed sleep onset at night, delayed wake time in the morning, and spending a major proportion of day asleep. Pregabalin brought significant relief to the symptoms of RLS and sleep quality.. RLS during opioid withdrawal was an independent illness seen in half of the patients. It appeared to be mediated through mu-receptors, with contributions from other factors. Pregabalin improved symptoms of RLS and quality of sleep in these patients.

Topics: Adult; Analgesics; Buprenorphine; Female; Humans; Male; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Pregabalin; Restless Legs Syndrome; Sleep; Substance Withdrawal Syndrome

Treating patients with opioid use disorder (OUD) and traumatic brain injury illustrates 6 neurobiological principles about the actions of 2 contrasting opioid analgesics, morphine and fentanyl, as well as pharmacotherapies for OUD, methadone, naltrexone, and buprenorphine.. This literature review focused on a patient with traumatic brain injury who developed OUD from chronic morphine analgesia. His treatment is described in a neurobiological framework of 6 opioid action principles.. The 6 principles are (1) coactivation of neuronal and inflammatory immune receptors (Toll-like receptor 4), (2) 1 receptor activating cyclic adenosine monophosphate and β-arrestin second messenger systems, (3) convergence of opioid and adrenergic receptor types on 1 second messenger, (4) antagonist (eg, naltrexone)-induced receptor trafficking, (5) genetic μ-opioid receptor variants influencing analgesia and tolerance, and (6) cross-tolerance vs receptor antagonism as the basis of OUD pharmacotherapy with methadone or buprenorphine vs naltrexone.

Topics: Analgesics, Opioid; Brain Injuries, Traumatic; Buprenorphine; Humans; Methadone; Naltrexone; Opioid-Related Disorders; Pain; Receptors, Opioid, mu

Internal fixation with volar locking plate (VLP) was widely adopted as a first-line choice in treatment of distal radius fracture (DRF).. We showed that patients receiving transdermal buprenorphine and codeine/ibuprofen had decreased VAS scores during rehabilitative exercise, better compliance to the rehabilitation program, and thus faster functional recovery.. We recommend transdermal buprenorphine or codeine/ibuprofen for pain management during rehabilitation after distal radius fracture stabilized with VLP.

Topics: Bone Plates; Buprenorphine; Codeine; Female; Fracture Fixation, Internal; Hand Strength; Humans; Ibuprofen; Male; Middle Aged; Pain; Pain Management; Prospective Studies; Radius Fractures; Range of Motion, Articular; Recovery of Function; Shoulder; Treatment Outcome

Topics: Analgesics, Opioid; Animals; Buprenorphine; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Freund's Adjuvant; Hyperalgesia; Inflammation; Male; Nociception; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Recovery of Function; Running; Sex Factors

Topics: Analgesics, Opioid; Buprenorphine; Humans; Narcotic Antagonists; Pain; Receptors, Opioid

Positive-controlled clinical studies have shown a dose dependent effect of buprenorphine transdermal system on QTc interval prolongation. This study provides assessment of the buprenorphine transdermal system and cardiac arrhythmia using US FDA and WHO postmarketing reporting databases.. Disproportionality analysis of spontaneously reported adverse events to assess whether the reporting rate of cardiac arrhythmia events was disproportionately elevated relative to expected rates of reporting in both FDA and WHO databases. Cardiac arrhythmia events were identified using the standardized Medical Dictionary for Regulatory Activities query for torsade de pointes and/or QT prolongation (TdP/QTP). The threshold for a signal of disproportionate adverse event reporting was defined as the lower 90% confidence limit ≥ 2 of the Empiric Bayes geometric mean in FDA database and as the lower 95% confidence limit of the Informational Component >0 in WHO database.. There were 124 (<1%) and 77 (2%) cardiac arrhythmia event cases associated with buprenorphine transdermal as compared to 3206 (12%) and 2913 (14%) involving methadone in the FDA and WHO databases, respectively. In the FDA database methadone was associated with a signal of disproportionate reporting for TdP/QTP (EB05 3.26); however, buprenorphine transdermal was not (EB05 0.33). In the WHO database methadone was associated with a signal of disproportionate reporting for TdP/QTP (IC025 2.66); however, buprenorphine transdermal was not (IC025 -0.88). Similar trends were observed in sensitivity analyses by age, gender, and specific terms related to ventricular arrhythmia.. The signal identified in the transdermal buprenorphine thorough QTc study, which led to a dose limitation in its US label, does not translate into a signal of increased risk for cardiac arrhythmia in real world use, as assessed by this method of analyzing post-market surveillance data.

Topics: Administration, Cutaneous; Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Buprenorphine; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Pain; Torsades de Pointes; United States; United States Food and Drug Administration; World Health Organization; Young Adult

Animal models of rheumatoid arthritis are important in the elucidation of etiopathogenic mechanisms of the disease and for the development of promising new therapies. Species specificity of new biological compounds and their mode of action preclude safety and efficacy testing in rodent models of disease. Nonhuman primates (NHP) can fill this niche and provide the only relevant model. Over the last two decades models of collagen-induced arthritis (CIA) were developed in the rhesus monkey and the common marmoset. However, NHP are higher-order animals and complex sentient beings. So especially in models where pain is an intricate part of the disease, analgesia needs to be addressed because of ethical considerations. In our model, a morphine-based pain relief was used that does not interfere with the normal development of disease allowing us to evaluate important mechanistic aspects of the arthritis.

Topics: Analgesics, Opioid; Animals; Arthritis, Experimental; Buprenorphine; Callithrix; Drug Administration Schedule; Macaca mulatta; Pain; Pain Management; Pain Measurement; Severity of Illness Index

Pharmacogenetic studies have identified the non-synonymous single nucleotide polymorphism (A118G) in the human mu opioid receptor (MOR) gene (OPRM1) as a critical genetic variant capable of altering the efficacy of opioid therapeutics. To date few studies have explored the potential impact of the OPRM1 A118G polymorphism on the pharmacological effects of buprenorphine (BPN), a potent MOR partial agonist and kappa opioid receptor antagonist, which is approved by the FDA for the treatment of opioid addiction and chronic pain. The goal of these studies was to determine whether the MOR-mediated behavioral effects of BPN were altered in the Oprm1 A112G mouse model of the human OPRM1 A118G SNP. All studies were conducted in female, AA, AG and GG mice. BPN's maximal analgesic effect in the hot plate test was significantly blunted in AG and GG mice compared to wild type AA mice. Similarly, the BPN-induced reduction of latency to consume food in the novelty induced hypophagia test was blocked entirely in AG and GG mice compared to their AA littermates. In addition, GG mice exhibited marked reductions in psychostimulant hyperlocomotor activity compared to the AA group. In contrast, reduced immobility in the forced swim test, an effect of BPN mediated by kappa opioid receptors, was not affected by genotype. These studies demonstrate the ability of the Oprm1 A112G SNP to attenuate the analgesic, anxiolytic and hyperlocomotor effects of BPN. Overall, these data suggest that the OPRM1 A118G SNP will significantly impact the clinical efficacy of BPN in its therapeutic applications.

Topics: Analgesics, Opioid; Animals; Anti-Anxiety Agents; Buprenorphine; Choice Behavior; Dose-Response Relationship, Drug; Feeding Behavior; Female; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Narcotic Antagonists; Pain; Polymorphism, Single Nucleotide; Receptors, Opioid, mu

Topics: Acute Pain; Analgesics, Opioid; Buprenorphine; Humans; Opioid-Related Disorders; Pain; Pain Management; Pain Measurement

The result of the increase in drug abuse is a growing number of patients receiving methadone or buprenorphine\ substitution therapy. Physicians are increasingly confronted with patients on substitution therapy at the time when they\ are developing acute pain conditions or when they need surgery. Although pain has sensory qualities, it is a very personal\ and complex experience. The intensity and duration of pain are influenced by numerous factors. Poorly controlled pain\ leads to unnecessary suffering of the patients with the possibility of permanent changes in behavior and reduced quality\ of life. Efficacious pain treatment is considered a basic right of every patient. Because of the complex mechanisms of the\ emergence and transmission of pain and the emotional components that are involved in the experience of pain, appropriate\ pain relief in patients on substitution therapy is a major challenge for both the physicians and the patients. The article gives\ an overview of issues related to the treatment of acute pain and perioperative treatment in patients on substitution therapy\ with methadone and buprenorphine. The article highlights the wrong common misconception about pain treatment in these\ patients, which also are the most common cause of their inadequate treatment.

Topics: Acute Disease; Buprenorphine; Humans; Methadone; Opiate Substitution Treatment; Pain; Pain Management; Quality of Life

To evaluate the potential benefits of high-dose buprenorphine formulations for analgesia in cats, serial and crossover studies were undertaken to investigate their pharmacokinetics and thermal antinociceptive effects.. Twelve healthy adult domestic shorthair cats (6.0 ± 1.1 kg body weight) were studied. Aqueous solutions of buprenorphine hydrochloride at 0, 0.02, 0.06, 0.12 and 0.24 mg/kg body weight and formulations containing 0, 0.3, 0.6 and 1.2 mg/ml with and without preservatives were given subcutaneously. Blood samples were taken and thermal threshold (TT) measured prior to and at regular time points up to 72 h after dosing. Descriptive statistics and analyses of variance were applied as appropriate.. Baseline TT was 47.6 ± 4.1°C, which increased in all groups treated with all buprenorphine dosages and formulations. After doses of 0.12 mg/kg and above, TT was significantly higher than baseline at most time points from 1-30 h post-treatment. The time to maximum effect (Tmax) ranged between 0.25 and 2.00 h; and plasma concentrations associated with maximum antinociceptive effect (Cmax) were 1.01-1.72 ng/ml after the 0.02 mg/kg dose, 1.4-4.9 ng/ml after the 0.06 mg/kg dose, 4.6-51.4 ng/ml after the 0.12 mg/kg dose and 5.3-22.3 ng/ml after the 0.24 mg/kg dose. The range of estimates for the buprenorphine elimination half-life were as follows: 0.02 mg/kg = 1.35-5.33 h; 0.06 mg/kg = 16.1-31.2 h; 0.12 mg/kg = 10.1-34.0 h; and 0.24 = mg/kg 16.1-31.6 h. The mean 'plasma concentration for the offset of analgesia' was 2.3 ± 2.0 ng/ml. No adverse effects were seen. The addition of preservatives to a high-concentration buprenorphine formulation had no impact on antinociception nor any side effects.. Aqueous high-concentration buprenorphine formulations administered at 0.12 or 0.24 mg/kg have potential for clinical use in cats, providing prolonged antinociception in a single subcutaneous injection of minimal dose volume.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Cat Diseases; Cats; Injections, Subcutaneous; Pain; Pain Measurement

Pain control in critical limb ischemia (CLI) varies considerably between individuals.. To evaluate pharmacogenetically the response to transdermal buprenorphine (BUP-TTS) in patients with CLI who are awaiting revascularization.. One hundred and seven patients with CLI were treated with BUP-TTS. The following were analyzed: (1) pain perception (visual analog scale (VAS) before and 4 days after treatment) and (2) genetics: glucuronosyltransferase (UGT2B7), cytochrome (CYP3A4), and μ-opioid receptor (OPRM1) gene polymorphisms.. Ninety-three patients completed the study. The VAS score by the fourth day of analgesia dropped from 6.82 to 3.38 (P < 0.05). The analgesic response to BUP-TTS was greater in men than in women (P = 0.019). Patients who were AA homozygotes for the CYP3A4 gene showed the best response to analgesic treatment (P = 0.003). The combination of the CYP3A4 gene with UGT2B7 or OPRM1 was favorable to the effect of the CYP3A4 gene (P = 0.045 and P = 0.026, respectively). The combination of UGT2B7 with OPRM1 was ineffective (P = 0.648). The 3 polymorphisms together had no effect on response to treatment (P = 0.461).. BUP-TTS is efficacious in the control of pain in patients with CLI. The homozygous AA carriers of the CYP3A4 gene respond better to treatment with BUP-TTS.

Topics: Administration, Cutaneous; Adult; Analgesics, Opioid; Buprenorphine; Cytochrome P-450 CYP3A; Female; Glucuronosyltransferase; Humans; Ischemia; Lower Extremity; Male; Middle Aged; Pain; Pain Management; Pain Measurement; Polymorphism, Single Nucleotide; Receptors, Opioid, mu

Nonfatal opioid overdose is an opportunity to identify and treat substance use disorders, but treatment patterns after the overdose are unknown.. To determine prescribed opioid dosage after an opioid overdose and its association with repeated overdose.. Retrospective cohort study.. A large U.S. health insurer.. 2848 commercially insured patients aged 18 to 64 years who had a nonfatal opioid overdose during long-term opioid therapy for noncancer pain between May 2000 and December 2012.. Nonfatal opioid overdose was identified using International Classification of Diseases, Ninth Revision, Clinical Modification, codes from emergency department or inpatient claims. The primary outcome was daily morphine-equivalent dosage (MED) of opioids dispensed from 60 days before to up to 730 days after the index overdose. We categorized dosages as large (≥100 mg MED), moderate (50 to <100 mg MED), low (<50 mg MED), or none (0 mg MED). Secondary outcomes included time to repeated overdose stratified by daily dosage as a time-varying covariate.. Over a median follow-up of 299 days, opioids were dispensed to 91% of patients after an overdose. Seven percent of patients (n = 212) had a repeated opioid overdose. At 2 years, the cumulative incidence of repeated overdose was 17% (95% CI, 14% to 20%) for patients receiving high dosages of opioids after the index overdose, 15% (CI, 10% to 21%) for those receiving moderate dosages, 9% (CI, 6% to 14%) for those receiving low dosages, and 8% (CI, 6% to 11%) for those receiving no opioids.. The cohort was limited to commercially insured adults.. Almost all patients continue to receive prescription opioids after an overdose. Opioid discontinuation after overdose is associated with lower risk for repeated overdose.. Health Resources and Services Administration.

Topics: Adolescent; Adult; Analgesics, Opioid; Benzodiazepines; Buprenorphine; Drug Overdose; Female; Humans; Male; Middle Aged; Narcotic Antagonists; Opioid-Related Disorders; Pain; Practice Patterns, Physicians'; Recurrence; Retrospective Studies; Time Factors; Young Adult

Topics: Administration, Cutaneous; Analgesics, Opioid; Breakthrough Pain; Buprenorphine; Humans; Pain; Pain Measurement; Renal Dialysis

Topics: Administration, Cutaneous; Analgesics, Opioid; Breakthrough Pain; Buprenorphine; Humans; Pain; Pain Measurement; Renal Dialysis

Mice purportedly require dosing with the opioid buprenorphine (Bup-HCl) at least every 8 to 12 h to maintain an adequate plane of analgesia. Here we used an experimental laparotomy model to determine the clinical efficacy of sustained-release formulations of buprenorphine (Bup-SR) after surgery in mice. Female CD1 mice underwent laparotomy and received either Bup-SR (0.6 mg/kg), Bup-HCl (0.1 mg/kg every 12 h), or saline (every 12 h). Pain was assessed at 1, 3, 6, 12, 24, 48, and 72 h according to the frequency of several behaviors (general activity, wheel-running activity, rearing, grooming, wound licking, orbital tightening, and percentage of integrated nest material) and daily body weight. Over time, wheel running was increased and wound licking was decreased in Bup-SR-treated mice compared with Bup-HCl- and saline-treated mice. Compared with Bup-HCl- and saline-treated mice, Bup-SR-treated mice had increased general activity and percentage of integrated nest material and decreased orbital tightening for 1 to 6 h after surgery. The Bup-HCl- and saline-treated mice had similar general activity, orbital tightening scores, and wheel running activity. Rearing activity and body weight did not differ throughout the study, and none of the observed behaviors differed between groups at 24, 48, and 72 h after surgery. These results suggest that Bup-SR at 0.6 mg/kg provides adequate analgesia after laparotomy in mice and can be used as an alternative analgesic in this context. Furthermore, Bup-HCl at 0.1 mg/kg every 12 h may be inadequate in providing analgesia for abdominal procedures in mice.

Topics: Analgesia; Analgesics, Opioid; Animals; Buprenorphine; Delayed-Action Preparations; Female; Laboratory Animal Science; Laparotomy; Mice; Motor Activity; Pain; Pain Management; Pain Measurement

When providers recognize that patients are abusing prescription drugs, review of the drugs they are prescribed and attempts to treat the substance use disorder are warranted. However, little is known about whether prescribing patterns change following such a diagnosis.. We used national longitudinal health claims data from the Market Scan® commercial claims database for January 2010-June 2011. We used a cohort of 1.85 million adults 18-64 years old prescribed opioid analgesics but without abuse diagnoses during a 6-month "preabuse" period. We identified a subset of 9009 patients receiving diagnoses of abuse of non-illicit drugs (abuse group) during a 6-month "abuse" period and compared them with patients without such a diagnosis (nonabuse group) during both the abuse period and a subsequent 6-month "postabuse" period.. During the abuse period 5.78% of the abuse group and 0.14% of the nonabuse group overdosed. Overdose rates declined to 2.12% in the abuse group in the postabuse period. Opioid prescribing rates declined 13.5%, and benzodiazepine rates declined 12.3% in the abuse group in the post-abuse period. Antidepressants and gabapentin were prescribed to roughly one half and one quarter of the abuse group, respectively, during all three periods. Daily opioid dosage did not decline in the abuse group following diagnosis.. Prescribing to people who abuse drugs changes little after their abuse is documented. Actions such as tapering opioid and benzodiazepine prescriptions, maximizing alternative treatments for pain, and greater use of medication-assisted treatment such as buprenorphine could help reduce risk in this population. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Topics: Adolescent; Adult; Analgesics, Opioid; Benzodiazepines; Buprenorphine; Databases, Factual; Drug Overdose; Humans; Longitudinal Studies; Middle Aged; Opioid-Related Disorders; Pain; Practice Patterns, Physicians'; Prescription Drug Misuse; Substance-Related Disorders; United States; Young Adult

Buprenorphine HCl (BUP) is a μ-opioid agonist used in laboratory rodents. New formulations of buprenorphine (for example, sustained-released buprenorphine [BUP SR], extended-release buprenorphine [BUP ER]) have been developed to extend the analgesic duration. In a crossover design, 8 adult rats were injected subcutaneously with either BUP, BUP SR, BUP ER, or saline, after which voluntary running-wheel activity, arterial blood gases, and thermal withdrawal latency were assessed. Wheel running was decreased at 24 h compared with baseline in all treatment groups but returned to baseline by 48 h. Arterial pH, HCO3(-), and CO2 were not changed between groups or over time. However, arterial oxygen was lower than baseline in the BUP (-8 ± 2 mm Hg), BUP SR (-7 ± 1 mm Hg), and BUP ER (-17 ± 2 mm Hg) groups compared with saline controls (3 ± 2 mm Hg); the BUP ER group showed the greatest decrease when all time points were combined. BUP increased the withdrawal latency at 1 h (15% ± 3%), whereas BUP ER increased latencies at 4, 8, 12, and 48 h (35% ± 11%, 21% ± 7%, 26% ± 7%, and 22% ± 9%, respectively) and BUP SR prolonged latencies at 24, 48, and 72 h (15% ± 6%, 18% ± 5%, and 20% ± 8%, respectively). The duration of thermal analgesia varied between buprenorphine formulations, but all 3 formulations reduced voluntary-running activity at 24 h after injection and might cause hypoxemia in normal adult rats.

Topics: Analgesia; Analgesics, Opioid; Animals; Blood Gas Analysis; Buprenorphine; Cross-Over Studies; Male; Monitoring, Physiologic; Pain; Pain Measurement; Rats; Running

Rodent grimace scales have been recently validated for pain assessment, allowing evaluation of facial expressions associated with pain. The standard scoring method is retrospective, limiting its application beyond pain research. This study aimed to assess if real-time application of the Rat Grimace Scale (RGS) could reliably and accurately assess pain in rats when compared to the standard method. Thirty-two male and female Sprague-Dawley rats were block randomized into three treatment groups: buprenorphine (0.03 mg/kg, subcutaneously), multimodal analgesia (buprenorphine [0.03 mg/kg] and meloxicam [2 mg/kg], subcutaneously), or saline, followed by intra-plantar carrageenan. Real-time observations (interval and point) were compared to the standard RGS method using concurrent video-recordings. Real-time interval observations reflected the results from the standard RGS method by successfully discriminating between analgesia and saline treatments. Real-time point observations showed poor discrimination between treatments. Real-time observations showed minimal bias (<0.1) and acceptable limits of agreement. These results indicate that applying the RGS in real-time through an interval scoring method is feasible and effective, allowing refinement of laboratory rat welfare through rapid identification of pain and early intervention.

Topics: Analgesia; Animal Welfare; Animals; Buprenorphine; Carrageenan; Computer Systems; Facial Expression; Feasibility Studies; Female; Male; Meloxicam; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Retrospective Studies; Thiazines; Thiazoles; Video Recording

Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ∼10- to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abuse-free opioid analgesics.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Cocaine; Drug-Related Side Effects and Adverse Reactions; Humans; Ligands; Opioid Peptides; Pain; Primates; Receptors, Opioid, mu; Respiratory Insufficiency

Topics: Buprenorphine; Humans; Pain; Suicidal Ideation; Suicide; Suicide, Attempted

Topics: Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Humans; Narcotic Antagonists; Pain

Providing appropriate analgesia is essential in minimizing pain and maintaining optimal animal care and welfare in laboratory animals. Guinea pigs are common animal models in biomedical research, often requiring analgesic support. Here we evaluated the pharmacokinetics and efficacy of a sustained-release formulation of buprenorphine (Bup-SR) in this species. Guinea pigs (n = 7 each group) received either Bup-HCl (0.05 mg/kg BID for 3 d) or Bup-SR (0.3 mg/kg once). Plasma collection and measurement of paw-withdrawal pressure (PWP) was conducted at 0, 1, 3, 6, 12, 26, 48, and 72 h after treatment. Plasma levels of Bup-HCl peaked at 2331 pg/mL at 1 h after administration and declined to 165 pg/mL by 12 h. Plasma concentrations of Bup-SR peaked at 1344 pg/mL at 26 h after administration and declined to 429 pg/mL by 48 h. The PWP of the Bup-HCltreated guinea pigs peaked at 674 g at 1 h and declined to 402 g at 6 h, whereas that of Bup-SRtreated guinea pigs at 1 h was 361 g, 555 g at 6 h (significantly higher than that after Bup-HCl), and peaked at 680 g at 12 h. The PWP of both treatments was similar from 24 to 72 h and ranged from 348 to 450 g. The plasma concentration and PWP showed good correlation. These results suggest that Bup-SR provides consistent analgesia equivalent to that of Bup-HCl for a prolonged period of time and that Bup-SR is an alternative method of analgesia in guinea pigs.

Topics: Analgesics, Opioid; Animals; Animals, Laboratory; Buprenorphine; Delayed-Action Preparations; Female; Guinea Pigs; Humans; Pain; Pain Management; Pain Measurement

For patients experiencing inadequate analgesia and intolerable opioid-related side effects on one strong opioid analgesic, pain relief with acceptable tolerability is often achieved by rotation to a second strong opioid. These observations suggest subtle pharmacodynamic differences between opioids in vivo. This study in rats was designed to assess differences between opioids in their in vivo profiles.. Male Sprague Dawley rats were given single i.c.v. bolus doses of morphine, morphine-6-glucuronide (M6G), fentanyl, oxycodone, buprenorphine, DPDPE ([D-penicillamine(2,5) ]-enkephalin) or U69,593. Antinociception, constipation and respiratory depression were assessed using the warm water tail-flick test, the castor oil-induced diarrhoea test and whole body plethysmography respectively.. These opioid agonists produced dose-dependent antinociception, constipation and respiratory depression. For antinociception, morphine, fentanyl and oxycodone were full agonists, buprenorphine and M6G were partial agonists, whereas DPDPE and U69,593 had low potency. For constipation, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, morphine produced a bell-shaped dose-response curve, whereas DPDPE and U69,593 were inactive. For respiratory depression, morphine, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, whereas DPDPE and U69,593 were inactive. The respiratory depressant effects of fentanyl and oxycodone were of short duration, whereas morphine, M6G and buprenorphine evoked prolonged respiratory depression.. For the seven opioids we assessed, no two had the same profile for evoking antinociception, constipation and respiratory depression, suggesting that these effects are differentially regulated. Our findings may explain the clinical success of 'opioid rotation'.. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Topics: Analgesics, Opioid; Animals; Benzeneacetamides; Buprenorphine; Castor Oil; Constipation; Diarrhea; Enkephalin, D-Penicillamine (2,5)-; Fentanyl; Hot Temperature; Male; Morphine; Morphine Derivatives; Oxycodone; Pain; Pyrrolidines; Rats, Sprague-Dawley; Respiratory Insufficiency

Buprenorphine is a potent analgesic with high affinity at μ, δ and κ and moderate affinity at nociceptin opioid (NOP) receptors. Nevertheless, NOP receptor activation modulates the in vivo activity of buprenorphine. Structure activity studies were conducted to design buprenorphine analogues with high affinity at each of these receptors and to characterize them in in vitro and in vivo assays.. Compounds were tested for binding affinity and functional activity using [(35) S]GTPγS binding at each receptor and a whole-cell fluorescent assay at μ receptors. BU08073 was evaluated for antinociceptive agonist and antagonist activity and for its effects on anxiety in mice.. BU08073 bound with high affinity to all opioid receptors. It had virtually no efficacy at δ, κ and NOP receptors, whereas at μ receptors, BU08073 has similar efficacy as buprenorphine in both functional assays. Alone, BU08073 has anxiogenic activity and produces very little antinociception. However, BU08073 blocks morphine and U50,488-mediated antinociception. This blockade was not evident at 1 h post-treatment, but is present at 6 h and remains for up to 3-6 days.. These studies provide structural requirements for synthesis of 'universal' opioid ligands. BU08073 had high affinity for all the opioid receptors, with moderate efficacy at μ receptors and reduced efficacy at NOP receptors, a profile suggesting potential analgesic activity. However, in vivo, BU08073 had long-lasting antagonist activity, indicating that its pharmacokinetics determined both the time course of its effects and what receptor-mediated effects were observed.. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Topics: Analgesics, Opioid; Animals; Anxiety; Behavior, Animal; Buprenorphine; CHO Cells; Cricetulus; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Hot Temperature; Humans; Male; Membrane Potentials; Mice, Inbred ICR; Narcotic Antagonists; Pain; Receptors, Opioid, mu

Anaesthetic and analgesic effects of three different injectable anaesthetic combinations for prepubertal gonadectomy (PPG) in cats were studied. One anaesthetic protocol was compared with a similar one for gonadectomy at traditional age (TAG). Kittens were randomly assigned to PPG or TAG. For PPG, three different protocols were compared: (1) intramuscular (IM) administration of 60 μg/kg dexmedetomidine plus 20 μg/kg buprenorphine followed by an IM injection of the anaesthetic agent (20 mg/kg ketamine) (DB-IM protocol); (2) oral transmucosal (OTM) administration of 80 μg/kg dexmedetomidine plus 20 μg/kg buprenorphine followed by an IM injection of 20 mg/kg ketamine combined with 20 µg/kg dexmedetomidine (DB-OTM protocol); (3) IM injection of a 40 μg/kg medetomidine-20 μg/kg buprenorphine-20 mg/kg ketamine combination (MBK-IM protocol). For TAG, a DB-IM protocol was used, but with different doses for dexmedetomidine (40 μg/kg) and ketamine (5 mg/kg). All cats (PPG and TAG) received a non-steroidal anti-inflammatory before surgery. Anaesthetic and analgesic effects were assessed pre- and postoperatively (until 6 h). Cumulative logit, linear and logistic regression models were used for statistical analysis. Compared with the DB-OTM protocol, the DB-IM and MBK-IM protocols provided better anaesthesia with fewer adverse effects in PPG cats. Postoperative pain was not significantly different between anaesthetic protocols. PPG and TAG cats anaesthetised with the two DB-IM protocols differed significantly only for sedation and pain scores, but sedation and pain scores were generally low. Although there were no anaesthesia-related mortalities in the present study and all anaesthetic protocols for PPG in cats provided a surgical plane of anaesthesia and analgesia up to 6 h postoperatively, our findings were in favour of the intramuscular (DB-IM and MBK-IM) protocols.

Topics: Anesthesia; Anesthetics; Animals; Buprenorphine; Cats; Dexmedetomidine; Female; Injections, Intramuscular; Ketamine; Medetomidine; Orchiectomy; Ovariectomy; Pain; Random Allocation; Sexual Maturation

Pain is believed to be undertreated in patients with dementia; however, no larger studies have been conducted. The aim was to investigate prevalent use of opioids in elderly with and without dementia in the entire elderly population of Denmark.. A register-based cross-sectional study in the entire elderly (≥65 years) population in 2010 was conducted. Opioid use among elderly with dementia (N = 35,455) was compared with elderly without (N = 870,645), taking age, sex, comorbidity, and living status into account.. Nursing home residents (NHRs) used opioids most frequently (41%), followed by home-living patients with dementia (27.5%) and home-living patients without dementia (16.9%). Buprenorphine and fentanyl (primarily patches) were commonly used among NHRs (18.7%) and home-living patients with dementia (10.7%) but less often by home-living patients without dementia (2.4%).. Opioid use in the elderly Danish population was frequent but particularly in patients with dementia and NHR, which may challenge patient safety and needs further investigation.

Topics: Age Factors; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Comorbidity; Cross-Sectional Studies; Dementia; Denmark; Female; Fentanyl; Humans; Male; Medical Staff, Hospital; Nursing Homes; Pain; Registries; Sex Factors

Opioid use disorder and pain often co-occur, complicating the treatment of each condition. Owing to its partial agonist properties, buprenorphine/naloxone (BUP/NX) may confer advantages over full agonist opioids for treatment of both conditions. The optimal dose of BUP/NX for comorbid pain is not known. We examined dose and other factors associated with pain intensity among patients initiating BUP/NX for opioid use disorder.. We studied 1106 patients initiating BUP/NX treatment for opioid use disorder from 2003 to 2010. Information on pain level, diagnoses, and treatment were extracted from medical records. Eligible patients had at least one self-reported pain intensity numerical rating score (NRS) within 30 days before BUP/NX initiation (baseline) and at least one between 15 and 90 days after BUP/NX initiation (during treatment). The primary outcome was NRS decrease (2 or greater) from baseline to during treatment. We used generalized estimating equations to model odds of the primary outcome with BUP/NX dose as the independent variable of interest in the subset of patients with a baseline NRS ≥ 2.. The sample was 94% male and 73% White. Mean age was 50. Psychiatric and non-opioid substance use comorbidities were common. The following demographic and clinical correlates were associated with a decrease in pain intensity: age 18-29 (compared to 30-39 and 40-49); absence of PTSD diagnosis and absence of a chronic pain diagnosis. BUP/NX dose was not associated with decreased pain intensity in bivariate or multivariable analysis.. BUP/NX maintenance treatment was generally consistent with improvements in pain intensity; however, factors other than BUP/NX dose contribute to improved pain intensity among those initiating the medication.

Topics: Adolescent; Adult; Analgesics, Opioid; Buprenorphine; Comorbidity; Female; Humans; Male; Middle Aged; Naloxone; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Pain Measurement; Retrospective Studies; Treatment Outcome; Young Adult

Sustained-release formulations of analgesic drugs are promising alternatives to repeated drug injections. Here, we compared a sustained-release formulation of buprenorphine (SB, 2.2 mg/kg) with a standard protocol of three injections of buprenorphine (Temgesic, 0.1 mg/kg/8 h) in mice. Buprenorphine serum concentration and analgesic action (thermal sensitivity) were determined in healthy mice. Additionally, the pain relief properties of both protocols were assessed after laparotomy using physiological and ethological measures of pain and recovery. Serum concentrations and thermal sensitivity tests indicated duration of action of at least 4 h (but less than 8 h) with the Temgesic protocol, and 24-48 h with SB. Behavioural and clinical parameters indicated at least partial pain relief after surgery for both protocols. Observed side-effects of buprenorphine independent of the protocol were increased activity, disturbed circadian rhythm and several abnormal behaviours. A tendency for decreased food and water intake as well as body weight reduction was also seen. Body weight decreased significantly in animals that received three injections of Temgesic, regardless of whether surgery was performed or not (P = 0.015; P = 0.023), hinting at a stress response towards this repeated intervention. In conclusion, an application interval of 8 h (Temgesic) appears too long and might lead to repeated periods with insufficient analgesia in animals undergoing lasting and/or substantial pain after surgery. In comparison to the standard protocol, SB provided a long-lasting, assured analgesia without possible stressful repeated injections in a standard surgical model, with only limited and acceptable behavioural side-effects.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Delayed-Action Preparations; Female; Hot Temperature; Injections, Subcutaneous; Laparotomy; Mice; Mice, Inbred C57BL; Pain; Pain Management; Pain Measurement

Opioids are among the most effective and commonly used analgesics in clinical practice for severe pain. However, the use of opioid medications is clinically limited by several adverse properties including dependence. While opioid dependence is a complex health condition, the treatment of HIV-infected individuals with opioid dependence presents additional challenges. The goal of this study was to examine the physical dependence to buprenorphine in the context of HIV.. Young adult male rats (Sprague-Dawley) were pretreated with HIV-1 envelope glycoprotein 120 (gp120) injected into the periaqueductal gray area (PAG) and we examined the impact on physical dependence to opioid.. It was found that the physical dependence to methadone occurred earlier than that to buprenorphine, and that gp120 did not enhance or precipitate the buprenorphine withdrawal.. The results suggest that buprenorphine could be the better therapeutic option to manage opioid dependence in HIV.

Topics: Animals; Buprenorphine; HIV Envelope Protein gp120; HIV Infections; Male; Methadone; Opioid-Related Disorders; Pain; Periaqueductal Gray; Rats; Rats, Sprague-Dawley

A 6-year-old, neutered male, domestic shorthair cat was presented with shifting leg lameness and palpable effusion of the carpal and tarsal joints. Blood work, arthrocentesis, and radiographs identified an immune-mediated erosive polyarthritis. The cat was positive for feline syncytia-forming virus, and with his signalment, was diagnosed with feline chronic progressive polyarthritis.

Topics: Amines; Analgesics; Animals; Anti-Inflammatory Agents; Arthritis; Buprenorphine; Cat Diseases; Cats; Chronic Disease; Cyclohexanecarboxylic Acids; Cyclosporine; Gabapentin; gamma-Aminobutyric Acid; Immunosuppressive Agents; Male; Pain; Prednisolone; Retroviridae Infections; Spumavirus

In this commentary on the medical use and regulation of transdermal buprenorphine we bring together our complimentary perspectives on the neuropharmacology of analgesics (Dr. Henningfield) and clinical medicine to address the needs of people with pain (Dr. Sun). Together, the neuropharmacology of buprenorphine, the clinical and abuse deterring benefits of the 7-day transdermal formulation, the low rates of harmful use and abuse detected in post-marketing surveillance studies, and the desirable clinical benefits in the elderly, in persons with compromised kidney function, and other populations support the regulation of buprenorphine comparable to tramadol-like analgesics. We support this approach and believe that it strikes the right balance of control to provide appropriate access to people with pain and their health providers, while still providing the basis for deterring harmful use and abuse.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Humans; Pain

Pain management with transdermal opioids is a useful choice in light of longer duration of action, being not affected by oral intake, and with less adverse effect Recently, transdermal fentanyl and buprenorphine are permitted for musculoskeletal non-malignant pain as a new indication. In Japan, one of the world's fastest aging society, it is a welcome step in terms of pain control. However, proper monitoring and management are required. This article reviews the pharmacology, therapeutic efficacy and adverse effect of buprenorphine transdermal patch, and clinical application in cancer pain management of fentanyl patch.

Topics: Analgesics, Opioid; Buprenorphine; Clinical Trials as Topic; Fentanyl; Humans; Pain; Pain Management; Time Factors

One of the key issues in the treatment of pain is to choose the appropriate route and dosage form of analgesics for each individual patient in pain. New drug forms of fentanyl absorbed by oral or nasal mucosa, and buprenorphine absorbed by rectal mucosa are described in this chapter. Only lipophilic opioids such as fentanyl and buprenorphine can be absorbed via the mucosa of oral or nasal cavity of the human body. The T max of rapid onset opioids (ROO) such as fentanyl buccal or sublingual tablets is the fastest among various dosage forms of opioid analgesics. However, such rapid increase in plasma concentration of fentanyl by ROO formulations may cause the risk of respiratory depression. Safe ways to use ROO analgesics are described.

Topics: Administration, Mucosal; Administration, Oral; Analgesics, Opioid; Buprenorphine; Fentanyl; Humans; Nasal Mucosa; Pain; Rectal Absorption

Transdermal buprenorphine (TDB) is a widely used analgesic for moderate pain. TDB is generally well tolerated, but both irritant and allergic contact dermatitis occur at patch application sites. Oral opioid tolerance in patients with allergic contact dermatitis to TDB remains controversial. Here, we describe 3 patients with allergic contact dermatitis to TDB who subsequently used oral opioid derivatives without adverse reactions. Thus, oral intolerance to opioid derivatives is not a rule in patients with allergic contact dermatitis to TDB, but the possibility should be taken into consideration.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Dermatitis, Allergic Contact; Female; Humans; Injections, Intradermal; Male; Middle Aged; Pain; Withholding Treatment

Topics: Analgesics, Opioid; Buprenorphine; Humans; Pain

Topics: Analgesics, Opioid; Buprenorphine; Humans; Pain

This study evaluated the prescribing trends of four commonly prescribed strong opioids in primary care and explored utilization in non-cancer and cancer users.. This cross-sectional study was conducted from 2000 to 2010 using the UK Clinical Practice Research Datalink. Prescriptions of buprenorphine, fentanyl, morphine and oxycodone issued to adult patients were included in this study. Opioid prescriptions issued after patients had cancer medical codes were defined as cancer-related use; otherwise, they were considered non-cancer use. Annual number of prescriptions and patients, defined daily dose (DDD/1000 inhabitants/day) and oral morphine equivalent (OMEQ) dose were measured in repeat cross-sectional estimates.. In total, there were 2,672,022 prescriptions (87.8% for non-cancer) of strong opioids for 178,692 users (59.9% female, 83.9% non-cancer, mean age 67.1 ± 17.0 years) during the study period. The mean annual (DDD/1000 inhabitants/day) was higher in the non-cancer group than in the cancer group for all four opioids; morphine (0.73 ± 0.28 vs. 0.12 ± 0.04), fentanyl (0.46 ± 0.29 vs. 0.06 ± 0.24), oxycodone (0.24 ± 0.19 vs. 0.038 ± 0.028) and buprenorphine (0.23 ± 0.15 vs. 0.008 ± 0.006). The highest proportion of patients were prescribed low opioid doses (OMEQ ≤ 50 mg/day) in both non-cancer (50.3%) and cancer (39.9%) groups, followed by the dose ranks of 51-100 mg/day (26.2% vs. 28.7%), 101-200 mg/day (15.1% vs. 19.2%) and >200 mg/day (8.25% vs. 12.1%).. There has been a huge increase in strong opioid prescribing in the United Kingdom, with the majority of prescriptions for non-cancer pain. Morphine was the most frequently prescribed, but the utilization of oxycodone, buprenorphine and fentanyl increased markedly over time.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Cross-Sectional Studies; Drug Prescriptions; Drug Utilization; Female; Fentanyl; Humans; Male; Middle Aged; Morphine; Oxycodone; Pain; Practice Patterns, Physicians'; Primary Health Care; United Kingdom; Young Adult

A few cases of adverse reactions linked to erroneous use of transdermal opioid patches have been reported in the literature. The aim of this study was to describe and characterize medication errors (MEs) associated with use of transdermal fentanyl and buprenorphine.. All events concerning transdermal opioid patches reported between 2004 and 2011 to a regional incident reporting system and assessed as MEs were scrutinized and characterized. MEs were defined as "a failure in the treatment process that leads to, or has the potential to lead to, harm to the patient".. In the study 151 MEs were identified. The three most common error types were wrong administration time 67 (44%), wrong dose 34 (23%), and omission of dose 20 (13%). Of all MEs, 118 (78%) occurred in the administration stage of the medication process. Harm was reported in 26 (17%) of the included cases, of which 2 (1%) were regarded as serious harm (nausea/vomiting and respiratory depression). Pain was the most common adverse reaction reported.. Of the reported MEs related to transdermal fentanyl and buprenorphine, most occurred during administration. Improved routines to ascertain correct and timely administration and educational interventions to reduce MEs for these drugs are warranted.

Topics: Adverse Drug Reaction Reporting Systems; Analgesics, Opioid; Buprenorphine; Fentanyl; Humans; Medication Errors; Pain; Transdermal Patch

To evaluate analgesic effects of an improved sustained-release buprenorphine (BUP-SR) formulation administered to mice.. 36 male Swiss-Webster mice.. Mice were assigned to each of 3 treatment groups (n = 12 mice/group). Treatments were administered SC (vehicle [control treatment], 1.5 mg of buprenorphine hydrochloride [BUP-HCl]/kg, and 1.5 mg of BUP-SR/kg). Mice were evaluated (total activity, gastrointestinal tract motility, respiratory rate, cataleptic behavior, and tall-flick and hot plate nociception tests) to determine behavioral and physiologic responses at 4, 24, and 48 hours after treatment administration. Body weight and respiratory rate were measured before and at each time point after treatment administration.. SC administration of BUP-SR resulted in significant antinociception effects for 48 hours for the hot plate and tall-flick nociception tests without substantial adverse effects. Gastrointestinal tract motility and total activity were higher at 4 hours for mice receiving BUP-SR than for mice receiving the vehicle, but values were the same between these groups at 24 and 48 hours. The BUP-SR group had a lower respiratory rate than did the control group at all times after treatment administration. Mice treated with BUP-SR had no significant changes in body weight during the study, whereas mice treated with BUP-HCl had a significant decrease in body weight at 24 and 48 hours.. BUP-SR administration resulted in antinociception effects for 48 hours. Results of this study indicated that the improved BUP-SR formulation could be safely administered SC and conferred superior analgesia, compared with that for BUP-HCl, in mice.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Delayed-Action Preparations; Male; Mice; Pain; Pain Measurement; Random Allocation

Based on in vitro assays and select animal models, buprenorphine is commonly called a 'partial agonist'. An implication is that it should produce less analgesic effect in humans than so-called 'full agonists' such as morphine or fentanyl. However, buprenorphine has a multimechanistic pharmacology, and thus partial agonism at a specific receptor is not particularly relevant to its overall analgesic action. We review published clinical trials that directly compared the magnitude of buprenorphine's analgesic effect to analgesics commonly considered full agonists.. Due to different signal transduction pathways, a drug can be a full agonist on one endpoint and a partial agonist on another. Therefore, we limited the present review to buprenorphine's analgesic effect.. Twenty-four controlled clinical trials were identified, plus a case report and dose-response curve. Based on complete or comparable pain relief, in buprenorphine had full clinical analgesic efficacy in 25 of the 26 studies.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Controlled Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Partial Agonism; Humans; Pain; Signal Transduction

Topics: Analgesics, Opioid; Buprenorphine; Drug Prescriptions; Female; Fentanyl; Humans; Male; Morphine; Oxycodone; Pain; Practice Patterns, Physicians'; Primary Health Care

Effective pain medication is important for animal stewardship and valid research results. We compared the pharmacokinetic assessments of standard, immediate-release buprenorphine (Bup IR) and a sustained-release buprenorphine formulation (Bup SR Lab) in male C57BL/6J mice, a mouse strain commonly used in biomedical research. We postulated that the administration of Bup SR Lab would achieve a more persistent blood drug concentration (>1 ng/mL) compared with single-dose Bup IR. The study assumed a blood buprenorphine concentration of 1 ng/mL as the minimum that may result in adequate analgesia, as previously reported. The 7 experimental groups included Bup IR (0.03, 0.05, 0.1, and 2 mg/kg), Bup SR Lab (0.3 and 1.2 mg/ kg), and saline placebo (0.7 mL/100 g). Blood sampling occurred at 0.5, 1, 3, 6, 12, 24, 48, and 72 h for evaluation by using a forensic ELISA. Bup IR at 0.03 and 0.05 mg/kg and Bup SR Lab at 0.3 mg/kg failed to obtain maximal blood concentrations (Cmax) above 1 ng/mL. All other doses (0.1 and 2 mg/kg Bup IR and 1.2 mg/kg Bup SR Lab) reached a Cmax above 1 ng/mL within 3 h after injection. In addition, 1.2 mg/kg Bup SR Lab and 2 mg/kg Bup IR provided blood concentrations above 1 ng/mL for up to 12 h, and 0.1 mg/kg Bup IR achieved this criterion for as long as 3 h. In conclusion, Bup SR Lab at 1.2 mg/kg and Bup IR at 0.1 or 2.0 mg/kg achieve or surpass the published threshold for adequate analgesia in mice.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Delayed-Action Preparations; Male; Mice, Inbred C57BL; Pain; Pain Measurement

Buprenorphine and carprofen, 2 of the most commonly used analgesics in mice, must be administered every 8 to 12 h to provide sustained analgesia. Sustained-release (SR) formulations of analgesics maintain plasma levels that should be sufficient to provide sustained analgesia yet require less frequent dosing and thus less handling of and stress to the animals. The pharmacokinetics of SR formulations of buprenorphine (Bup-SR), butorphanol (Butp-SR), fentanyl (Fent-SR), carprofen (Carp-SR), and meloxicam (Melox-SR) were evaluated in mice over 72 h and compared with those of traditional, nonSR formulations. Bup-SR provided plasma drug levels greater than the therapeutic level for the first 24 to 48 h after administration, but plasma levels of Bup-HCl fell below the therapeutic level by 4 h. Fent-SR maintained plasma levels greater than reported therapeutic levels for 12 h. Therapeutic levels of the remaining drugs are unknown, but Carp-SR provided plasma drug levels similar to those of Carp for the first 24 h after administration, whereas Melox-SR had greater plasma levels than did Melox for the first 8 h. Butp-SR provided detectable plasma drug levels for the first 24 h, with a dramatic decrease over the first 4 h. These results indicate that Bup-SR provides a stable plasma drug level adequate for analgesia for 24 to 48 h after administration, whereas Carp-SR, Melox-SR, Fent-SR, and Butp-SR would require additional doses to provide analgesic plasma levels beyond 24 h in mice.

Topics: Analgesics; Animals; Buprenorphine; Butorphanol; Carbazoles; Delayed-Action Preparations; Female; Meloxicam; Mice; Pain; Thiazines; Thiazoles

Topics: Acetaminophen; Analgesics; Buprenorphine; Clinical Protocols; Dementia; Female; gamma-Aminobutyric Acid; Humans; Male; Morphine; Pain; Pain Management

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Buprenorphine; Female; Humans; Male; Morphine; Neoplasms; Pain

Many head and neck cancer (HNC) patients experience painful therapy-related mucositis and dermatitis. This prospective observational study evaluated transdermal buprenorphine use in HNC patients to relieve treatment-related pain. During treatment with paracetamol or tramadol, visual analogue scale (VAS)-pain scores >30/100 occurred in 26/45 patients 4 weeks after starting cancer therapy, persisting for ≥2 weeks after treatment. These patients subsequently received transdermal buprenorphine. Pain therapy should be more accurately up-titrated to the maximum recommended dose (140 μg/hr) where necessary to maintain pain scores ≤30/100 and, for some patients, should be continued for 6 weeks after the last cancer treatment day.

Topics: Administration, Cutaneous; Aged; Analgesics, Opioid; Buprenorphine; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mucositis; Pain; Pain Management; Pain Measurement; Prospective Studies; Radiation Injuries; Radiodermatitis

Topics: Administration, Cutaneous; Adult; Analgesics, Opioid; Buprenorphine; Dermatitis, Allergic Contact; Erythema Nodosum; Female; Humans; Male; Middle Aged; Pain; Patch Tests

Topics: Analgesics, Opioid; Buprenorphine; Humans; Morphine; Pain; Pain Management; Respiration

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Humans; Pain

The authors examined the potential of the cyclooxygenase 2 (COX-2) inhibitor carprofen to reproducibly induce anastomotic leakage. In experiment 1, an anastomosis was constructed in both ileum and colon of 20 rats, and they were given carprofen (5 mg/kg subcutaneously every 24 hours) or buprenorphine (0.02 mg/kg subcutaneously every 12 hours). In another 20 rats an anastomosis was constructed in either ileum or colon, and all received carprofen (experiment 2). Animals were sacrificed after 3 days. In experiment 1, the ileal dehiscence rate was 60% in the carprofen group and 0% in the buprenorphine group (P = .0108). Colonic anastomoses in both groups remained patent. In experiment 2, the anastomotic leakage rate was 80% in ileum and 0% in colon. Thus, COX-2 inhibitors can severely interfere with intestinal healing, particularly in the ileum. Perioperative administration of carprofen yields a unique model for anastomotic leakage, which allows translational research on the effectiveness of perisuture line reinforcement.

Topics: Analgesics, Opioid; Anastomotic Leak; Animals; Buprenorphine; Carbazoles; Collagen; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Ileum; Male; Matrix Metalloproteinase 2; Pain; Perioperative Period; Pressure; Rats; Rats, Wistar; Surgical Wound Dehiscence; Weight Loss

To investigate the safety, sedative and analgesic properties of methadone in combination with acepromazine prior to neutering in cats.. Controlled clinical, block randomized, prospective, blinded study designed for regulatory purposes.. 24 female and 21 male healthy cats.. Cats received one of three opioids combined with acepromazine (0.05 mg kg(-1) ) intramuscularly (IM) for premedication: Group 1: buprenorphine (0.02 mg kg(-1) ), group 2: methadone (0.5 mg kg(-1) ), group 3 butorphanol (0.4 mg kg(-1) ). Sedation was assessed 30 minutes after premedication using a visual analogue scale (VAS) and simple descriptive scale. Anaesthesia was induced with alfaxalone and maintained with isoflurane in oxygen. Surgical ovariohysterectomy or castration was performed. Pain was assessed using an interactive VAS (IVAS) and mechanical nociceptive threshold (MNT) with a pressure rate onset device. Methadone (0.5 mg kg(-1) IM) and meloxicam (0.2 mg kg(-1) subcutaneously) were provided 6 and 8 hours after premedication respectively, or together as rescue analgesia (IVAS above 50).. Sedation scores, induction agent dose, pain scores at all time points and rescue analgesia were not statistically different between groups. In methadone treated cats there was no significant variation in MNT over time, suggesting a possible anti-hyperalgesic action, whereas in the other two groups lower thresholds were recorded at various time points after surgery compared to baseline. No cats required rescue analgesia after the second dose of methadone. No perioperative adverse effects occurred.. Methadone provided comparable sedation and analgesia to both buprenorphine and butorphanol when combined with acepromazine. Differences in analgesic efficacy between opioids might have been undetectable because of the surgical model and surgeon competency. Nevertheless, methadone is an effective analgesic in cats and its administration prior to feline neutering may be advantageous.

Topics: Acepromazine; Analgesics, Opioid; Anesthesia, General; Animals; Behavior, Animal; Buprenorphine; Butorphanol; Cats; Dopamine Antagonists; Drug Therapy, Combination; Female; Hysterectomy; Male; Methadone; Orchiectomy; Ovariectomy; Pain

The Substitution Treatment National Registry provided from mid 2006 till mid 2009 an exhaustive documentation on all patients being prescribed methadone or buprenorphine in Belgium. This endeavour was possible through cooperation of all community pharmacies and their representative organizations was supported at the time by the former Health federal minister. The Liberal belgian opiate medical substitution process authorizes untill now de facto any doctor to prescribe methadone and pharmacists are supported to dispense it. Results show the regional, provincial and county numbers of professionals and patients prevalence in the population. Nationwide, n = 16974 patients (prevalence for population aged 20-64: 26/10000) have been offered substitution from mid 2008 till mid 2009, n = 3390 pharmacies 164,4% of all pharmacies) and n = 2937 MDs (16,75% of all MDs) have been involved. Subutex or Suboxone have been dispensed to 11,1% of substitution patients with 7,4% receiving only buprenorphine on a yearly basis. Number of substitution patients by MD and prevalence by gender, age group and region are presented. Important variations are observed locally, possibly mirroring heroin addiction due to widespread access to substitution treatment. Younger patients are more prevalent in semi rural or border areas. The exhaustivity of available data enables also to observe patients quitting substitution altogether and a strong difference of maintenance rate is observed favoring methadone over buprenorphine.

Topics: Adult; Age Factors; Analgesics, Opioid; Belgium; Buprenorphine; Female; Heroin Dependence; Humans; Male; Middle Aged; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Pharmacies; Physicians; Prevalence; Sex Factors; Young Adult

Buprenorphine (BUP) is a partial agonist at μ-, δ- and ORL1 (opioid receptor-like)/nociceptin receptors and antagonist at the κ-opioid receptor site. BUP is known to have both analgesic as well as antihyperalgesic effects via its central activity, and is used in the treatment of moderate to severe chronic pain conditions. Recently, it was shown that intravenous (IV) administration of 0.2mg/70 kg BUP modulates the blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) response to acute noxious stimuli in healthy human subjects. The present study extends these observations by investigating the effects of BUP dose and route of administration on central nervous system (CNS) pain circuitry. Specifically, the modulation of evoked pain BOLD responses and resting state functional connectivity was measured following IV (0.1 and 0.2mg/70 kg) and sublingual (SL) (2mg) BUP administration in healthy human subjects. While 0.1mg/70 kg IV BUP is sub-analgesic, both 0.2mg/70 kg IV BUP and 2.0mg SL BUP are analgesic doses of the drug. Evoked BOLD responses were clearly modulated in a dose-dependent manner. The analgesic doses of BUP by both routes of administration yielded a potentiation in limbic/mesolimbic circuitry and attenuation in sensorimotor/sensory-discriminative circuitry. In addition, robust decreases in functional connectivity between the putamen and the sensorimotor/sensory-discriminative structures were observed at the two analgesic doses subsequent to measuring the maximum plasma BUP concentrations (C(max)). The decreases in functional connectivity within the sensorimotor/sensory-discriminative circuitry were also observed to be dose-dependent in the IV administration cohorts. These reproducible and consistent functional CNS measures at clinically effective doses of BUP demonstrate the potential of evoked pain fMRI and resting-state functional connectivity as objective tools that can inform the process of dose selection. Such methods may be useful during early clinical phase evaluation of potential analgesics in drug development.

Topics: Administration, Sublingual; Adult; Analgesics, Opioid; Brain; Buprenorphine; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Injections, Intravenous; Magnetic Resonance Imaging; Male; Pain

Assessment of locomotion following exposure of animals to noxious or painful stimuli can offer significant insights into underlying mechanisms of injury and the effectiveness of various treatments. We developed a novel method to track the movement of mice in two dimensions using computer vision and neural network algorithms. By using this system we demonstrated that mice exposed to chlorine (Cl(2)) gas developed impaired locomotion and increased immobility for up to 9 h postexposure. Postexposure administration of buprenorphine, a common analgesic agent, increased locomotion and decreased immobility times in Cl(2)- but not air-exposed mice, most likely by decreasing Cl(2)-induced pain. This method can be adapted to assess the effectiveness of various therapies following exposure to a variety of chemical and behavioral noxious stimuli.

Topics: Algorithms; Animals; Artificial Intelligence; Buprenorphine; Chlorine; Computers; Inhalation Exposure; Locomotion; Male; Mice; Mice, Inbred C57BL; Neural Networks, Computer; Pain; Software

Topics: Analgesics, Opioid; Buprenorphine; Humans; Opioid-Related Disorders; Pain

Topics: Analgesics, Opioid; Buprenorphine; Drug and Narcotic Control; Drug Approval; Health Services Accessibility; Healthcare Disparities; Humans; Legislation, Drug; Methadone; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Oxycodone; Pain; Prescription Drugs; Substance-Related Disorders; United States; United States Food and Drug Administration

Mechanical allodynia during ambulation in osteoarthritis (OA) animal models can be assessed as decreased extent of loading or decreased duration of loading. We propose to measure gait adaptation to pain by both mechanisms with the development of Limb Idleness Index (LII) in a rat model of knee OA.. Rats were assigned to anterior cruciate ligament transection (ACLT), Sham, or Normal group (n = 6). Gait data were collected at pre-injury, 1, 2, 3 and 6 months post-injury. Ratios of target print intensity, anchor print intensity, and swing duration were combined to obtain LII. The association of gait changes with pain was assessed by buprenorphine treatment at 3 and 6 months post-injury. At 6 months, OA-related structural changes in knee joints were examined by μCT and results from histological scoring were correlated with LII.. As compared to pre-injury level (range 0.75-1.20), LII in ACLT group was increased at 6 months post-injury, which was significantly higher than that in Sham and Normal groups (P = 0.024). The increase in LII in ACLT group was effectively reversed by buprenorphine treatment (P = 0.004). ACLT group exhibited a significantly higher maximum Osteoarthritis Research Society International (OARSI) score as compared to Sham (P = 0.005) and Normal (P = 0.006) groups. Significant correlation was found between LII and side-to-side difference in OARSI score (r = 0.893, P < 0.001).. LII presents a good measurement for OA-related knee pain in rat model.

Topics: Adaptation, Physiological; Analgesics, Opioid; Animals; Arthritis, Experimental; Buprenorphine; Extremities; Female; Gait; Movement; Osteoarthritis; Pain; Pain Measurement; Radiography; Rats; Rats, Sprague-Dawley; Stifle; Weight-Bearing

Immunization with complete Freund adjuvant (CFA) or incomplete Freund adjuvant (IFA) is commonly viewed as painful, yet rodents may not receive analgesics due to concerns that these drugs affect the desired immune responses. Here we tested the hypothesis that pain associated with immunization with CFA or IFA in mice can be relieved without compromising the effectiveness of the immune response. After subcutaneous immunization in the leg with antigen in CFA or IFA, mice were assessed for signs of pain by using behavioral tests, including unrestricted locomotion in an open field, forced running on an automated treadmill, and voluntary wheel running. Effects of the analgesics acetaminophen, meloxicam, and buprenorphine on behavioral and antibody responses were assessed after primary and secondary immunization with the model antigen ovalbumin and after repeated immunization with a limiting dose of recombinant protective antigen from Bacillus anthracis. Open field activity and the distance traveled during forced gait analysis and voluntary wheel running both decreased after immunization. Treatment with each of the analgesics normalized some but not all of these behaviors but did not decrease the mean or maximal antibody titer after primary or repeated immunization with a moderate dose of ovalbumin or after repeated immunization with a limiting dose of protective antigen. In summary, after immunization with CFA or IFA, mice showed behavioral responses suggestive of pain. Acetaminophen, meloxicam, and buprenorphine attenuated these effects without decreasing antibody responses. Therefore, the use of these analgesics for managing rodent pain associated with CFA- or IFA-containing vaccines can be encouraged.

Topics: Acetaminophen; Analgesia; Analgesics; Animals; Animals, Laboratory; Antibody Formation; Behavior, Animal; Buprenorphine; Freund's Adjuvant; Immunization; Lipids; Meloxicam; Mice; Pain; Pain Management; Thiazines; Thiazoles

Buprenorphine HCl is a common analgesic for laboratory mice undergoing surgical procedures. The documented duration of action of buprenorphine HCl is as short as 3 to 5 h in mice, potentially necessitating readministration for continued analgesia. A long-acting buprenorphine formulation would reduce handling-associated stress and provide uninterrupted analgesia. This study used the hot-plate assay to assess the antinociceptive effects of a single injection of sustained-release buprenorphine (bup-SR), buprenorphine-HCl (bup-HCl), and saline over 72 h in young adult male BALB/cJ and SWR/J mice. SWR/J mice had shorter baseline latencies than did BALB/cJ mice, possibly reflecting greater sensitivity to thermal nociception. Relative increase from baseline latency (% maximal possible effect) was significant for buprenorphine-SR at 2, 6, and 12 h compared with saline. According to results from a hot-plate assay, the analgesic efficacy of buprenorphine-SR appears to last at least 12 h in male BALB/cJ and SWR/J mice.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Pain; Pain Measurement; Species Specificity

Buprenorphine is the most commonly used drug for peri-operative pain relief in laboratory rodents. The systemic concentrations of buprenorphine were measured in mice following administration intravenously (i.v.), subcutaneously (s.c.), orally by gavage and by voluntary ingestion, to determine the post-administration serum concentration of buprenorphine. Voluntarily ingested buprenorphine resulted in long-lasting high serum concentrations, as did oral gavage administration (24 h serum concentration: 110 ng h/mL for both routes of administration). In contrast, buprenorphine administered parenterally remained in the circulation for a substantially shorter time (24 h serum concentration for i.v. and s.c. were 40 ng h/mL and 30 ng h/mL, respectively). This marked difference was probably due to the higher dose used for oral administration, which is regarded necessary for sufficient analgesic effect, and to the slower absorption of the oral boli, as well as saturation of the hepatic buprenorphine metabolising pathways. Voluntary ingestion of buprenorphine was found to constitute a practical way to provide laboratory mice with efficient pain relief.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Buprenorphine; Eating; Injections, Intravenous; Injections, Subcutaneous; Male; Mice; Mice, Inbred Strains; Pain; Time Factors

To assess the antinociceptive efficacy of transdermal (TD) buprenorphine (B) in dogs, a prospective, positive-controlled experimental study was performed in 10 healthy Beagles. In an open label crossover design, the dogs initially received intravenous B (IVB, 0.02 mg kg(-1)) as a positive control, followed by TDB (52.5 μg h(-1)) 4 months later. Blood was collected at regular intervals for determination of the plasma concentrations of B ([B]) and its metabolite norbuprenorphine. The antinociceptive efficacy was assessed using thermal and mechanical models of nociception. The peak concentration [B] was 1.54 ng mL(-1) (±1.98) 60 h after TDB application, although three dogs had no measurable [B] after TDB. Maximum thermal threshold (TT) was 52.6 °C (±0.48) at 1h after IVB administration and 51.63 °C (±1.01) 72 h after TDB application. The significant increase in TT indicated that effective antinociception was achieved beyond 36 h after the application of TDB, lasting until patch removal. There was hysteresis between [B] and the antinociceptive effect.

Topics: Administration, Cutaneous; Analgesics, Opioid; Animals; Buprenorphine; Cross-Over Studies; Dogs; Female; Male; Pain; Prospective Studies; Random Allocation; Treatment Outcome

Sensory neuron opioid receptors are targets for spinal, epidural, and peripheral opioid application. Although local nerve growth factor (NGF) has been identified as a mediator of sensory neuron μ-opioid receptor (MOR) up-regulation, the signaling pathways involved have not been yet identified.. Wistar rats were treated with intraplantar vehicle, Freund's complete adjuvant, NGF, NGF plus intrathecal p38 mitogen-activated protein kinase (MAPK) inhibitors, or NGF plus extracellular signal-regulated kinase-1/2 MAPK inhibitors. After 4 days of treatment, paw pressure thresholds of an intraplantar full (fentanyl) or partial (buprenorphine) opioid agonist were determined by algesiometry. Tissue samples from rat dorsal root ganglia were subjected to radiolabeled ligand binding, Western blot analysis, and confocal immunofluorescence.. Exogenous and endogenous NGF resulting from Freund's complete adjuvant inflammation produced significant potentiation and enhanced efficacy in fentanyl- and buprenorphine-induced dose-dependent antinociception, respectively. Furthermore, in the ipsilateral dorsal root ganglia, NGF produced a significant increase in MOR binding sites, proteins, and immunoreactive neurons. In parallel, phosphorylated p38-MAPK protein, the number of phosphorylated p38-MAPK immunoreactive neurons expressing MOR in dorsal root ganglia, and the peripherally directed axonal transport of MOR significantly increased. Finally, NGF-induced effects occurring in dorsal root ganglia, on axonal transport, and on the potentiation or enhanced efficacy of opioid antinociception were abrogated by inhibition of p38, but not extracellular signal-regulated kinase-1/2, MAPK.. Local NGF through activation of the p38-MAPK pathway leads to adaptive changes in sensory neuron MOR toward enhanced susceptibility to local opioids. This effect may act as a counter-regulatory response to p38-MAPK-induced pain (e.g., inflammatory pain) to facilitate opioid-mediated antinociception.

Topics: Analgesics, Opioid; Animals; Blotting, Western; Buprenorphine; Dose-Response Relationship, Drug; Drug Synergism; Fentanyl; Fluorescent Antibody Technique; Male; Nerve Growth Factor; p38 Mitogen-Activated Protein Kinases; Pain; Radioligand Assay; Rats; Rats, Wistar; Receptors, Opioid, mu; Sensory Receptor Cells; Up-Regulation

Certain behavioral features of buprenorphine, including a bell-shaped curve for antinociception and attenuation of alcohol consumption, are thought to be mediated by activation of nociceptin/orphanin FQ peptide (NOP) receptors, despite moderate affinity and low efficacy at NOP receptors. We hypothesized that ligands with buprenorphine's physical properties, but possessing increased NOP receptor affinity and efficacy, would improve the profile as a drug abuse medication and reduce addiction liability. Using this strategy, we designed several compounds with universally high affinity, i.e., less than 10 nM at μ, δ, κ, and NOP receptors. Among these, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028) has high affinity at all opioid receptors and increased NOP receptor efficacy in vitro in the [³⁵S]GTPγS binding assay, however, while still being a partial agonist. In vivo, BU08028 was evaluated in an acute thermal antinociception assay, for its ability to induce conditioned place preference (CPP), and for its effect on cocaine-induced CPP. BU08028 is a very potent long-lasting analgesic. It produces an increase in locomotor activity and a significant CPP. As a pretreatment to cocaine, BU08028 does not alter cocaine CPP but causes a further increase in cocaine-induced locomotor activity. The analgesic, rewarding, and stimulant effects are probably caused by μ receptor stimulation. It is likely that with BU08028, a partial agonist at both NOP and μ receptors, μ-mediated activity overpowers NOP-mediated effects. Thus, it is possible that a different buprenorphine analog that is a universal high-affinity opioid ligand but with "full agonist" activity at NOP may counteract traditional opioid-mediated effects such as antinociception and reward.

Topics: Acute Disease; Analgesics, Opioid; Animals; Buprenorphine; CHO Cells; Cocaine; Cricetinae; Cricetulus; Disease Models, Animal; Humans; Ligands; Male; Mice; Mice, Inbred ICR; Pain; Pain Measurement; Protein Binding; Receptors, Opioid; Reward

Topics: Analgesics, Opioid; Buprenorphine; Cocaine; Drug Overdose; Drug Prescriptions; Health Knowledge, Attitudes, Practice; Heroin; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Substance-Related Disorders; United States

Topics: Analgesics, Opioid; Buprenorphine; Humans; Pain; Perioperative Care; Phenols; Tapentadol; Tramadol

Topics: Anti-Bacterial Agents; Buprenorphine; Gentamicins; Humans; Opiate Substitution Treatment; Pain; Physician Assistants; Tobramycin

Topics: Analgesics, Opioid; Buprenorphine; Humans; Pain; Practice Patterns, Physicians'

To evaluate the use of a buprenorphine transdermal patch (Transtec*) in routine clinical practice, including dosage, indications, efficacy and tolerability.. This prospective, open-label, non-comparative, non-interventional, post-marketing study was performed in Poland by 339 investigators in a range of clinical practice settings. Patients with chronic moderate to severe cancer pain, or chronic severe non-cancer pain that was insufficiently controlled by non-opioids, were prescribed buprenorphine transdermal patch 35, 52.5 or 70 μg/hour (changed twice weekly), and followed up for 3 months. Additional analgesia, and adjuvant/supportive treatments were allowed at the discretion of the physician.. The study enrolled 4030 patients, with a mean age of 62.8 years. Most patients had cancer-related pain (80.7%). Non-cancer pain was generally musculoskeletal or neuropathic. A starting dose of 35, 52.5 or 70 μg/hour was used in 73.4%, 21.5%, and 4.8% of patients, respectively. Buprenorphine dose was increased in 44.7% of patients during the observation, generally from 35 to 52.5 μg/hour. Mean pain intensity (using a 100 mm visual analogue scale) decreased by 73.5% from 62.3 mm at baseline to 16.5 mm after 3 months. Most patients rated pain relief as 'very good' (41.4%) or 'good' (44.5%). Sleep quality also improved. 48.1% of patients needed no additional analgesics during buprenorphine treatment. Most patients (96%) rated the buprenorphine transdermal patch as 'very easy' or 'easy' to change. The most common treatment-related reasons for discontinuation were lack of analgesic effect (3.3% of patients) and adverse drug reactions (ADRs, 0.8%). ADRs, all non-serious, occurred in 34 patients (0.8%), most commonly local skin reactions or vomiting. At study end, it was planned to continue treatment with transdermal buprenorphine in 70.1% of patients. The main limitations related to the observational study design, balanced by advantages gained from the 'real life' exploration of transdermal buprenorphine use.. In routine Polish clinical practice, transdermal buprenorphine was effective and generally well-tolerated in patients with chronic moderate to severe cancer pain or chronic severe non-malignant pain insufficiently controlled by non-opioids.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Chronic Disease; Female; Humans; Male; Middle Aged; Neoplasms; Pain; Poland; Product Surveillance, Postmarketing; Prospective Studies; Severity of Illness Index; Treatment Outcome; Young Adult

The FDA has approved the partial opioid agonist buprenorphine in a transdermal formulation (Butrans-Purdue) for treatment of moderate to severe chronic pain. Buprenorphine has been available in the US for years in parenteral formulations for pain and in sublingual tablets for opioid dependence. Transdermal buprenorphine has been available in Europe for several years.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Chronic Disease; Drug Interactions; Humans; Pain; Randomized Controlled Trials as Topic; Receptors, Opioid, mu

A limitation of animal models of central pain is their inability to recapitulate all clinical characteristics of the human condition. Specifically, many animal models rely on reflexive measures of hypersensitivity and ignore, or cannot assess, spontaneous pain, the hallmark characteristic of central pain in humans. Here, we adopt a conditioned place preference paradigm to test if animals with lesions in the anterolateral quadrant of the spinal cord develop signs consistent with spontaneous pain. This paradigm relies on the fact that pain relief is rewarding to animals, and has been used previously to show that animals with peripheral nerve injury develop tonic pain. With the use of 2 analgesic treatments commonly used to treat patients with central pain (clonidine infusion and motor cortex stimulation), we demonstrate that analgesic treatments are rewarding to animals with spinal cord lesions but not sham-operated controls. These findings are consistent with the conclusion that animals with spinal cord injury suffer from tonic pain.. The hallmark characteristic of central pain in humans is spontaneous pain. Animal models of central pain rely on reflexive measures of hypersensitivity and do not assess spontaneous pain. Demonstrating that animals with spinal cord injury suffer from tonic pain is important to study the etiology of central pain.

Topics: Analgesics; Animals; Buprenorphine; Clonidine; Conditioning, Operant; Disease Models, Animal; Electric Stimulation; Female; Hyperalgesia; Motor Cortex; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries

We showed recently that elevated brain levels of the chemokine stromal cell-derived growth factor-1α (SDF-1α/CXCL12, a ligand for the human immunodeficiency virus [HIV] co-receptor CXCR4) diminish the antinociceptive effect of morphine, but failed to influence buprenorphine-induced antinociception.. Because the HIV-1 coat protein, glycoprotein 120 (gp120) T-tropic strain, binds to the same receptor as SDF-1α/CXCL12, the present experiments were designed to investigate the consequence of administering gp120 to rat brain on buprenorphine-induced antinociception in the 54°C hot plate test. For comparative purposes, the effect of gp120 on an equi-antinociceptive dose of methadone was also examined.. A sterilized stainless-steel C313G guide cannula was implanted into the periaqueductal grey (PAG), a brain region critical for the processing of pain signals, and a primary site of action of many analgesics. Rats were pretreated with gp120, administered into the PAG.. The subsequent antinociception associated with methadone was diminished whereas buprenorphine-induced antinociception was unaffected. Buprenorphine thus appears to be a more effective analgesic than methadone in the presence of gp120 in the brain, a condition that is associated with HIV-related pain and infection.

Topics: Analgesia; Analgesics, Opioid; Animals; Buprenorphine; HIV Envelope Protein gp120; Hot Temperature; Male; Methadone; Pain; Pain Measurement; Pain Threshold; Periaqueductal Gray; Rats; Rats, Sprague-Dawley

Topics: Analgesics; Bone Density Conservation Agents; Bone Diseases, Metabolic; Buprenorphine; Dipyrone; Drug Therapy, Combination; Female; Humans; Naproxen; Osteoporosis, Postmenopausal; Pain; Vitamin D

Topics: Amines; Analgesia; Analgesics; Animals; Buprenorphine; Cat Diseases; Cats; Cyclohexanecarboxylic Acids; Drug Therapy, Combination; Gabapentin; gamma-Aminobutyric Acid; Injections, Intravenous; Male; Methadone; Multiple Trauma; Pain; Pain Measurement

The long-lasting high-affinity opioid buprenorphine has complex pharmacology, including ceiling effects with respect to analgesia and respiratory depression. Plasma concentrations of the major buprenorphine metabolites norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide approximate or exceed those of the parent drug. Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacologic activity of the two glucuronide metabolites, and in comparison with buprenorphine and norbuprenorphine.. Competitive inhibition of radioligand binding to human μ, κ, and δ opioid and nociceptin receptors was used to determine glucuronide binding affinities for these receptors. Common opiate effects were assessed in vivo in SwissWebster mice. Antinociception was assessed using a tail-flick assay, respiratory effects were measured using unrestrained whole-body plethysmography, and sedation was assessed by inhibition of locomotion measured by open-field testing.. Buprenorphine-3-glucuronide had high affinity for human μ (Ki [inhibition constant] = 4.9 ± 2.7 pM), δ (Ki = 270 ± 0.4 nM), and nociceptin (Ki = 36 ± 0.3 μM) but not κ receptors. Norbuprenorphine-3-glucuronide had affinity for human κ (Ki = 300 ± 0.5 nM) and nociceptin (Ki = 18 ± 0.2 μM) but not μ or δ receptors. At the dose tested, buprenorphine-3-glucuronide had a small antinociceptive effect. Neither glucuronide had significant effects on respiratory rate, but norbuprenorphine-3-glucuronide decreased tidal volume. Norbuprenorphine-3-glucuronide also caused sedation.. Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures, which occur after buprenorphine. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Buprenorphine; Cells, Cultured; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Female; Glucuronides; Humans; Male; Mice; Motor Activity; Nociceptin Receptor; Pain; Pain Measurement; Plethysmography, Whole Body; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Respiratory Insufficiency; Tidal Volume

Oral administration of buprenorphine is becoming a popular method of providing analgesia for laboratory rodents. The mixing of buprenorphine with flavoured jello, which rodents find palatable, is becoming a commonly used method as it is thought to improve the efficacy of oral buprenorphine by increasing the time available for it to be absorbed via the oral mucosa. The aim of this study was to assess the effect of various methods of buprenorphine administration (subcutaneous saline, subcutaneous buprenorphine [0.05 mg/kg], buprenorphine gavage [0.5 mg/kg], buprenorphine in jello [0.5 mg/kg] and buprenorphine in golden syrup [0.5 mg/kg]) on thermal antinociceptive thresholds in laboratory rats. Buprenorphine administered subcutaneously, by gavage, in jello and in syrup induced significant increases in thermal antinociceptive thresholds compared with saline. This effect was observed up to 5 h postadministration for buprenorphine administered subcutaneously and by gavage, but only for one hour postadministration for buprenorphine administered in jello and in syrup.

Topics: Administration, Oral; Analgesics, Opioid; Animal Feed; Animals; Buprenorphine; Eating; Feeding Behavior; Female; Food Preferences; Gelatin; Hot Temperature; Injections, Subcutaneous; Male; Pain; Pain Threshold; Rats; Rats, Inbred Lew; Rats, Wistar; Reaction Time

Topics: Administration, Cutaneous; Buprenorphine; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Narcotics; Oropharynx; Pain; Pain Measurement; Stomatitis

Pain complaints are common among individuals with opioid dependence. However, few studies investigate pain during opioid detoxification or the impact this pain has on continued opioid use. This secondary analysis utilized data from two Clinical Trials Network randomized controlled trials of buprenorphine-naloxone for short-term opioid detoxification to examine the extent to which pain was associated with continued opioid use during and immediately following a 13-day detoxification protocol. At follow-up, more severe pain was associated with a greater number of self-reported days of opioid use during the prior 30 days (p < .05) but was not associated with urine toxicology results collected at follow-up. These results, although mixed, have potentially important clinical implications for assessing and addressing pain during opioid detoxification. Pain that is experienced during and immediately following medically monitored detoxification may be associated with continued opioid use. These findings lend further support for continued research on pain among patients with opioid dependence.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Drug Combinations; Female; Follow-Up Studies; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Randomized Controlled Trials as Topic; Severity of Illness Index; Substance Withdrawal Syndrome

Topics: Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Drug Tolerance; Humans; Methadone; Naloxone; Opioid-Related Disorders; Pain; Pain Measurement

Buprenorphine is a mixed opiate receptor agonist-antagonist growing in popularity as an office-based treatment for opioid-dependent patients. It has high affinity, but only partial agonism at the micro-opioid receptor resulting in a ceiling analgesic effect. At higher doses, buprenorphine potentiates antagonism at the kappa-opioid receptor. These properties make buprenorphine an effective maintenance treatment for opioid-dependent patients. These same properties, however, can interfere with the management of acute pain in patients on maintenance buprenorphine therapy. We present a case of a young multisystem trauma patient in whom adequate analgesia could not be achieved due to buprenorphine treatment before and through the early course of admission. Discontinuation of buprenorphine allowed for appropriate pain management and successful analgesia. Further education of acute care clinicians about buprenorphine pharmacology and careful selection of patients for buprenorphine maintenance therapy are needed to avoid delays of pain control in trauma patients.

Topics: Accidents, Traffic; Adult; Analgesics, Opioid; Buprenorphine; Drug Interactions; Humans; Male; Narcotic Antagonists; Opioid-Related Disorders; Pain

Outpatient-based opioid treatment (OBOT) with buprenorphine is an important treatment for people with opioid dependence. No quantitative empirical research has examined rationales for use of illicit buprenorphine by U.S. opioid-dependent treatment seekers. The current study sequentially screened OBOT admissions (n = 129) during a 6-month period in 2009. This study had two stages: (a) a cross-sectional epidemiological analysis of new intakes and existing patients already receiving a legal OBOT prescription (n = 78) and (b) a prospective longitudinal cohort design that followed 76% of the initial participants for 3 months of treatment (n = 42). The primary aims were to establish 2009 prevalence rates for illicit buprenorphine use among people seeking OBOT treatment, to use quantitative methods to investigate reasons for this illicit use, and to examine the effect of OBOT treatment on illicit buprenorphine use behavior. These data demonstrate a decrease in illicit use when opioid-dependent treatment seekers gain access to legal prescriptions. These data also suggest that the use of illicit buprenorphine rarely represents an attempt to attain euphoria. Rather, illicit use is associated with attempted self-treatment of symptoms of opioid dependence, pain, and depression.

Topics: Adult; Buprenorphine; Cohort Studies; Cross-Sectional Studies; Depression; Female; Humans; Longitudinal Studies; Male; Middle Aged; Narcotics; Opioid-Related Disorders; Pain; Prevalence; Prospective Studies; Self Medication; United States

Visceral pain modulation by chronic stress in mice has been little studied. Electromyography (EMG) recording of abdominal muscle contractions, as a proxy to the visceromotor response (VMR), requires electrode implantation and post-surgical single housing (SH) which could affect the VMR to stress. To test this hypothesis, male mice had electrode implantation surgery (S) plus SH, or no surgery and were group housed (NS-GH) or single housed (NS-SH) and exposed to either water avoidance stress (WAS, 1 h/day) or left undisturbed in their home cages for 10 days. The VMR to phasic ascending colorectal distension (CRD) was assessed before (basal) and 24 h after 10 days of WAS or no stress using a surgery-free method of intraluminal colonic pressure (ICP) recording (solid-state manometry). WAS heightened significantly the VMR to CRD at 30, 45, and 60 mmHg in S-SH vs. NS-GH, but not compared to NS-SH conscious mice. Compared to basal CRD, WAS increased VMR at 60 mmHg in the S-SH group and decreased it at 30-60 mmHg in NS-GH mice, while having no effect in NS-SH mice. The average defecation during the hour of repeated WAS over 10 days was 1.9 and 2.4 fold greater in S-SH vs. NS-GH and NS-SH mice, respectively. These data indicate that the combination of S-SH required for VMR monitoring with EMG is an important component of repeated WAS-induced post-stress visceral hypersensitivity and defecation in mice.

Topics: Abdominal Muscles; Animals; Atropine; Buprenorphine; Colon; Defecation; Dilatation, Pathologic; Electrodes, Implanted; Electromyography; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Pain; Pain Threshold; Social Isolation; Stress, Psychological; Viscera; Water

There have been recent increases in the use of methadone and buprenorphine in the United States. Methadone is increasingly being used for pain management, and buprenorphine use has expanded to include treatment for opioid addiction, leading to exposures of these drugs in new populations. There is a debate about the relative safety of these two drugs in routine outpatient medical use.. Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Programs were used to analyze rates of abuse, misuse, and diversion using the Drug Diversion, Key Informant, Poison Center and Opioid Treatment Programs, 2003-2007. National rate and rate ratios were calculated using population and person-time exposed denominators. Detailed data are presented on severity of medical outcome and drug formulations.. Between 2003 and 2007, there were steady increases in the rates of abuse, misuse, and diversion of both methadone and buprenorphine. Rate ratios (per 100,000 population per quarter) of abuse, misuse, and diversion were consistently higher for methadone than buprenorphine. RADARS System poison centers received 7,476 calls for methadone and 1,117 calls for buprenorphine. After accounting for availability, there were higher rates of calls for methadone misuse, abuse, and diversion than buprenorphine in three of the four programs. The numbers of exposures requiring medical attention correspond to 46.8% and 25.8% of all calls, for methadone and buprenorphine, respectively. The most commonly diverted form of methadone was solid oral tablets (which are typically dispensed at pharmacies, not at opioid treatment programs), comprising 73% of cases.. Buprenorphine appears to have a better safety profile than methadone during routine outpatient medical use. However, both medications have roles in the treatment of pain and opioid addiction, and further research into their respective benefits and risks should be conducted.

Topics: Analgesics, Opioid; Buprenorphine; Data Collection; Humans; Marketing; Methadone; Opioid-Related Disorders; Pain; United States

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Chronic Disease; Drug Delivery Systems; Humans; Narcotics; Pain; Risk Assessment

This study determined the frequency of reporting being introduced to opioids by a physician among opioid-dependent patients. Cross-sectional analyses were performed using baseline data from a cohort of opioid addicts seeking treatment with buprenorphine. The primary outcome was a response to the question: "Who introduced you to opiates?" Covariates included sociodemographics, depression, pain, and current and prior substance use. Of 140 participants, 29% reported that they had been introduced to opioids by a physician. Of those who were introduced to opioids by a physician, all indicated that they had initially used opioids for pain, versus only 11% of those who did not report being introduced to opioids by a physician (p < .01). There was no difference in current pain (78% vs. 85%, p = .29); however, participants who were introduced to opioids by a physician were more likely to have chronic pain (63% vs. 43%, p = .04). A substantial proportion of individuals with opioid dependence seeking treatment may have been introduced to opioids by a physician.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Cross-Sectional Studies; Data Collection; Depressive Disorder; Diagnosis, Dual (Psychiatry); Female; Humans; Male; Middle Aged; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Practice Patterns, Physicians'

Sepsis research relies on animal models. The models that most closely resemble clinical disease, such as cecal ligation and puncture, require surgery. After surgery, analgesics may not be included in experimental protocols because of concern over effects on inflammatory responses. This often generates animal welfare controversies within institutions; however, there are no scientific studies directly addressing the effects of analgesics on surgical models of sepsis. The purpose of this study was to characterize the effects of opioids on key parameters used in sepsis research.Female ICR mice were divided into four treatment groups (Ringer's lactate solution, high- or low-dose tramadol,buprenorphine) for 3-week mortality studies (n = 12 per treatment). Experimental groups were then repeated, and mice were killed at 12, 24, and 48 h postsurgery for cell counts, differentials, and cytokine levels in blood, peritoneum, and airways. Mortality studies demonstrated no significant differences between controls and any treatment group. However,significant differences were noted between buprenorphine and high-dose tramadol, revealing more and later deaths with tramadol. For comparison of immune parameters, Mann-Whitney U or Student t test was performed, emphasizing comparisons between treatment and control. Although several results were significant, comparisons between control and any treatment group yielded no differences that remained consistently apparent during the observation period. Again,differences were observed between the treatments. The results suggest that judicious and limited use of some analgesics may not dramatically affect the outcome of similarly conducted cecal ligation and puncture studies when compared with those not using analgesics. However, when different analgesics are used, comparisons between studies may be complicated.

Topics: Animal Welfare; Animals; Ascitic Fluid; Bronchoalveolar Lavage Fluid; Buprenorphine; Cecum; Cell Count; Cytokines; Female; Intestinal Perforation; Leukocyte Count; Ligation; Macrophages; Mice; Mice, Inbred ICR; Models, Animal; Narcotics; Pain; Pain Perception; Peritonitis; Shock, Septic; Tramadol

The aim of the study was to investigate the relationship between methadone and buprenorphine treatment and self-reported symptoms in HIV-infected opioid dependent individuals receiving antiretroviral therapy (ART).. Longitudinal study.. The French MANIF2000 cohort was used to compare self-reported symptoms in buprenorphine and methadone patients also receiving ART.. We selected individuals receiving ART and OAT (342 visits among 106 patients).. Symptoms were self-reported using a list of 14 symptoms (e.g. nausea, fatigue, fever) perceived during the previous 4 weeks, including three painful symptoms (abdominal or muscular pain, headaches). A two-step Heckman approach enabled us to account for the non-random assignment of OAT: a probit model identified predictors of starting either buprenorphine or methadone. A Poisson regression based on generalized estimating equations (GEE) was then used to identify predictors of the number of symptoms while adjusting for the non-random assignment of OAT.. The median (interquartile range) number of symptoms was 4 (1-6) and 2 (1-6) among buprenorphine and methadone patients, respectively. After adjustment for non-random assignment of OAT type, depressive and opioid withdrawal symptoms, anxiolytics consumption and daily cannabis use, methadone patients were more likely to report a lower number of symptoms than those receiving buprenorphine.. Methadone patients on ART report fewer symptoms than buprenorphine patients on ART under current treatment conditions in France. Further experimental research is still needed to identify an OAT-ART strategy which would minimize the burden of self-reported symptoms and potential interactions, while assuring sustainability and response to both treatments.

Topics: Anti-Retroviral Agents; Attitude to Health; Buprenorphine; Cohort Studies; Depression; Female; France; Health Services Accessibility; HIV Infections; Humans; Longitudinal Studies; Male; Medication Adherence; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Self Report; Substance Abuse, Intravenous; Substance Withdrawal Syndrome; Treatment Outcome

The transdermal 7-day buprenorphine matrix patch provides a constant and user-friendly pain management when chronic musculoskeletal pain requires opioids. This analysis of clinical routine data evaluated the benefit of this treatment for patients previously receiving oral long-term treatment with weak opioids alone. Data of 310 patients previously treated with tramadol or tildate/naloxone and part of a multicentre observational study with 3295 patients were analyzed. In 89.7% of the 310 patients oral treatment with weak opioids was replaced by the 7-day buprenorphine patch due to insufficient analgesia. During treatment with the 7-day buprenorphine patch there was a clinically significant decrease of the mean pain intensity at rest during the day from 5.7 to 2.9, on physical effort during the day from 7.3 to 3.8 and at night from 5.2 to 2.3 (11-point NRS scale, p < or = 0.001). In addition, quality of life aspects such as mobility, self-reliance and quality of sleep improved, which are relevant for individual patient satisfaction with pain management. For patients with previous long-term tramadol or tilidate/naloxone treatment the switch to the 7-day buprenorphine matrix patch proved to be effective and safe for the management of chronic pain. The user-friendly 7-day application interval contributes to improving compliance and a reducing exposure to tablets.

Topics: Activities of Daily Living; Administration, Cutaneous; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Chronic Disease; Drug Substitution; Female; Germany; Humans; Long-Term Care; Male; Middle Aged; Naloxone; Pain; Pain Measurement; Prospective Studies; Quality of Life; Tilidine; Tramadol

Topics: Buprenorphine; Buprenorphine, Naloxone Drug Combination; Documentation; Humans; Naloxone; Opioid-Related Disorders; Pain; Patient Compliance; Practice Guidelines as Topic; Prescription Drugs

The dose-related antinociceptive effects of intravenous (IV) buprenorphine were evaluated in cats. Thermal (TT) and mechanical threshold (MT) devices were used for nociceptive stimulation. After baseline threshold recordings, buprenorphine was administered IV (0.01, 0.02 or 0.04 mg/kg; B1, B2 and B4, respectively) in a randomised, blinded and cross-over study. Data were analysed by ANOVA (P<0.05) using 95% confidence intervals (CI). TT increased 15, 30, 45 min and 1 (5.2+/-2.7 degrees C), 2, 3 and 4 h after B1; 15, 30, 45 min and 1 (5.1+/-3.9 degrees C) and 2 h after B2, and 15, 30, 45 min and 1 (5.4+/-3.3 degrees C), 2, 3, 6 and 8 h after B4. MT increased 15 and 45 min after B2 (260+/-171 mmHg), and 30 (209+/-116 mmHg) and 45 min and 1 and 2 h after B4. At 45 min, MT values were significantly higher after B2 compared to B1 (P<0.05). With MT, B2 and B4 produced more antinociception and longer duration of action than B1, respectively. No dose response to thermal stimulation was detected.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Buprenorphine; Cats; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hot Temperature; Infusions, Intravenous; Male; Pain; Pressure; Random Allocation

We present three cases of children (aged 3-5 years) in which cancer-related pain was adequately controlled by Transdermal Buprenorphine. The endpoints for evaluating analgesic efficacy consisted of the assessment of pain using a visual scale and the possibility of reducing other pain treatment. Improvement of pain level was demonstrated by the decrease in pain scores, by reduction of the overall amount of medications, especially opioids, and by improvement of uninterrupted sleep. Only limited data is available on the use of Transdermal Buprenorphine in children. In our experience, Transdermal Buprenorphine allowed good analgesia without significant side effects in these three children with cancer-related pain.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Child, Preschool; Humans; Male; Neoplasms; Pain

Opioid analgesics are known to impact on the central nervous system (CNS). These CNS side effects, such as dizziness and confusion, have been shown to lead to an increased risk of falling with subsequent fractures in elderly patients being treated with opioids. The risk of experiencing fractures has been shown to be dependent on the substance administered. Therefore, a health economic model was developed to investigate the cost-effectiveness of the most commonly used strong opioids in Germany, focussing on opioid-related fractures. By means of a Markov model, the consequences of hip, spine and forearm fractures due to the prior administration of transdermal (TD) buprenorphine, TD fentanyl, oral oxycodone as well as oral morphine were assessed from the perspectives of the German statutory health insurance (SHI) and the German social security (GSS) system over a time horizon of 6 years. The most frequently prescribed strength/package-size combinations of these opioids were taken into consideration, including generics where available. The results of the present analysis predict that TD buprenorphine is dominant compared to TD fentanyl and oxycodone by showing better effects [life years gained/quality adjusted life years (QALY) gained] at lower cost. From the SHI perspective, the incremental cost-effectiveness ratio (ICER) compared to morphine is 6,801.61 per life year gained, and 7,766.11 per QALY gained. From the GSS perspective, the ICER is 2,496.77 per life year gained and 2,850.83 per QALY gained. The model is robust regarding probabilistic variations of all parameters in the sensitivity analyses. Focussing on fractures due to the prior administration of strong opioids, TD buprenorphine is less costly and more effective than TD fentanyl and oxycodone and represents a cost-effective treatment option versus morphine in patients with chronic pain from both the SHI and GSS perspective in Germany.

Topics: Accidental Falls; Aged; Analgesics, Opioid; Buprenorphine; Chronic Disease; Cost-Benefit Analysis; Fractures, Bone; Germany; Health Services; Humans; Markov Chains; Middle Aged; Models, Economic; Morphine; Oxycodone; Pain; Quality-Adjusted Life Years

The aim of this study was to evaluate the equianalgesic ratio of transdermal buprenorphine (TD BUP) with oral morphine and TD fentanyl in a sample of consecutive cancer patients receiving stable doses of 120-240 mg of oral morphine or 50-100 microg of TD fentanyl, reporting adequate pain and symptom control.. Patients receiving daily stable doses of opioids for more than 6 days, with no more than two doses of oral morphine (20 and 40 mg, respectively) as needed, were switched to TD BUP using a fentanyl-BUP ratio of 0.6:0.8 and an oral morphine-BUP ratio of 70:1. Opioid doses, pain and symptom intensity, global satisfaction, and number of breakthrough medication were recorded before switching (T0), 3 days after (T3), and 6 days after (T6). Eleven patients were recruited in a period of 1 year, and data were complete for ten patients. The mean age was 61.6 (SD 9.5), and five patients were males. No significant changes in pain and symptom intensity were found, except improvement in reported constipation (p = 0.014), as well as in global satisfaction with the analgesic treatment. No significant changes in breakthrough pain medication were observed.. The results of this study suggest that stable patients receiving relatively high doses of oral morphine or TD fentanyl could be safely switched to TD BUP, by using a ratio of 70:1 and 0.6:0.8, respectively, maintaining the same level of analgesia.

Topics: Administration, Cutaneous; Aged; Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Female; Fentanyl; Humans; Male; Middle Aged; Neoplasms; Pain; Patient Satisfaction; Prospective Studies

Topics: Administration, Cutaneous; Administration, Oral; Analgesics, Opioid; Buprenorphine; Drug and Narcotic Control; Drug Prescriptions; Fentanyl; Guideline Adherence; Humans; Italy; Morphine; Neoplasms; Oxycodone; Pain; Practice Guidelines as Topic; Practice Patterns, Physicians'; Time Factors

The aim of this study was to prospectively evaluate the frequency, indications, outcomes, and predictive factors associated with opioid switching, using a protocol that had been clinically applied and viewed as effective for many years. A prospective study was carried out on a cohort of consecutive cancer patients who were receiving opioids but had an unacceptable balance between analgesia and adverse effects, despite symptomatic treatment of side effects. The initial conversion ratio between opioids and routes was as follows (mg/day): oral morphine 100=intravenous morphine 33=transdermal fentanyl 1=intravenous fentanyl 1=oral methadone 20=intravenous methadone 16=oral oxycodone 70=transdermal buprenorphine 1.3. The switch was assisted by opioids used as needed, and doses were changed after the initial conversion according to clinical response in an acute care setting. Intensity of pain and symptoms associated with opioid therapy were recorded. A distress score (DS) was calculated as a sum of symptom intensity. A switch was considered successful when the intensity of pain and/or DS, or the principal symptom necessitating the switch, decreased to at least 33% of the value recorded before switching. One hundred eighteen patients underwent opioid substitutions. The indications for opioid switching were uncontrolled pain and adverse effects (50.8%), adverse effects (28.8%), uncontrolled pain (15.2%), and convenience (4.2%). Overall, 103 substitutions were successful. Ninety-six substitutions were successful after the first switching, and a further substitution was successful in seven patients who did not respond to the first switch. The mean time to achieve dose stabilization after switching was 3.2 days. The presence of both poor pain control and adverse effects was related to unsuccessful switching (P<0.004). No relationship was identified between unsuccessful switching and the opioid dose, opioid sequence, pain mechanism, or use of adjuvant medications. Opioid switching was an effective method to improve the balance between analgesia and adverse effects in more than 80% of cancer patients with a poor response to an opioid. The presence of both poor pain relief and adverse effects is a negative factor for switching prognosis, whereas renal failure is not.

Topics: Adult; Aged; Analgesics, Opioid; Buprenorphine; Female; Fentanyl; Humans; Male; Methadone; Middle Aged; Morphine; Pain; Palliative Care; Prospective Studies; Treatment Outcome

Buprenorphine displays attributes of opioids, but also some features distinct from them. We examined spinal and supraspinal signal transduction of buprenorphine-induced anti-nociception in mice compared with morphine and fentanyl.. The opioid receptor antagonist naloxone, Pertussis toxin (PTX), G(z) protein antisense and nociceptin/orphanin-FQ receptor agonist nociceptin, and antagonist, JTC-801, were injected supraspinally (intracerebroventricular) and spinally (intrathecal). Also the cell-permeable Ser/Thr protein phosphatase inhibitor okadaic acid was given supraspinally.. Spinal naloxone (20 microg) or PTX (1 microg) attenuated morphine, fentanyl and buprenorphine (s.c.) anti-nociception. Supraspinal naloxone or PTX attenuated morphine and fentanyl, but not buprenorphine anti-nociception. Spinal G(z) protein antisense did not alter buprenorphine, morphine or fentanyl anti-nociception and supraspinal G(z)-antisense did not alter morphine or fentanyl anti-nociception. However, supraspinal G(z)-antisense (not random sense) reduced buprenorphine anti-nociception. Peripheral JTC-801 (1 mgxkg(-1), i.p.) enhanced the ascending (3 mgxkg(-1)) and descending (30 mgxkg(-1)) portions of buprenorphine's dose-response curve, but only spinal, not supraspinal, nociceptin (10 nmolxL(-1)) enhanced buprenorphine anti-nociception. Intracereboventricular okadaic acid (0.001-10 pg) produced a biphasic low-dose attenuation, high-dose enhancement of buprenorphine(3 or 30 mgxkg(-1), s.c.) anti-nociception, but did not affect morphine or fentanyl anti-nociception.. Buprenorphine has an opioid component to its supraspinal mechanism of analgesic action. Our present results reveal an additional supraspinal component insensitive to naloxone, PTX and nociceptin/orphanin-FQ, but involving G(z) protein and Ser/Thr protein phosphatase. These data might help explain the unique preclinical and clinical profiles of buprenorphine.

Topics: Acetylcholine; Adrenergic alpha-Antagonists; Aminoquinolines; Analgesics, Opioid; Anesthetics, Local; Animals; Benzamides; Brain; Buprenorphine; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fentanyl; GTP-Binding Proteins; Injections, Intraventricular; Injections, Spinal; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Okadaic Acid; Oligonucleotides, Antisense; Opioid Peptides; Pain; Pain Measurement; Pain Threshold; Pertussis Toxin; Phosphoprotein Phosphatases; Piperazines; Pyridines; Receptor, Serotonin, 5-HT1A; Receptors, Opioid; Serotonin 5-HT1 Receptor Antagonists; Serotonin Antagonists; Signal Transduction; Yohimbine

Chronic tendinopathy is characterized with longstanding activity-related pain with degenerative tendon injuries. An objective tool to measure painful responses in animal models is essential for the development of effective treatment for tendinopathy. Gait analysis has been developed to monitor the inflammatory pain in small animals. We reported the use of motion analysis to monitor gait changes in a rat model of degenerative tendon injury. Intratendinous injection of collagenase into the left patellar tendon of Sprague Dawley rat was used to induce degenerative tendon injury, while an equal volume of saline was injected in the control groups. Motion analyses with a high speed video camera were performed on all rats at pre-injury, 2, 4, 8, 12 or 16 weeks post injection. In the end-point study, the rats were sacrificed to obtain tendon samples for histological examination after motion analyses. In the follow-up study, repeated motion analyses were performed on another group of collagenase-treated and saline-treated rats. The results showed that rats with injured patellar tendon exhibited altered walking gait as compared to the controls. The change in double stance duration in the collagenase-treated rats was reversible by administration of buprenorphrine (p=0.029), it suggested that the detected gait changes were associated with pain. Comparisons of end-point and follow-up studies revealed the confounding effects of training, which led to higher gait velocities and probably a different adaptive response to tendon pain in the trained rats. The results showed that motion analysis could be used to measure activity-related chronic tendon pain.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Biomechanical Phenomena; Buprenorphine; Chronic Disease; Collagenases; Disease Models, Animal; Gait; Lameness, Animal; Male; Pain; Pain Measurement; Predictive Value of Tests; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Tendon Injuries; Tendons; Video Recording; Walking

The semi-synthetic opioid, buprenorphine, has the general structure of morphine but differs from it in significant ways, both pharmacologically and clinically. A number of long-term studies have shown effective, long-lasting analgesia in moderate to severe cancer and non-cancer pain, including neuropathic pain, with a low incidence of constipation, nausea, dizziness and tiredness. The treatment of moderate to severe chronic pain has improved as a result of the development of new methods of administration of this substance, particularly the introduction of the transdermal drug delivery system, which offers a number of advantages over the usual oral and parenteral routes.. A panel of experts specialising in palliative care and pain treatment was convened in November 2007 to discuss their clinical experiences with transdermal buprenorphine and other analgesics. The aim was to provide practical guidance on the treatment of cancer pain with transdermal buprenorphine, particularly when there is a need for increasing pain relief leading to high and increasing doses. A literature search on the use of transdermal buprenorphine was carried out for the panel meeting (based on a search of PubMed to November 2007 - since updated by an additional search for the period to February 2009) and a number of case histories were presented and discussed. This commentary article presents this evidence and the consensus findings of the expert panel.. The Panel reached consensus that transdermal buprenorphine was a valuable treatment for chronic cancer pain, including its neuropathic components. A number of general recommendations were made. Large-scale, randomised clinical studies are needed to provide product comparisons on the use of analgesics in the treatment of neuropathic pain although it was recognised that such studies may not be practicable. Data on the treatment of acute and chronic pain should be kept separate in general. Physicians should be made more aware of the problem of hyperalgesic effects of some opioids in long term use. Buprenorphine in contrast has been described to exert an antihyperalgesic effect. The development of analgesic tolerance with some opioids in long term use and the lack of it with buprenorphine requires further studies. The registered dose range of 35-140 microg/h was considered adequate to achieve sufficient pain relief in most patients although some members of the panel presented data showing that increases beyond this dose range provided improved pain relief if slow titration is used. However, it was generally felt that more evidence was needed before this could become generally acceptable.. The consensus was that transdermal buprenorphine has a valuable role to play in the treatment of chronic cancer pain because of its efficacy and good safety and tolerability profile, including a low risk of respiratory depression, a lack of immunosuppression and a lack of accumulation in patients with impaired renal function.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Consensus; Expert Testimony; Guidelines as Topic; Humans; Neoplasms; Pain; Palliative Care

Empirical evidence is needed to guide adequate postpartum pain relief of methadone and buprenorphine stabilized patients.. To first determine the adequacy of pain control using non-opioid and opioid medication in participants stabilized on buprenorphine or methadone before a vaginal delivery. Second, to compare the amount of non-opioid and opioid medication needed for adequate pain control for buprenorphine-and methadone-maintained patients during the immediate postpartum period.. Pain control adequacy and amount of non-opioid and opioid medication needed in buprenorphine- (n = 8) and methadone-maintained (n = 10) patients over the first five days postpartum were examined.. Pain ratings and number of opioid medication doses decreased over time in both medication groups. While the buprenorphine and methadone groups began with similar mean daily ibuprofen (IB) doses, the buprenorphine group decreased its IB use, while the methadone group increased its IB use.. Patients treated daily with either buprenorphine or methadone can have adequate pain control postpartum with opioid medication and IB. Pain control is dependent on the opioid-agonist medication in use at delivery, and must be individualized.

Topics: Acute Disease; Adult; Analgesics, Non-Narcotic; Analgesics, Opioid; Buprenorphine; Controlled Clinical Trials as Topic; Double-Blind Method; Female; Humans; Ibuprofen; Methadone; Opioid-Related Disorders; Pain; Pain Measurement; Postpartum Period; Pregnancy; Pregnancy Complications

Topics: Administration, Topical; Aged; Analgesics, Opioid; Buprenorphine; Cholestasis; Chronic Disease; Drug Combinations; Female; Humans; Injections, Intravenous; Naloxone; Narcotic Antagonists; Neoplasms; Pain; Pain Measurement; Palliative Care; Pruritus; Treatment Outcome

Activation of brain nociceptin/orphanin FQ (NOP) receptors leads to attenuation of mu-opioid receptor (MOP receptor)-mediated antinociception. Buprenorphine, a high-affinity partial MOP receptor agonist also binds to NOP receptors with 80 nM affinity. The buprenorphine-induced inverted U-shaped dose-response curve for antinociception may be due to NOP receptor activation, given that, in the presence of the NOP receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J113397), or in NOP receptor knockout mice, buprenorphine has a steeper dose-response curve and acts as a full agonist. To further explore the involvement of the direct activation of NOP receptors by buprenorphine and other compounds that activate both NOP and MOP receptors, the antinociceptive effects of 1-(1-(2,3,3alpha,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one. (SR16435), 3-ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one (SR16507), buprenorphine, pentazocine, and morphine, compounds with varying levels of MOP and NOP receptor affinity and efficacy, were assessed in mice using the tail-flick assay. The ability of the selective NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) to potentiate antinociception induced by the above compounds was examined to investigate whether activation of NOP receptors leads to attenuation of MOP receptor-mediated antinociception. SB-612111 potentiated antinociception induced by buprenorphine and the other mixed NOP/MOP receptor agonists SR16435 and SR16507. However, SB-612111 had no effect on pentazocine or morphine antinociception, two compounds with no NOP receptor-binding affinity. These results further support the hypothesis that activation of NOP receptors can lead to attenuation of MOP receptor-mediated antinociception elicited by mixed NOP/MOP receptor compounds such as buprenorphine, SR16435, and SR16507 and that, although buprenorphine has low efficacy in vitro, it has significant NOP receptor agonist activity in vivo.

Topics: Analgesics, Opioid; Animals; Benzimidazoles; Buprenorphine; CHO Cells; Cricetinae; Cricetulus; Cycloheptanes; Dose-Response Relationship, Drug; Humans; Ligands; Male; Mice; Mice, Inbred ICR; Narcotic Antagonists; Nociceptin Receptor; Pain; Pain Measurement; Pain Threshold; Piperidines; Protein Binding; Receptors, Opioid; Receptors, Opioid, mu; Transfection

The 7-day, low-dose buprenorphine patch has been available in the United Kingdom since 2005 for the treatment of chronic nonmalignant pain that is unresponsive to nonopioid analgesics. Osteo-arthritis pain, a significant cause of pain and disability in the elderly, is a common reason for prescribing bu-prenorphine patches.. The goals of this study were to investigate utilization and treatment persistence in patients receiving low-dose buprenorphine patches and the expected patterns of treatment 12 months after the initiation of treatment.. This was a retrospective cohort study of patients who were prescribed low-dose buprenorphine patches in general practice in the United Kingdom. Patients in this cohort were matched by age, sex, and practice with comparator cohorts prescribed oral codeine, dihydrocodeine, or tramadol. Data on baseline characteristics, utilization, and adverse events were obtained from the General Practice Research Database, which contains computerized medical records from UK general practice. Treatment persistence was determined based on repeat prescribing within 90 days after the expected end of a prescription; rates of persistence were compared between the buprenorphine and comparator cohorts. Cox proportional hazards regression models were used to compare the incidence of typical opioid adverse effects (constipation, dizziness, and nausea and/or vomiting) between cohorts.. The study cohort included 4968 patients who were prescribed low-dose buprenorphine patches. The majority of patients (64.2%) were aged >65 years, and the most frequently recorded indication for low-dose buprenorphine patches was osteoarthritis (48.7%). Most patients (76.1%) started treatment at the lowest patch strength (5 microg/h). The mean patch strength prescribed over time stabilized at 10 to 12 microg/h. Persistence with low-dose buprenorphine patches over 6 months was significantly higher than with codeine, dihydrocodeine, and tramadol (28.9%, 22.4%, 24.4%, and 23.8%, respectively; P < 0.01). Persistence over 12 months also was significantly higher with low-dose buprenorphine patches compared with the comparators (18.5%, 16.1%, 18.0%, and 17.6%; P < 0.01). After 12 months, the difference in persistence levels between cohorts was not statistically significant. In the Cox proportional hazards regression models, patients using buprenorphine patches had an increased incidence of constipation, dizziness, and nausea and vomiting compared with those who used the comparator opioids (P < 0.05).. Significantly more patients receiving low-dose buprenorphine patches in this study persisted with treatment at 6 and 12 months compared with those receiving other opioid analgesics. Treatment with low-dose buprenorphine patches was most frequently initiated at the lowest patch strength and stabilized at a mean of 10 to 12 microg/h.

Topics: Administration, Cutaneous; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Chronic Disease; Codeine; Cohort Studies; Databases, Factual; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Medication Adherence; Middle Aged; Pain; Primary Health Care; Proportional Hazards Models; Retrospective Studies; Time Factors; Tramadol; United Kingdom; Young Adult

To obtain information on the efficacy, tolerability and safetyofa transdermal buprenorphine patch (Transtec PRO) in patients with moderate to severe chronic pain. In addition it should be evaluated to what extent the two fixed patch change days per weekare simplifyingthe therapy.. In this prospective multi-center post marketing surveillance study patients with chronic cancer and non-cancer pain were treated with transdermal buprenorphine for up to eight weeks. The evaluation included pain intensity, the dosage of the applied analgesics and additional therapies, the renal function (by serum creatinine) and adverse events.. 3654 patients were treated for a mean of 50.4 days. Using the NRS-11 the mean pain intensity decreased from 6.3 at the time when patients were switched to the transdermal buprenorphine patch to 2.6 at the last treatment evaluation. The matrix patch was safe and well tolerated also in patients with advanced renal insufficiency. Adverse events were reported in 6.7% of the patients. 89.3% of the physicians quoted to prefer transdermal buprenorphine with the two fixed patch change days per week compared to the pre-treatment.. The buprenorphine-containing matrix patch was effective and well tolerated in patients with moderate to severe chronic cancer and noncancer pain. From the physicians view the two fixed patch change days per week facilitate the guidance of therapy. In patients with advanced renal insufficiency a dose adjustment is not necessary.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Neoplasms; Pain; Product Surveillance, Postmarketing; Prospective Studies

Topics: Analgesics, Opioid; Buprenorphine; Chronic Disease; Humans; Methadone; Opioid-Related Disorders; Pain

Buprenorphine is a low-molecular-weight, lipophilic, opioid analgesic. The transdermal delivery system (TDS) containing it has skin irritation potential, but at least two cases of contact allergy to the active principal have been described previously.. To confirm allergic contact dermatitis from transdermal buprenorphine (TDB) in five older patients suffering from chronic pain and who developed persistent, pruritic erythematous plaques at the contact sites, with two of them also presenting with a generalized skin eruption.. Besides the baseline patch test series, all five patients were tested with the TDB, four of whom were also tested with the placebo transdermal delivery system as provided by the manufacturer; one patient was also tested with other preparations containing buprenorphine.. All reacted to the TDB containing the active principal, the placebo being negative in the four patients tested. The patient tested with the other buprenorphine preparations did react positively to them as well. Tests with TDB in 28 healthy controls were negative.. We report five cases of delayed hypersensitivity reactions to a TDS containing buprenorphine. Such adverse reactions might be under-reported. A fentanyl-containing TDS is a good alternative in these cases.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Dermatitis, Allergic Contact; Erythema Nodosum; Female; Humans; Male; Middle Aged; Pain; Patch Tests

Pain still afflicts most cancer patients, mainly in the metastatic phases, and undertreatment is well documented. Transdermal delivery systems (TDS) could potentially have advantages over oral and parental routes, but evidence from comparative trials are scanty. In the framework of a wider initiative, an Outcome Research Study was carried out in Italy in 2006 to evaluate the effects of various analgesic options, particularly TDS Buprenorphine. Despite the limitations due to the observational design, these findings may be useful to clinicians to better judge the value of the drug under evaluation and to help researchers to design further comparative studies.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Chronic Disease; Dose-Response Relationship, Drug; Female; Humans; Italy; Male; Middle Aged; Neoplasms; Outcome Assessment, Health Care; Pain; Pain Measurement; Palliative Care; Prospective Studies; Quality of Life; Research Design; Surveys and Questionnaires; Treatment Outcome

The use of heroin, cocaine, and other drugs is well researched in New York City, but prescription opioids (POs) have been overlooked. This study documents patterns of PO use, misuse, and diversion among street drug users, and begins to indicate how drug culture practices interact with the legitimate therapeutic goals of PO prescriptions (e.g. pain management).. Staff completed interviews inquiring about the reasons for use of POs and illicit drugs with 586 street drug users. Ethnographers wrote extensive field notes about subjects' complex patterns of PO use.. Methadone was used (71.9%) and sold (64.7%) at a higher level than OxyContin, Vicodin, and Percocet, used by between 34% and 38% of the users and sold by between 28% and 41% of the sellers. Recent PO use is associated with the recency of using heroin and cocaine (p<.001). Half of the heroin/cocaine sellers sold POs, and one quarter of the PO sellers only sold POs. Subjects were classified into four groups by whether they diverted POs or used POs to relieve pain or withdrawal rather than for euphoria. This classification was associated with frequency of PO use, whether POs were obtained from doctors/pharmacies or from drug dealers and family members, and those mostly likely to use POs for pain and withdrawal.. POs are an important component of street drug users' drug-taking regimes, especially those who are Physically Ill Chemical Abusers (PICA). Future research is needed to model PO use, misuse, and diversion among this population.

Topics: Administration, Intranasal; Adult; Aged; Analgesics, Opioid; Buprenorphine; Cocaine-Related Disorders; Drug Prescriptions; Ethnicity; Female; Heroin Dependence; Humans; Male; Methadone; Middle Aged; Narcotic Antagonists; Narcotics; New York City; Pain; Patient Selection; Socioeconomic Factors; Substance Abuse, Intravenous; Substance Withdrawal Syndrome; Substance-Related Disorders

Compounds that activate both NOP and mu-opioid receptors might be useful as analgesics and drug abuse medications. Studies were carried out to better understand the biological activity of such compounds.. Binding affinities were determined on membranes from cells transfected with NOP and opioid receptors. Functional activity was determined by [(35)S]GTPgammaS binding on cell membranes and using the mouse vas deferens preparation in vitro and the tail flick antinociception assay in vivo.. Compounds ranged in affinity from SR14150, 20-fold selective for NOP receptors, to buprenorphine, 50-fold selective for mu-opioid receptors. In the [(35)S]GTPgammaS assay, SR compounds ranged from full agonist to antagonist at NOP receptors and most were partial agonists at mu-opioid receptors. Buprenorphine was a low efficacy partial agonist at mu-opioid receptors, but did not stimulate [(35)S]GTPgammaS binding through NOP. In the mouse vas deferens, each compound, except for SR16430, inhibited electrically induced contractions. In each case, except for N/OFQ itself, the inhibition was due to mu-opioid receptor activation, as determined by equivalent results in NOP receptor knockout tissues. SR14150 showed antinociceptive activity in the tail flick test, which was reversed by the opioid antagonist naloxone.. Compounds that bind to both mu-opioid and NOP receptors have antinociceptive activity but the relative contribution of each receptor is unclear. These experiments help characterize compounds that bind to both receptors, to better understand the mechanism behind their biological activities, and identify new pharmacological tools to characterize NOP and opioid receptors.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Cell Membrane; CHO Cells; Cricetinae; Cricetulus; Guanosine 5'-O-(3-Thiotriphosphate); Indoles; Ligands; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nociceptin Receptor; Pain; Pain Measurement; Protein Binding; Receptors, Opioid; Receptors, Opioid, mu; Vas Deferens

Opioids produce analgesia via different pain pathways. The aim of these case studies was to address the issue of opioid rotation or switching, raising the important issue of conversion ratios between different compounds and routes of administration.. We present two cases of neuropathic pain and two cases of nociceptive pain with a significant neuropathic component, which were successfully treated with transdermal buprenorphine after the failure of other opioids.. In each case, effective pain relief was produced by a lower dose than the proposed equipotency ratio of 1:75 would indicate, suggesting that a ratio of 1:110 to 1:115 may be more appropriate.

Topics: Administration, Cutaneous; Aged; Analgesics, Opioid; Buprenorphine; Chronic Disease; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Pain

Topics: Administration, Cutaneous; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Dermatitis, Allergic Contact; Drug Hypersensitivity; Female; Humans; Pain; Patch Tests; Skin

The aim of this preliminary study was to explore the possibility of using higher doses of transdermal buprenorphine (TD-BUP) than those commonly used and available as manufactured patches, which are based on the assumption that BUP may have a ceiling effect that has never been determined yet.. Ten patients who were already receiving TD-BUP (70 microg/h, which is about 1.6 mg/day) and were no longer responsive to this dosage were administered higher doses up to a maximum of 140 microg/h within 6 days, when the study was completed.. In six patients, dose increments of TD-BUP were effective, and patients achieved adequate analgesia within 6 days. Four patients discontinued the treatment due to inefficacy of TD-BUP 140 microg/h and were switched to other opioids until achieving stabilization (oxycodone 320 and 400 mg/day, methadone 120 mg/day, transdermal fentanyl 200 microg/h). This group of patients required higher doses than those chosen for TD-BUP, underlying the need to escalate the dose rapidly, a modality not accomplished with transdermal drugs. Adverse effects did not change and were similar to those observed before increasing the dose of TD-BUP. On the basis of these preliminary data, patients requiring doses higher than 70 microg/h of TD-BUP, in the range of 105-140 microg/h, may still have an analgesic benefit without important consequences in terms of adverse effects. It cannot be excluded that even higher doses may be effective, as some patients required rapid titration with higher morphine equivalent doses, and according to the protocol, other opioids were provided to facilitate this process. Further studies should clarify the role and the benefit of TD-BUP in specific clinical circumstances.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Maximum Tolerated Dose; Neoplasms; Pain; Pilot Projects; Treatment Outcome

Topics: Administration, Cutaneous; Adult; Analgesics, Opioid; Buprenorphine; Cold Temperature; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Electric Stimulation; Female; Fentanyl; Hot Temperature; Humans; Immersion; Male; Pain; Pain Measurement; Sensitivity and Specificity

Topics: Buprenorphine; Heroin Dependence; Humans; Injections; Long-Term Care; Methadone; Naltrexone; Narcotic Antagonists; Narcotics; Pain; Prisoners; Treatment Outcome

To evaluate a prototype pressure stimulus device for use in the cat and to compare with a known thermal threshold device.. Eight healthy adult cats weighing between 3.0 and 4.9 kg.. Pressure stimulation was given via a plastic bracelet taped around the forearm. Three 2.4 mm diameter ball bearings, in a 10-mm triangle, were advanced against the craniolateral surface of the antebrachium by manual inflation of a modified blood pressure bladder. Pressure in the cuff was recorded at the end point (leg shake and head turn). Thermal threshold was also tested. Stimuli were stopped if they reached 55 degrees C or 450 mmHg without response. After four pressure and thermal threshold baselines, each cat received SC buprenorphine 0.01 mg kg(-1), carprofen 4 mg kg(-1) or saline 0.3 mL in a three period cross-over study with a 1-week interval. The investigator was blinded to the treatment. Measurements were made at 0.25. 0.5, 0.75, 1, 2, 3, 4, 6, 8, and 24 hours after injection. Data were analyzed by using ANOVA.. There were no significant changes in thermal or pressure threshold after administration of saline or carprofen, but thermal threshold increased from 60 minutes until 8 hours after administration of buprenorphine (p < 0.05). The maximum increase in threshold from baseline (DeltaT(max)) was 3.5 +/- 3.1 degrees C at 2 hours. Pressure threshold increased 2 hours after administration of buprenorphine (p < 0.05) when the increase in threshold above baseline (DeltaP(max)) was 162 +/- 189 mmHg.. This pressure device resulted in thresholds that were affected by analgesic treatment in a similar manner but to a lesser degree than the thermal method. Pressure stimulation may be a useful additional method for analgesic studies in cats.

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Carbazoles; Cat Diseases; Cats; Cross-Over Studies; Double-Blind Method; Female; Hot Temperature; Injections, Subcutaneous; Male; Pain; Pain Measurement; Pressure; Sodium Chloride

MRL/MpJ-Fas(lpr) (MRL/lpr) mice are an accepted animal model to study human systemic lupus erythematosus. We tested if a commonly used analgesic (buprenorphine hydrochloride) would reduce pain and distress in these mice without impacting the progression of autoimmune disease. Female MRL/lpr mice were randomly separated into four groups. Experimental groups received cyclophosphamide (25 mg/kg i.p. weekly), buprenorphine (0.09 mg/kg/mouse/day via drinking water), or cyclophosphamide+buprenorphine from 11 to 21 weeks of age. Controls received no treatments. Mice were monitored daily by a licensed veterinarian (blinded observer) and assigned a score weekly on parameters associated with pain and distress as well as progression of disease. Proteinuria was measured weekly, and serum anti-dsDNA antibody levels were determined at 11, 15, and 18 weeks of age. At 21 weeks of age, the animals were euthanized and the kidneys and spleens were removed for evaluation. Regardless of the parameter observed, buprenorphine did not significantly decrease distress when compared to the controls. Buprenorphine did not alter the progression of autoimmune disease, based on characteristics of splenic architecture and splenocyte cell profiles, development of lymphadenopathy, or kidney histology as compared to controls. This study indicates that buprenorphine at this dose and route of administration was ineffective in reducing distress associated with disease progression in the MRL/lpr strain. More studies are needed to determine if, at a different dose or route, buprenorphine would be useful as adjunctive therapy in reducing distress in MRL/lpr mice.

Topics: Analgesics; Animal Welfare; Animals; Autoantibodies; Biomarkers; Buprenorphine; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Kidney; Lupus Erythematosus, Systemic; Mice; Mice, Inbred MRL lpr; Pain; Proteinuria; Random Allocation; Spleen

Topics: Administration, Sublingual; Analgesia; Analgesics, Opioid; Animals; Buprenorphine; Female; Horses; Neck Injuries; Pain

The opioid systems play an important role in mediating both physical pain and negative affects (eg, the pain of social isolation). From an evolutionary perspective, it is not surprising that the neurocircuitry and neurochemistry of physical pain would overlap with that involved in complex social emotions. Exposure to trauma as well as a range of gene variants in the opioid system may be associated with alterations in opioid systems function, with changes in reward processing, and with vulnerability to substance abuse. A role for interventions with opioid agents in depression and anxiety disorders has been suggested.

Topics: Adult; Brain; Buprenorphine; Cerebrovascular Circulation; Combined Modality Therapy; Endorphins; Heroin Dependence; Humans; Magnetic Resonance Imaging; Male; Narcotic Antagonists; Nociceptors; Pain; Pain Management; Psychotherapy; Receptors, Opioid, mu; Rejection, Psychology; Social Isolation

The therapeutic use of opioids has been associated with altered cognition and impaired psychomotor function. Several studies have demonstrated the impact of opioid therapy on psychomotor performance and cognition, but there are no data about the effect of long-term treatment with transdermal buprenorphine on driving ability.. Thirty patients suffering from chronic noncancer pain, who had been treated with stable doses of transdermal buprenorphine, included in a prospective trial and compared with 90 healthy volunteers (matched pairs). A computerized test battery, developed to assess the driving ability of traffic delinquents in Germany, was used. Attention reaction, visual orientation, motor coordination, and vigilance were evaluated. The data from 14 variables were assessed, and for each test, a relevant score was defined. As the primary end-point, the sum score of the three relevant scores was determined. A weaker statistical means to assess the patient's performance is to compare the test results to an age-independent control group. Individuals performing worse than the 16th percentile of this control group are considered to be unable to drive according to German law.. According to tests that predict driving ability, patients receiving transdermal buprenorphine were shown to be noninferior to the control group. Driving ability, as defined as a result above the 16th percentile, did not differ significantly between the patients and the control group.. Long-term use of transdermal buprenorphine for chronic noncancer pain does not impair driving ability, but because of the individual variability of test results, an individual assessment is recommended.

Topics: Administration, Cutaneous; Adult; Aged; Automobile Driving; Buprenorphine; Chronic Disease; Cognition; Female; Humans; Long-Term Care; Male; Middle Aged; Pain; Prospective Studies; Psychomotor Performance; Reaction Time

Buprenorphine has been widely used and studied for over 20 years and has been shown to be an effective opioid analgesic. Some years ago a buprenorphine formulation for transdermal therapy of chronic cancer-related and non-cancer-related pain became available. We report the case of a woman who received a lower dosed transdermal buprenorphine patch (3/5 of a 35 microg/h patch corresponding to release of 21 microg/h buprenorphine) during pregnancy without any complication for herself or the child. The patient has now being using the transdermal system for more than 2 years and has reported continuous excellent pain relief. The buprenorphine patch was well tolerated and produced no effect on vigilance over the whole period of administration.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Female; Humans; Pain; Pregnancy; Pregnancy Complications

The present study was designed to study the impact of intermittent hemodialysis on the disposition of the partial agonist buprenorphine and its metabolite norbuprenorphine during therapy with transdermal buprenorphine in chronic pain patients with end-stage kidney disease. Ten patients (mean age 63 years) who had received transdermal buprenorphine for at least 1 week, were asked to provide blood samples immediately before and after hemodialysis. Blood samples were analysed for buprenorphine and its metabolite norbuprenorphine. The median buprenorphine plasma concentrations were found to be 0.16 ng/ml before and 0.23 ng/ml after hemodialysis. A significant correlation between plasma levels and administered doses was observed (Spearman R=0.74; P<0.05). In three patients norbuprenorphine plasma levels were detected. No differences in pain relief before and after hemodialysis were observed. This investigation shows no elevated buprenorphine and norbuprenorphine plasma levels in patients with renal insufficiency receiving transdermal buprenorphine up to 70 microg/h. Furthermore, hemodialysis did not affect buprenorphine plasma levels, leading to stable analgesic effects during the therapy.

Topics: Administration, Cutaneous; Adult; Aged; Analgesics, Opioid; Buprenorphine; Chronic Disease; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Pain; Renal Dialysis

The slow association and incomplete dissociation of buprenorphine from opioid receptors observed in vitro have been suggested to reduce the accessibility of opioid receptors in vivo. If so, it might be expected that buprenorphine continues to occupy opioid receptors long after the antinociceptive activity has dissipated. To examine this hypothesis, buprenorphine (46.4 microg/kg i.v.) was administered to rats 1, 2, 4 or 8 h before isolation of their forebrain membranes and the maximal binding capacity (Bmax) for [3H]-[D-Ala2, N-methyl-Phe4-Gly5-ol]-enkephalin ([3H]DAMGO) was determined to measure the number of mu-opioid receptor binding sites remaining. Extent and duration of the reduction of Bmax by buprenorphine (ED50 11.2 microg/kg 1 h post-application) correlated with the antinociceptive activity in the rat tail flick (ED50 16.4 microg/kg i.v. 1 h post-application). At 8 h after administration there was still residual antinociception but no further attenuation of Bmax was detectable. Thus receptor occupancy by buprenorphine does not cause impairment of mu-opioid receptor accessibility beyond the duration of its antinociceptive activity. Therefore, no impairment of antinociception in the case of an opioid switch is to be expected.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Buprenorphine; Cinnamates; Dose-Response Relationship, Drug; Female; Injections, Intravenous; Kinetics; Models, Animal; Morphine; Morphine Derivatives; Narcotic Antagonists; Pain; Pain Measurement; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

Topics: Administration, Sublingual; Adult; Algorithms; Analgesics, Opioid; Biological Availability; Buprenorphine; Cross-Over Studies; Double-Blind Method; Female; Humans; Hyperalgesia; Injections, Intravenous; Male; Middle Aged; Models, Statistical; Pain; Pain Measurement; Placebos; Receptors, Opioid, mu; Transcutaneous Electric Nerve Stimulation; Treatment Outcome

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Neoplasms; Pain; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Acute Disease; Adult; Analgesics, Opioid; Antineoplastic Agents, Alkylating; Buprenorphine; Humans; Ifosfamide; Male; Osteosarcoma; Pain; Pelvic Neoplasms; Respiratory Insufficiency; Skull Neoplasms

The purpose of this study was the evaluation of clinical heroin symptoms and buprenorphine drug addiction in the withdrawal period with the purpose of their comparison, study of parameters of bone metabolism in the both groups. In the study group were included 40 patients with heroin and 27 with buprenorphine addiction in the period of abstinence. Our investigations have shown, that in the both groups, among clinical symptoms ossalgias, arthralgias and mialgias attributes to the expressed dysfunction of vegetative system, were most prominent. Decrease of sexual functions was found in half of inspected patients. Biochemical investigations have shown intensive clearance of calcium with the urine that indicates intensifying resorbtion processes in the bone tissue. Symptoms of hypogonadism were accompanied by the decrease of the level of testosterone in the blood. Parameters of mineral consistency of the bone tissue was decreased both in patients with heroin and buprenorphine addiction.

Topics: Behavioral Symptoms; Biomarkers; Bone and Bones; Bone Density; Buprenorphine; Female; Heroin; Heroin Dependence; Humans; Male; Morphine Dependence; Pain; Radiography; Substance Withdrawal Syndrome

Transdermal buprenorphine is available in Europe for the treatment of moderate to severe chronic pain. It has been evaluated at doses of 35, 52.5, and 70 microg/h for the management of moderate to severe chronic cancer and noncancer pain in 3 randomized, double-blind, placebo-controlled trials, each of limited duration (approximately 14 days each). Long-term data are essential to determining the performance of an analgesic in the management of chronic pain.. The purpose of this follow-up study was to obtain data on the efficacy and tolerability of long-term treatment with transdermal buprenorphine in cancer and noncancer patients with chronic persistent pain of moderate to severe intensity.. This was an open-label, uncontrolled, follow-up study in patients from the 3 previous clinical trials who elected to continue treatment with transdermal buprenorphine 35 microg/h and sublingual buprenorphine tablets (0.2 mg) as needed for breakthrough pain. The patch was to be changed every 72 hours throughout the patient's course of pain therapy. At visits every 2 weeks for the first 4 weeks and every 4 weeks for the remainder of study participation, patients evaluated their pain relief retrospectively on a 4-point verbal rating scale. They also rated the ease of patch handling using a 3-point verbal rating scale. Patterns of dose escalation and dose stability were monitored over time. Adherence to therapy was determined based on the number of patients who complied with the dosing schedule. Adverse events were documented by type, intensity, location (systemic or local), and relationship to study medication.. Two hundred thirty-nine patients were included in this follow-up study (120 women, 119 men; 100% white; mean [SD] age, 58 [11.3] years; mean weight, 70.8 [14.7] kg). One hundred thirty-four had cancer-related pain and 105 had pain of noncancerous origin. The mean duration of participation was 7.5 months, and 37 (15.5%) patients participated for >12 months. Maximum study participation was 3.4 years in cancer patients and 5.7 years in noncancer patients. One hundred eighty-eight (78.7%) patients were considered adherent to therapy. The majority (65.9%) of patients managed their pain with the patchalone or took no more than 1 additional sublingual tablet daily for breakthrough pain. At least satisfactory pain relief was reported by 215 (90.0%) patients, and the buprenorphine patch was generally well tolerated. The most common systemic adverse drug reactions were nausea (9.2%), dizziness (4.6%), vomiting (4.2%), constipation (3.8%), and tiredness (2.9%), whereas the most common local adverse drug reactions were erythema (12.1%), pruritus (10.5%), and exanthema (8.8%).. Transdermal buprenorphine was generally well tolerated and effective for the long-term treatment of chronic cancer or noncancer pain in these patients who had previously received buprenorphine in 3 short-term clinical trials.

Topics: Administration, Cutaneous; Administration, Sublingual; Analgesics, Opioid; Buprenorphine; Chronic Disease; Delayed-Action Preparations; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pain

Buprenorphine is a semi-synthetic opioid derived from thebaine. The transdermal formulation of buprenorphine has been available in Belgium for 3 years, during which time the Pain Clinic of the St Elisabeth of Verviers Hospital has gained experience in the use of transdermal buprenorphine for the treatment of moderate-to-severe pain. This paper presents four cases of chronic, non-malignant pain, and one case of chronic cancer pain. By starting patients on low doses and slowly titrating upwards, transdermal buprenorphine matrix patches provided effective analgesia and were well tolerated. Low doses of transdermal buprenorphine were created by cutting the smallest available matrix patch (35 mug/h) into halves or quarters. The initial dose was then gradually titrated upwards to the dose needed for optimum pain relief by the patients. No problems were encountered in switching patients from prior analgesic therapy with other opioids to transdermal buprenorphine.

Topics: Administration, Cutaneous; Adult; Analgesics, Opioid; Buprenorphine; Chronic Disease; Female; Humans; Male; Middle Aged; Pain

Previous studies have suggested that buprenorphine may have a low association with tolerance development compared with other strong opioids. In a previous study by our group, mean cohort and intraindividual dosage increases over an entire course of treatment and on a per-day basis were significantly lower with transdermal (TD) buprenorphine than with TD fentanyl. However, no information concerning the relationship between qualitative and quantitative dose changes is available.. The aim of this study was to compare TD buprenorphine and TD fentanyl with respect to dosage increases, dosage stability, and the nature of dosage changes.. This retrospective analysis used data from the IMS Disease Analyzer-Mediplus database, which contains patient-related data documented by 400 medical practices in Germany. Data from patients with noncancer or cancer pain treated with TD buprenorphine or TD fentanyl for at least 3 months between May 2002 and April 2005 were analyzed. Daily dosages were directly determined from the prescribed patch strength, taking into account the possibility of multiple patches applied simultaneously. To determine dosage stability, patients were classified based on the type of dosage change (stable, increase, alternating, or decrease) of the prescribed dosages. From the prescribed daily dosages, mean percentage increases were calculated on a per-patient basis for the entire treatment period and per day, and these were assessed in relation to the type of dosage change.. In total, 631 patients with noncancer pain and 605 patients with cancer pain were included in the analysis (782 women, 454 men; mean age, 76.3 years [range, 29-100 years]). Treatment indications included osteoarthritis, low back pain, osteoporosis (noncancer groups), and neoplasm (cancer groups). Patients had similar analgesic premedication requirements based on steps 1 to 3 of the World Health Organization analgesic ladder. Comedication requirements for breakthrough pain were also similar between the TD buprenorphine and TD fentanyl groups. The mean percentage increases per day were 0.10% (TD buprenorphine) and 0.25% (TD fentanyl) in the noncancer groups and 0.19% (TD buprenorphine) and 0.47% (TD fentanyl) in the cancer groups (both, P < 0.05). A significantly larger proportion of patients receiving TD buprenorphine had stable dosages over the entire treatment period compared with patients receiving TD fentanyl (noncancer groups: 56.9% vs 41.6%; cancer groups: 50.0% vs 26.2% [both, P < 0.05]). Compared with TD buprenorphine, the proportion of patients with alternating dosage changes was significantly greater in patients receiving TD fentanyl (noncancer groups: 22.7% vs 13.1%; cancer groups: 30.6% vs 11.8% [both, P < 0.05]).. In this retrospective data analysis, compared with TD buprenorphine, the increase in mean daily dosage was significantly greater in patients treated with TD fentanyl. Also, compared with TD buprenorphine, alternating dosage changes were seen in a significantly greater proportion of patients receiving TD fentanyl. On the other hand, a significantly greater proportion of patients treated with TD buprenorphine had stable dosages over their entire treatment periods.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Female; Fentanyl; Humans; Male; Middle Aged; Neoplasms; Pain; Pain, Intractable; Retrospective Studies

We carried out a cost-effectiveness evaluation of transdermal fentanyl compared to three other widely used opioids: transdermal buprenorphine, sustained-release morphine, and controlled-release oxycodone from a third-party-payers perspective. A decision analytic model with data from a structured database search and from panel data and assumptions was used to derive both cost and utility results. Probabilistic sensitivity analysis was performed to ensure the findings. Transdermal fentanyl patients gain more quality adjusted life-days or quality-adjusted life-years per euro. The incremental cost per quality-adjusted life-year is 1,625.65 euro for transdermal fentanyl compared to sustained-release morphine and 1,003.03 euro compared to CO, and it is cost-saving compared to transdermal buprenorphine (-203.38 euro per patient). Transdermal fentanyl is thus cost-effective compared to both sustained-release morphine and CO and dominant compared to transdermal buprenorphine in the treatment of adults with nonmalignant moderate to severe chronic pain.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Chronic Disease; Cost-Benefit Analysis; Delayed-Action Preparations; Fentanyl; Germany; Health Services; Humans; Morphine; Oxycodone; Pain; Quality-Adjusted Life Years

A long-acting analgesic may be particularly desirable in patients suffering from long-lasting pain. The aim of the study was to evaluate the antinociceptive effect of a novel depot of buprenorphine decanoate and its metabolic profiles in human and animal blood.. Following their intramuscular injections in guinea pigs, the antinociceptive effects of the novel depot of buprenorphine decanoate (in oil) and the traditional dosage form of buprenorphine HCl (in saline) were evaluated. An in vitro metabolic study of buprenorphine decanoate in human and animal blood was also carried out. The antinociception of drugs was evaluated using the plantar test. The blood concentrations of drugs were assayed using a high performance liquid chromatography.. We found that both the buprenorphine HCl (in saline) and buprenorphine decanoate (in oil) produced dose-related antinociceptive effect but of different duration of action. Under an equi-mole basis of 0.6 micromol/kg, the durations of action of buprenorphine HCl and decanoate were 4 and 72 h, respectively. In in vitro metabolic study in human and animal bloods, buprenorphine decanoate was totally converted to buprenorphine. Buprenorphine decanoate is a prodrug of buprenorphine.. Intramuscular injection of the depot of buprenorphine decanoate in guinea pigs produced a dose-related long-lasting antinociceptive effect which was much longer than that of the traditional dosage form of buprenorphine HCl. Moreover, buprenorphine decanoate is a prodrug of buprenorphine.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Guinea Pigs; Injections, Intramuscular; Male; Pain

This study compared pressure and thermal thresholds after administration of three opioids in eight cats. Pressure stimulation was performed via a bracelet taped around the forearm. Three ball-bearings were advanced against the forearm by inflation of a modified blood pressure bladder. Pressure in the cuff was recorded at the end point (leg shake and head turn). Thermal threshold was tested as previously reported using a heated probe held against the thorax [Dixon et al. (2002) Research in Veterinary Science, 72, 205]. After baseline recordings, each cat received subcutaneous methadone 0.2 mg/kg, morphine 0.2 mg/kg, buprenorphine 0.02 mg/kg or saline 0.3 mL in a four period cross-over study. Measurements were made at 15, 30, 45 min and 1, 2, 3, 4, 8, 12 and 24 h after the injection. Data were analysed by anova (P<0.05). There were no significant changes in thresholds after saline. Thermal threshold increased at 45 min after buprenorphine (maximum 2.8+/-3 degrees C), 1-3 h after methadone (maximum 3.4+/-1.9 degrees C) and 45 min to 1 h (maximum 3.4+/-2 degrees C) after morphine. Pressure threshold increased 30-45 min (maximum 238+/-206 mmHg) after buprenorphine, 45-60 min after methadone (maximum 255+/-232 mmHg) and 45-60 min and 3-6 h (maximum 255+/-232 mmHg) after morphine. Morphine provided the best analgesia, and methadone appears a promising alternative. Buprenorphines limited effect was probably related to the subcutaneous route of administration. Previously, buprenorphine has produced much greater effects when given by other routes.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Cats; Female; Hot Temperature; Injections, Subcutaneous; Male; Methadone; Morphine; Pain; Pain Measurement; Pressure

Buprenorphine is a potent opioid analgesic clinically used to treat moderate to severe pain. The present study assessed its analgesic efficacy in a broad range of rodent models of acute and chronic pain. In the phenylquinone writhing, hot plate, and tail flick mouse models of acute pain, full analgesic efficacy was obtained (ED50 values: 0.0084-0.16 mg/kg i.v.). Full analgesic efficacy was also obtained in yeast- and formalin-induced inflammatory pain (ED50 values: 0.0024-0.025 mg/kg i.v., rats and mice) and in mustard-oil-induced spontaneous pain, referred allodynia, and referred hyperalgesia in mice (ED50 values: 0.018-0.025 mg/kg i.v.). Buprenorphine strongly inhibited mechanical and cold allodynia in mononeuropathic rats, as well as mechanical hyperalgesia and cold allodynia in polyneuropathic rats (ED50 values: 0.055 and 0.036 mg/kg i.v. and 0.129 and 0.038 mg/kg i.p., respectively). It is concluded that buprenorphine shows a broad analgesic profile and offers the opportunity to treat different pain conditions, including neuropathic pain.

Topics: Acute Disease; Analgesics, Opioid; Animals; Buprenorphine; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley

The use of opioids for treating neuropathic pain is controversial, and some studies have indicated that neuropathic pain may be relatively insensitive to typical mu-opioid analgesics such as morphine. However, it is becoming clear that different opioids produce analgesia by affecting different pain pathways. We present two cases of neuropathic pain and two cases of nociceptive pain with a significant neuropathic component that were treated with transdermal buprenorphine. In each case, sufficient pain relief was obtained and no problems were encountered in switching from prior analgesic therapy with larger doses of other opioids.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Female; Humans; Male; Middle Aged; Pain

The study examined the efficacy of preemptive or postoperative analgesia on surgical pain in the mouse. Radiotelemetry transmitters were surgically implanted in 28 female ICR mice. A mock ova implantation surgery was then performed. Mice were treated with a single dose of buprenorphine or flunixin meglumine prior to or after surgery, three doses of buprenorphine, or were untreated. Heart rate, blood pressure, home cage activity, food and water consumption, and body weight were measured. The no-analgesia group showed no significant differences between any parameters collected prior to surgery and those collected at similar times during the day of surgery. Significant increases in mouse activity on the day of surgery occurred with all analgesic treatments, compared with pre-surgical activity. There were no consistent significant changes in any other telemetry parameter after treatment with analgesics compared with no analgesia. Food consumption and body weight the day after surgery were reduced significantly in the animals treated with three doses of buprenorphine compared with untreated mice and mice given a single dose of buprenorphine. We conclude that the mock ova implant procedure does not induce sufficient pain to cause alterations in heart rate and blood pressure in the mouse. Activity was significantly reduced in the first 6 h after surgery in mice without analgesia, compared with activity prior to surgery. There were no significant differences between pre-emptive and postoperative analgesia. Body weight and food and water consumption were poor measures of pain because analgesia alone affected these parameters.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Buprenorphine; Clonixin; Drinking; Eating; Female; Mice; Narcotics; Pain; Postoperative Period; Telemetry

Topics: Analgesics, Opioid; Buprenorphine; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Finland; Follow-Up Studies; Gestational Age; Humans; Monitoring, Physiologic; Pain; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Risk Assessment

The equipotency ratio of transdermal (TD) fentanyl to oral morphine has been established as 1:100; for buprenorphine TD, a ratio of 1:75 has been proposed, although this ratio has not been confirmed in clinical studies. Growing evidence from clinical practice, in which much lower doses of buprenorphine are used, suggests that this conversion ratio may be too high.. The aim of this study was to compare calculated equipotent oral morphine doses of fentanyl TD with equipotent oral morphine doses of buprenorphine TD prescribed in clinical practice.. This retrospective study identified patients with cancer and noncancer pain who had received > or =1 prescription for fentanyl TD or buprenorphine TD (the all-patients groups) from the German IMS Disease Analyzer-mediplus database, which contains all relevant data concerning drug prescriptions from 400 practices in Germany. Also identified were subgroups of the all-patients groups who had received long-term treatment with fentanyl TD or buprenorphine TD and were considered to have similar pain intensity, as they had previously received similar analgesic medication (the identical-cohort groups). Mean prescribed daily doses for the all-patients and identical-cohort groups were calculated based on the distribution of prescribed patch strengths. Because patients could have applied >1 patch, mean prescribed daily doses were also calculated based on an assumption of double application when appropriate. Equipotent oral morphine doses were estimated using equipotency ratios of 1:100 for fentanyl TD and 1:75 for buprenorphine TD.. The all-patients groups consisted of 2198 patients with noncancer pain and 2544 patients with cancer pain; the identical-cohort groups consisted of 380 patients with noncancer pain and 496 patients with cancer pain (529 women, 347 men; mean age, 74 years [range, 25-101 years]). Equipotent doses of oral morphine were significantly lower in patients receiving buprenorphine TD compared with those receiving fentanyl TD (P < 0.001). In cancer patients, the equipotent oral morphine doses of fentanyl TD and buprenorphine TD were 130.9 to 138.9 mg and 85.2 to 88.8 mg, respectively; in noncancer patients, the corresponding values were 117.0 to 118.3 mg and 80.2 to 80.9 mg. Based on these results, an equipotency ratio of 1:110 to 1:115 for buprenorphine TD would appear to be more appropriate than the proposed ratio of 1:75.. The fact that this retrospective analysis conducted in identical cohorts showed lower calculated equipotent oral morphine doses in the buprenorphine TD groups compared with the fentanyl TD groups calls into question the proposed 1:75 ratio for conversion of buprenorphine TD to equipotent oral morphine doses. Based on the findings of the present study, an equipotency ratio of 1:110 to 1:115 may be more appropriate. However, confirmative data from prospective randomized clinical trials are needed.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Chronic Disease; Cohort Studies; Female; Fentanyl; Hospitalization; Humans; Male; Middle Aged; Neoplasms; Pain; Referral and Consultation; Retrospective Studies

A new transdermal delivery system (TDS) for the rate-controlled systemic delivery of buprenorphine is available in 3 patch strengths, with release rates of 35, 52.5, and 70 microg/h over 72 hours, delivering daily amounts of 0.8, 1.2, and 1.6 mg, respectively. Randomized, double-blind, placebo-controlled, Phase III clinical trials in >400 patients with severe pain of malignant or nonmalignant origin have shown the analgesic efficacy of buprenorphine TDS.. This study investigated the effectiveness and tolerability of buprenorphine TDS for the relief of chronic pain in routine clinical practice.. This was a multicenter, open-label, uncontrolled, prospective, observational, 3-month follow-up study in patients who were beginning buprenorphine TDS treatment for moderate to severe cancer or noncancer pain that had not responded to nonopioid analgesics. Patches were to be changed every 72 hours. Patients were evaluated at 1 and 3 months after the start of treatment. Those who dropped out were considered treatment failures. Pain relief was assessed on a 5-category verbal rating scale, and quality of life was assessed using the European Quality of Life 5D (EQ-5D) questionnaire. Tolerability was determined based on adverse events recorded during the follow-up period.. The study recruited 1223 patients, most of whom were outpatients. Of the 1212 patients for whom sex data were available, 820 (67.7%) were women. In the 1188 patients with age data, the mean (SD) age was 64.9 (12.9) years. In the 1175 patients with data on the etiology of pain, 82.4% had noncancer pain. Six hundred eighty-eight (56.3%) patients completed the 3-month follow-up period. The median daily amount of buprenorphine TDS received at the beginning of the study was 0.8 mg (corresponding to 35 microg/h). Over the study period, there was a significant increase in the proportion of patients reporting very good or good pain relief (P < 0.001), from 3.6% (43/1205) at baseline to 63.2% (762/1205) after 1 month and 56.8% (685/1205) after 3 months. Quality of life also improved, from a mean (SD) EQ-5D score of 40.6 (20.5) at baseline to 56.8 (23.5) at 3 months (P < 0.001). Five hundred seventeen (42.3%) of the original 1223 patients experienced adverse events; the investigator judged 397 (32.5%) of these events possibly or probably related to study drug. The likelihood of experiencing a drug-related adverse event was greater in noncancer patients than in cancer patients. The most common adverse events were nausea (11.0%), vomiting (9.2%), and constipation (7.8%); the most common local adverse events were pruritus (1.4%), dermatitis (1.3%), and erythema (1.3%).. In the population studied, buprenorphine TDS was effective in alleviating cancer and noncancer pain and was well tolerated overall.

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Chronic Disease; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Pain; Pain Measurement; Quality of Life

Evidence suggests that gonadal hormones can modulate sensitivity to nociceptive stimuli and opioid antinociception. However, cross-study comparisons addressing the nature of this modulation have been complicated by a number of methodologic factors, including the use of different rodent strains and opioids. The present study examined the influence of estrous cycle and gonadal hormone depletion (ovariectomy) on thermal nociception and opioid antinociception in female F344, Lewis, Long Evans, and Wistar rats. Estrous cycle-dependent differences in nociceptive sensitivity were not observed in any of the strains. Ovariectomy decreased nociceptive sensitivity relative to their intact female counterparts. In normal cycling females, morphine and buprenorphine were generally most potent in metestrus and proestrus and least potent in estrus. The magnitude of these differences was consistently larger with buprenorphine. Ovariectomy increased the antinociceptive potency of morphine and buprenorphine, with this effect also being larger with buprenorphine. These data suggest that in adult females of a number of rat strains, estrous cycle and gonadal hormone depletion modulate the antinociceptive potency of opioids, with the magnitude of this effect being dependent on the type of opioid. In contrast, depletion of gonadal hormones, but not estrous cycle, modulates thermal nociceptive sensitivity in adult female rats.. Gonadal hormones influence opioid antinociception, and this effect is apparent across different genetic backgrounds. These results suggest that the phase of the menstrual cycle might alter the effectiveness of certain opioids administered to relieve pain in women.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Down-Regulation; Drug Resistance; Estrous Cycle; Female; Gonadal Steroid Hormones; Morphine; Ovariectomy; Ovary; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Rats; Rats, Inbred F344; Rats, Inbred Lew; Rats, Long-Evans; Rats, Wistar; Sex Characteristics; Species Specificity; Thermosensing

The objective of this post-marketing surveillance study was to collect effectiveness and safety data on the labelled use of buprenorphine transdermal patches (Transtec*) under routine clinical conditions.. For this open, observational study, patients with moderate to severe cancer or non-cancer pain requiring treatment with an opioid analgesic were recruited at hospitals, outpatient clinics and general practitioners' practices in Germany. Buprenorphine transdermal patches (35 microg/h, 52.5 microg/h or 70 microg/h) were prescribed at physicians' discretion in accordance with the product's Summary of Product Characteristics (SmPC). Patients assessed their pain relief as 'very good', 'good', 'satisfactory', 'poor' or 'no effect'. Investigators were instructed to report all adverse events throughout the observation period. On completion, effectiveness and tolerability were evaluated for the overall study population, cancer and non-cancer patients, and patients < 70 years and > or = 70 years. Other analyses assessed pain relief with respect to previous opioid treatment and increased patch strength, and in patients who remained on their original dose. The total observation time was 9 months, and the average individual documented treatment time was 60.8 days.. A total of 13,179 patients were evaluated; 3690 (28%) with cancer pain and 9489 (72%) with non-cancer pain. The most frequent diagnoses in non-cancer patients were musculoskeletal disorders (77%) and neuropathy (23%). In the great majority of cases (78%), treatment was started with the 35 microg/h patch. The initial dose needed to be increased subsequently only in about 18% of subjects. Buprenorphine transdermal patches provided effective, sustained and dose-dependent analgesia in patients with cancer and non-cancer pain, irrespective of the patients' age or pain syndromes. Whereas good or very good pain relief was documented only for 6% of the patients with the initial assessment, this percentage increased to 71% at the first follow-up and 80% at the final assessment. Fewer than 5% of subjects discontinued treatment owing to unsatisfactory pain relief. Altogether, adverse events were documented for 2874 patients (22%), whereas a relationship with trans dermal buprenorphine (adverse drug reactions) was assumed for only 10% (2220 adverse drug reactions in 1330 patients). The tolerability profile was as expected for an opioid and did not vary to a relevant extent with either the patient's age or the cause of pain (cancer or non-cancer). No evidence emerged of any previously unknown side effects.. Buprenorphine transdermal patches are well tolerated and effective in the treatment of chronic cancer and non-cancer pain, irrespective of the patients' age. There was no clinically relevant development of tolerance.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Chronic Disease; Female; Health Care Surveys; Humans; Male; Middle Aged; Observation; Pain; Product Surveillance, Postmarketing; Treatment Outcome

Availability of different WHO-step 3 opioids has encouraged the discussion on their value and led to the concepts of opioid rotation. Rotation is suggested, when other measures fail to achieve optimal analgesia and tolerability in cancer pain treatment. Opioid use was assessed in a prospective cohort study of 412 palliative care patients from 14 inpatient and outpatient palliative care facilities in Germany. The most frequently used opioids at baseline were morphine and fentanyl. The most frequent changes in medication (N=106) occurred from oral to parenteral morphine. Only in 49 cases true switches to other long acting opioids were recorded. This is far less than expected from other reports. True switches and adverse side effects were found to occur more frequently in inpatients, while efficacy problems were more frequently recorded in outpatients. There was no correlation between the opioid used at baseline and switch frequency, but numbers of cases receiving other opioids than fentanyl or morphine were low. Reasons for and frequencies of changes in medication were found to be largely shaped by the setting reflecting patients' needs and clinical necessities. Recommendation of first line therapy and availability of opioid formulations define the frequency of opioid use. This impedes evaluation of specific differences between the opioids.

Topics: Aged; Ambulatory Care Facilities; Analgesics, Opioid; Buprenorphine; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Drug Therapy, Combination; Drug Utilization Review; Female; Fentanyl; Hospitals; Humans; Hydromorphone; Male; Middle Aged; Morphine; Oxycodone; Pain; Palliative Care; Prospective Studies; Treatment Outcome

Buprenorphine is a potent opioid analgesic with partial agonistic properties at mu-opioid receptors. This study investigated the interaction potential with several full mu-agonists in the tail-flick test in mice. We further examined the reversibility of buprenorphine antinociception by different mu-opioid receptor antagonists. Combination of buprenorphine with morphine, oxycodone, hydromorphone and fentanyl in the analgesic dose range resulted in additive or synergistic effects. When given after the decline of the acute buprenorphine effect, both morphine and fentanyl also showed full efficacy. A moderate antagonistic effect according to the partial mu-agonistic properties of buprenorphine was only seen when high doses exceeding the therapeutic dose ranges were combined. Under these conditions antinociception of morphine was reduced to the effect of buprenorphine alone. Prophylactic administration of naloxone (10 mg/kg i.v.), naltrexone (1 mg/kg i.v.) and clocinnamox (5 mg/kg s.c.) fully and persistently blocked the antinociception of a high dose of buprenorphine. An established effect of buprenorphine was less sensitive, although repeated administration of naloxone induced complete antagonism, as did the irreversible antagonist clocinnamox under prophylactic and curative treatment conditions. Our results suggest that the antinociceptive effect of buprenorphine is mainly, if not exclusively, mediated by activation of mu-opioid receptors. They confirm clinical experience that in the analgesic dose range a switch between buprenorphine and full mu-agonists is possible without loss of analgesic efficacy and without a refractory period between the termination of buprenorphine analgesia and the onset of action of the new mu-opioid treatment. Antinociception of buprenorphine is sensitive towards mu-opioid receptor antagonists and incomplete inhibition can be improved by increasing the dose or repetitive dosing.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Central Nervous System; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Male; Mice; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Receptors, Opioid, mu

During long-term therapy with strong opioids (step III opioids according to the World Health Organization [WHO] analgesic ladder), dose increases are often necessary because of deterioration of the primary disease or development of tolerance.. The purpose of this study was to compare changes in dosages of transdermal (TD) fentanyl and TD buprenorphine in patients with cancer and non-cancer pain.. In a retrospective study, patients with cancer and noncancer pain being treated with TD fentanyl or TD buprenorphine for at least 3 months between January 2001 and December 2003 were identified from the IMS Disease Analyzer-mediplus database, which contains all patient-related data documented from 400 medical practices in Germany. The indications for treatment were defined according to the International Classification of Diseases, 10th Revision, and included neoplasm (cancer groups), and osteoarthritis, low back pain, and osteoporosis (noncancer groups). The cohort patients were considered to have comparable pain intensity because they had received similar analgesic premedication classified according to steps I to III of the WHO analgesic ladder (cohort groups). The mean prescribed daily doses on first and last prescription were documented, and the mean percentile increases were calculated over the whole treatment duration and per day. Additionally, the mean percentile intraindividual increases (on a per-patient basis) were estimated.. The cohort groups consisted of 448 patients with noncancer pain and 446 patients with cancer pain (552 women and 342 men; mean age, 74 years; range, 25-101 years). The mean percentile increases in dosages over the whole treatment duration and adjusted per day were significantly higher in patients taking TD fentanyl (P < 0.05). Differences were even greater for the mean percentile intraindividual increases per day, which totaled 0.42%and 0.17% for cancer patients taking TD fentanyl and TD buprenorphine, respectively; corresponding values were 0.25% and 0.09%in noncancer patients (P < 0.001).. This retrospective analysis showed a significantly higher increase in the mean daily doses of TD fentanyl as compared with TD buprenorphine. The results must be verified in prospective, randomized clinical studies.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Cohort Studies; Dose-Response Relationship, Drug; Female; Fentanyl; Germany; Humans; Male; Middle Aged; Neoplasms; Pain; Retrospective Studies

Topics: Analgesics, Opioid; Buprenorphine; Chronic Disease; Humans; Hyperalgesia; Pain

To compare the effectiveness of preoperative PO and SC administration of buprenorphine and meloxicam for prevention of postoperative pain-associated behaviors in cats undergoing ovariohysterectomy.. Randomized controlled study.. 51 female cats (4 to 60 months old; weight range, 1.41 to 4.73 kg [3.1 to 10.4 lb]).. Cats received 1 of 5 treatments at the time of anesthetic induction: buprenorphine PO (0.01 mg/kg [0.0045 mg/lb]; n = 10), buprenorphine SC (0.01 mg/kg; 10), meloxicam SC (0.3 mg/kg 10.14 mg/lb]; 10), meloxicam PO (0.3 mg/kg; 10), or 0.3 mL of sterile saline (0.9% NaCI) solution SC (control group; 11). Sedation scores and visual analog scale and interactive visual analog scale (IVAS) pain-associated behavior scores were assigned to each cat 2 hours before and at intervals until 20 hours after surgery.. Cats receiving meloxicam PO or SC had significantly lower IVAS scores (2.91 and 2.02, respectively), compared with IVAS scores for cats receiving buprenorphine PO (755). Pain-associated behavior scores for cats administered buprenorphine or meloxicam PO or SC preoperatively did not differ significantly from control group scores. Rescue analgesia was not required by any of the cats receiving meloxicam, whereas 3 of 10 cats receiving buprenorphine PO, 2 of 10 cats receiving buprenorphine SC, and 1 of 11 cats receiving the control treatment required rescue analgesia.. On the basis of pain-associated behavior scores, cats receiving meloxicam PO or SC before ovariohysterectomy appeared to have less pain after surgery than those receiving buprenorphine PO preoperatively.

Topics: Administration, Oral; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Behavior, Animal; Buprenorphine; Cats; Drug Administration Routes; Female; Hysterotomy; Injections, Subcutaneous; Meloxicam; Ovariectomy; Pain; Postoperative Care; Thiazines; Thiazoles; Time Factors; Treatment Outcome

Groups of mice were infected with tachyzoites of the RH strain of Toxoplasma gondii, treated with the opioid analgesic buprenorphine, sodium sulfadiazine, a combination of buprenorphine and sodium sulfadiazine, or nothing in the drinking water, on days -1 to 12 postinfection. Mice in the T. gondii-infected buprenorphine-treated group did not live significantly longer (P > 0.05) than mice given T. gondii and not treated with buprenorphine. Clinical observations of mice indicated that buprenorphine treatment reduced distress and pain in mice with acute toxoplasmosis. Mice treated with sodium sulfadiazine alone or sodium sulfadiazine combined with buprenorphine survived the 28-day study. Mice treated with buprenorphine and not infected with T. gondii also survived the 28 days. This study demonstrates that buprenorphine does not adversely interfere with acute T. gondii infection and indicates that buprenorphine can be given to mice to alleviate pain and distress associated with a T. gondii infection, and not adversely influence the results of toxoplasmosis studies. Analgesic (buprenorphine) treatment should now be the standard of care for mice in acute toxoplasmosis studies.

Topics: Acute Disease; Analgesics, Opioid; Animals; Buprenorphine; Cell Line; Chlorocebus aethiops; Coccidiostats; Disease Models, Animal; Female; Mice; Pain; Sulfadiazine; Toxoplasma; Toxoplasmosis, Animal

Buprenorphine is a relatively nonselective opioid receptor partial agonist that is used in the management of both pain and addiction. To improve understanding of the opioid receptor subtypes important for buprenorphine effects, we now report the results of our investigation on the roles of mu-, delta-, and kappa-opioid receptors in antinociceptive responses and place preferences induced by buprenorphine. Buprenorphine antinociception, assessed by hot-plate and tail-flick tests, was significantly reduced in heterozygous mu-opioid receptor knockout (MOR-KO) mice and abolished in homozygous MOR-KO mice. In contrast, buprenorphine retained its ability to establish a conditioned place preference (CPP) in homozygous MOR-KO, although the magnitude of place preference was reduced as the number of copies of wild-type mu-opioid receptor genes was reduced. The remaining CPP of buprenorphine was abolished by pretreatment with the nonselective opioid antagonist naloxone, but only partially blocked by pretreatment with either the delta-selective opioid antagonist naltrindole or the kappa-selective opioid antagonist norbinaltorphimine. These data, and biochemical confirmation of buprenorphine actions as a partial delta-, mu-, and kappa-agonist, support the ideas that mu-opioid receptors mediate most of analgesic properties of buprenorphine, but that mu- and delta- and/or kappa-opioid receptors are each involved in the rewarding effects of this drug.

Topics: Analgesics, Opioid; Animals; Buprenorphine; CHO Cells; Conditioning, Operant; Cricetinae; Cyclic AMP; DNA, Complementary; Hot Temperature; Humans; Mice; Mice, Knockout; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Radioligand Assay; Reaction Time; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reward

The development of buprenorphine as a treatment for opiate abuse and dependence has drawn attention to opioid ligands that have agonist actions followed by long-lasting antagonist actions. In a search for alternatives to buprenorphine, we discovered a bridged pyrrolidinomorphinan (BU72). In vitro, BU72 displayed high affinity and efficacy for mu-opioid receptors, but was also a partial delta-opioid receptor agonist and a full kappa-opioid receptor agonist. BU72 was a highly potent and long-lasting antinociceptive agent against both thermal and chemical nociception in the mouse and against thermal nociception in the monkey. These effects were prevented by mu-, but not kappa- or delta-, opioid receptor antagonists. Once the agonist effects of BU72 had subsided, the compound acted to attenuate the antinociceptive action of morphine. BU72 is too efficacious for human use but manipulation to reduce efficacy could provide a lead to the development of a treatment for opioid dependence.

Topics: Analgesics; Animals; Binding, Competitive; Buprenorphine; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Female; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Ileum; In Vitro Techniques; Macaca mulatta; Male; Mice; Mice, Inbred ICR; Morphinans; Morphine; Muscle Contraction; Pain; Pain Measurement; Pyrroles; Radioligand Assay; Rats; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Sulfur Radioisotopes; Time Factors; Tritium; Vas Deferens

Three patients suffering from pain arising from renal and metastasing prostate and breast cancer were successfully treated with transdermal buprenorphine. The three cases demonstrate that transdermal buprenorphine is an easy-to-use and effective therapeutic option for the treatment of advanced cancer pain, that it can also be used in opioid rotation as an alternative after formerly applied steps II or III opioids have failed and that long-term treatment without dose escalation or compromise in tolerability is possible.

Topics: Administration, Cutaneous; Adult; Aged; Analgesics, Opioid; Breast Neoplasms; Buprenorphine; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Pain; Pain Measurement; Prostatic Neoplasms

The use of mice in biomedical research is increasing, largely due to the production and use of genetically engineered animals. Providing postoperative pain control in mice presents many challenges, and long-acting analgesic preparations would be advantageous for this species. A single subcutaneous injection of a liposome-encapsulated (LE) preparation of oxymorphone was compared with multiple injections of buprenorphine or saline in outbred mice undergoing splenectomy. Control groups were given isoflurane alone or isoflurane and an injection of LE oxymorphone but did not undergo surgery. The following parameters were evaluated for 5 days after surgery and were compared with presurgical baseline data for each group: food and water consumption, body weight, ethographic score, and voluntary exercise on a running wheel. Ethographic scores indicated less postsurgical pain in both groups of mice that received either analgesic preparation compared with mice that received only saline. However, mice given LE oxymorphone had superior postoperative recovery, as measured by wheel-running distance and body weight gain, compared with mice given buprenorphine or saline. Mice undergoing splenectomy had significant decreases in body weight, food and water consumption, voluntary exercise, and other normal behaviors. Administration of liposomal oxymorphone at the time of surgery improved postsurgical recovery as measured by these parameters compared with multiple injections of buprenorphine or saline alone. Administration of LE oxymorphone at the time of surgery improved postsurgical recovery, as measured by these parameters.

Topics: Analgesics, Opioid; Animals; Animals, Outbred Strains; Behavior, Animal; Body Weight; Buprenorphine; Drinking; Eating; Injections, Subcutaneous; Laboratory Animal Science; Liposomes; Male; Mice; Mice, Inbred ICR; Oxymorphone; Pain; Pain Measurement; Physical Conditioning, Animal; Specific Pathogen-Free Organisms; Splenectomy

In Germany and many other countries, buprenorphine has been used for a long time for the management of pain in both cancer and non-cancer patients. Although a transdermal delivery system for buprenorphine (Transtec) has recently been introduced, the clinical experience in daily practice with this drug, delivered in a matrix patch, is only now being evaluated. In preliminary data from a survey of 3,255 patients with chronic pain, 26% had cancer pain, while the most common diagnoses of the other respondents included back pain (33%), osteoarthritis (22%), osteoporosis (17%), and neuropathic pain (10%, multiple entries). Before being switched to the buprenorphine patch, most patients had been pretreated with World Health Organization (WHO) Step II opioids (47%) or WHO Step III opioids (18%), including tramadol (in 35% of patients) and a tilidin/naloxone combination (15%); 9% had not been prescribed any opioids in advance of receiving transdermal buprenorphine. Most patients (77%) in the survey had been started on the lowest dose of the buprenorphine patch (35 microg/h), and nearly half (49%) were placed on adjuvant analgesics, including tramadol or tilidin/naloxone. Pain relief was rated as good or very good by 81% of the respondents. Adverse effects were similar to those seen on other opioids, although their intensity was mild in most cases. Local side effects, including erythema (4% of cases) and pruritus (1%), were transitory. Based on the survey results, transdermal buprenorphine is considered an effective opioid treatment for patients with stable cancer and non-cancer pain; it may prove particularly useful in patients who have experienced side effects taking oral analgesic preparations, as well as in those who are taking extensive co-medications.

Topics: Administration, Cutaneous; Adult; Analgesics, Opioid; Buprenorphine; Female; Germany; Humans; Middle Aged; Pain; Tramadol

Antagonistic properties of buprenorphine for epsilon- and micro -opioid receptors were characterized in beta-endorphin- and [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO)-induced antinociception, respectively, with the tail-flick test in male ICR mice. epsilon-Opioid receptor agonist beta-endorphin (0.1-1 micro g), micro -opioid receptor agonist DAMGO (0.5-20 ng), or buprenorphine (0.1-20 micro g) administered i.c.v. dose dependently produced antinociception. The antinociception induced by 10 micro g of buprenorphine given i.c.v. was completely blocked by the pretreatment with beta-funaltrexamine (beta-FNA) (0.3 micro g i.c.v.), indicating that the buprenophine-induced antinociception is mediated by the stimulation of the micro -opioid receptor. The antinociceptive effects induced by beta-endorphin (1 micro g i.c.v.) and DAMGO (16 ng i.c.v.) were dose dependently blocked by pretreatment with smaller doses of buprenorphine (0.001-1 micro g i.c.v.), but not by a higher dose of buprenorphine (10 micro g i.c.v.). beta-FNA at a dose (0.3 micro g i.c.v.) that strongly attenuated DAMGO-induced antinociception had no effect on the antinociception produced by beta-endorphin (1 micro g i.c.v.). However, pretreatment with buprenorphine (0.1-10 micro g) in mice pretreated with this same dose of beta-FNA was effective in blocking beta-endorphin-induced antinociception. beta-FNA was 226-fold more effective at antagonizing the antinociception induced by DAMGO (16 ng i.c.v.) than by beta-endorphin (1 micro g i.c.v.). The antinociception induced by delta-opioid receptor agonist [d-Ala2]deltorphin II (10 micro g i.c.v.) or kappa1-opioid receptor agonist trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamine methanesulfonate salt [(-)-U50,488H] (75 micro g i.c.v.) was not affected by pretreatment with buprenorphine (0.1-1.0 micro g i.c.v.). It is concluded that buprenorphine, at small doses, blocks epsilon-opioid receptor-mediated beta-endorphin-induced antinociception and micro -opioid receptor-mediated DAMGO-induced antinociception, and at high doses produces a micro -opioid receptor-mediated antinociception.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; beta-Endorphin; Buprenorphine; Disease Models, Animal; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors

Opioids mediate their analgesic effects by activating mu-opioid receptors (MOR) not only within the central nervous system but also on peripheral sensory neurons. The peripheral analgesic effects of opioids are best described under inflammatory conditions (e.g., arthritis). The present study investigated the effects of inflammation on MOR binding and G-protein coupling of full versus partial MOR agonists in dorsal root ganglia (DRG) of primary afferent neurons. Our results show that Freund's complete adjuvant (FCA) unilateral hindpaw inflammation induces a significant up-regulation of MOR binding sites (25 to 47 fmol/mg of protein) on DRG membranes without affecting the affinity of either full or partial MOR agonists. In our immunohistochemical studies, the number of MOR-immunoreactive neurons consistently increased. This increase was mostly caused by small-diameter nociceptive DRG neurons. The full agonist DAMGO induced MOR G-protein coupling in DRG of animals without FCA inflammation (EC50 = 56 nM; relative Emax = 100%). FCA inflammation resulted in significant increases in DAMGO-induced MOR G-protein coupling (EC50 = 29 nM; relative Emax = 145%). The partial agonist buprenorphine hydrochloride (BUP) showed no detectable G-protein coupling in DRG of animals without FCA inflammation; however, partial agonist activity of BUP-induced MOR G-protein coupling was detectable in animals with FCA inflammation (EC50 = 1.6 nM; relative Emax = 82%). In behavioral studies, administration of BUP produced significant antinociception only in inflamed but not in noninflamed paws. These findings show that inflammation causes changes in MOR binding and G-protein coupling in primary afferent neurons. They further underscore the important differences in clinical studies testing peripherally active opioids in inflammatory painful conditions.

Topics: Animals; Behavior, Animal; Binding Sites; Buprenorphine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Ganglia, Spinal; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Immunohistochemistry; Inflammation; Male; Neurons, Afferent; Pain; Rats; Rats, Wistar; Receptors, Opioid, mu; Sciatic Nerve; Sulfur Radioisotopes

Patients with moderate to severe pain were treated with buprenorphine patches in one of 3 concentrations: 35 micrograms/h, 52.5 micrograms/h and 70 micrograms/h (= 0.8 mg/d, 1.2 mg/d and 1.6 mg/d respectively). The aim of this review was to assess the efficacy and tolerability of this transdermal system (TDS) in patients with chronic pain. A total of 445 patients were included in 3 double-blinded studies. The dosage titration with buprenorphine patches followed pretreatment with buprenorphine sublingual tablets, higher doses of weak opioids (level 2 substances), low dose morphine (level 3) or other analgesics. Patients with chronic tumour or non-tumour pain were recruited for these studies and treated with buprenorphine patches or placebo for 6 to 15 days. All patients were offered, in addition, buprenorphine sublingual tablets to be taken as required for supplementary pain relief. Pain intensity, analgesia, consumption of buprenorphine sublingual tablets and sleep duration were all assessed. All patients in the double-blinded studies were between the ages of 22 and 88. 249 patients suffered from tumour pain and 196 patients suffered from non-tumour pain. To examine long-term efficacy and tolerability of the transdermal system, treatment was expanded, if the patients were interested in participating in an open-label-study. In all 3 studies, the number of patients with moderate, severe and very severe pain increased in the placebo-patch treated group, while the patients in the buprenorphine transdermal system treated group had a greater incidence of mild or no pain. A further benefit in the buprenorphine transdermal system treated group was evidenced by a great number of patients with a daily sleep duration of more than 6 hours compared to the placebo group--an indicator of greater well-being. The systemic side-effects were typically opioid in nature and rare and usually only mild. Of particular note was the very low incidence of constipation in only 5.3% of cases. Dermatological reactions to the patches were only rarely encountered. The dermatological reactions consisted mainly of erythema and pruritus with a mild to moderate extent. Half the cases of erythema and more than on third of the cases of pruritus were spontaneously reversible. More than half the patients (53.7%) in the double blind studies wished to continued treatment with buprenorphine transdermal system. These results demonstrate that buprenorphine patches achieved a very good analgesic effe

Topics: Administration, Cutaneous; Analgesics, Opioid; Buprenorphine; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Humans; Long-Term Care; Neoplasms; Pain; Pain Measurement; Randomized Controlled Trials as Topic; Treatment Outcome

Kinking of an epidural catheter with resultant failure to inject drug is a complication of lumbar epidural analgesia. Here, we report a case of kinking of epidural catheter 1 cm proximal to its tip after 20 days of insertion. It was inserted to a female for pain relief, suffering from carcinoma of the cervix.

Topics: Analgesia, Epidural; Analgesics, Opioid; Buprenorphine; Catheterization; Equipment Failure; Female; Humans; Middle Aged; Pain

We have studied and compared the antinociceptive and anti-hyperalgesic effect of the partial opioid receptor agonist buprenorphine in normal and neuropathic rats. In normal rats, systemic buprenorphine produced dose-dependent antinociception on the hot plate test. In rats with peripheral nerve or spinal cord injury, buprenorphine markedly alleviated neuropathic pain-related behaviors, including mechanical and cold allodynia/hyperalgesia at doses comparable to that producing antinociception. The results suggest that buprenorphine may be a useful analgesic for treating neuropathic pain and thus is an atypical opioid since morphine tends to be less potent after nerve injury.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Dose-Response Relationship, Drug; Female; Injections, Spinal; Injections, Subcutaneous; Male; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Spinal Cord Injuries; Time Factors

To determine that opioid rotation can be useful for establishing a more advantageous analgesia/toxicity relationship in rheumatologic pain.. Among patients treated with opioids for rheumatologic non-malignant pain, 67 patients with opioid rotation were enrolled retrospectively. In all cases, the other analgesics had failed. The opioids used were: oral morphine, oral hydromorphone, oral buprenorphine and transdermal fentanyl. The reasons for rotation were noted and the improvement of pain was assessed by comparing baseline and post-treatment visual analog scales (VAS in mm).. The 67 patients suffered from low back pain with sciatica in 27 cases, inflammatory arthritis in 14 cases, brachial neuralgia in six cases, osteoarthritis in eight cases and miscellaneous in 12 cases. The opioid rotations were the substitution of morphine by transdermal fentanyl, by oral hydromorphone in most of the cases. The principal reason for opioid rotation was failure of the first treatment. The mean of VAS improvement was 30 mm (P < 0.001).. In rheumatologic non-malignant pain, the opioid rotation might allow the physician to bypass side effects or failure to alleviate pain in most cases.

Topics: Administration, Cutaneous; Administration, Oral; Analgesics, Opioid; Buprenorphine; Drug Administration Schedule; Fentanyl; Humans; Hydromorphone; Joints; Morphine; Pain; Pain Measurement; Retrospective Studies; Rheumatic Diseases; Rheumatology; Treatment Outcome

Adequate pain control is vital in the treatment of patients with musculoskeletal disease. These diseases are characterised by a number of pain-induced vicious circles, and satisfactory control of pain acts to disrupt these self-perpetuating processes. Consequently, early mobilisation can be achieved in patients with painful osteoporotic vertebral fractures, low back pain and sciatica, for example. In other cases analgesics may act simply to maintain the mobility of patients and in this way preserve their quality of life. When simple analgesics are not sufficient, the use of opioid-type analgesics is justified. Buprenorphine transdermal therapeutic system (TDS) is a novel formulation of a well-tolerated and highly effective drug for satisfactory pain control that can also be used in patients with chronic non-malignant pain (CNMP) due to musculoskeletal diseases. Three case reports are presented to illustrate the effectiveness of buprenorphine TDS in such patients.

Topics: Administration, Oral; Analgesics, Opioid; Buprenorphine; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Middle Aged; Musculoskeletal Diseases; Pain; Pain Measurement; Patient Satisfaction; Severity of Illness Index; Treatment Outcome

HS-599 is a didehydroderivative of buprenorphine that displays high affinity and good selectivity for mu-opioid receptors. We studied its antinociceptive properties after s.c. injection in mice with the tail-flick and hot-plate tests. In the tail-flick test HS-599 (AD50 = 0.2801 micromol/kg s.c.) behaved as a full agonist and was twice as potent as buprenorphine (AD50=0.4569 micromol/kg s.c.) and 50 times more potent than morphine (AD50 = 13.3012 micromol/kg s.c.). Whereas the mu-opioid receptor antagonists naloxone (1-10 mg/kg s.c.) and naltrexone (5-15 mg/kg s.c.) antagonized HS-599 induced analgesia, the delta-opioid receptor antagonist naltrindole (20 mg/kg s.c.) and the kappa-opioid receptor antagonist nor-binaltorphimine (20 mg/kg s.c.) did not. With the hot-plate test at 50 degrees C, HS-599 (AD50 = 0.0359 micromol/kg s.c.) was a full agonist about 130 times more potent than morphine (AD50 = 4.8553 micromol/kg s.c.). With a high intensity nociceptive stimulus (55 degrees C) HS-599 (AD50 = 1.0382 micromol/kg s.c.) remained 7 times more potent than morphine (AD50 = 7.0210 micromol/kg s.c.) but never exceeded the 55% of the maximum possible effect, behaving as a partial agonist able to antagonize morphine antinociception in a dose-dependent manner. HS-599 promises to be a potent and safe new analgesic, preferentially acting at spinal level.

Topics: Analgesics, Opioid; Animals; Binding, Competitive; Brain; Buprenorphine; Cell Fractionation; Intracellular Membranes; Male; Mice; Mice, Inbred Strains; Morphine; Pain; Pain Threshold; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Tail

The aim of this study was to investigate objective characterisation of gait as a marker of the chronic pain of adjuvant arthritis (AA). Video recorded images of spontaneous rat ambulations were analysed to quantify various temporal and spatial parameters and compare these between the AA and control groups. Changes were also recorded after the administration of a single dose of buprenorphine (15 ?g). Individual temporal parameters were significantly reduced (velocity (P=0.05), stride length (P=0.007), single stance time (P<0.001), swing time (P=0.001)), or increased (dual stance time (P<0.001)) at 10 days in the AA group compared to control. The rear paws showed reduced ground contact and the fore paws an increase in proximal pad and decrease in digit area, although these changes were not all statistically significant. Some of the gait parameters showed significant reversal following administration of buprenorphine (velocity (P<0.001) and stride length (P<0.001) were increased and single stance time (P=0.014) reduced). It is proposed that changes in gait are a marker of AA chronic pain in this model. These behavioural changes were significant at a very early stage (day 10), before the development of physical deformities and increase in paw volume and might permit an earlier detection of pain than other models.

Topics: Analgesics, Opioid; Animals; Area Under Curve; Arthritis, Experimental; Body Weight; Buprenorphine; Chronic Disease; Disease Models, Animal; Female; Freund's Adjuvant; Gait; Hindlimb; Injections, Subcutaneous; Motor Activity; Pain; Pain Measurement; Rats

We determined the analgesic effects of epidural administration of either bupivacaine at 62.5, 125, 250, and 500 micrograms/kg; buprenorphine at 5 and 10 micrograms/kg; and the combination of bupivacaine at 125 micrograms/kg and buprenorphine at 5 or 10 micrograms/kg, using the tail flick (TF) and colorectal distension (CD) tests in rats and compared the results with those obtained using morphine at 100 micrograms/kg. In both the TF and CD tests, all doses of bupivacaine alone produced potent anti-nociceptive effects, although the effect rapidly diminished after 20-30 min of administration. The administration of buprenorphine at 10 and 5 micrograms/kg produced mild to moderate anti-nociceptive effects in both the TF and CD tests, and the effects were relatively constant throughout the 2-h experimental period. Combinations of 5 or 10 micrograms/kg of buprenorphine with 125 mg/kg of bupivacaine produced a significantly higher percentage of maximum possible analgesic effect (%MPE) than that of the calculated additive effect of each drug alone in the TF and CD tests. The analgesic effect of this combination was similar to that of morphine. Minimal ataxia was observed in rats administered this combination.

Topics: Analgesia, Epidural; Analgesics, Opioid; Animals; Bupivacaine; Buprenorphine; Drug Therapy, Combination; Male; Motor Activity; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley

1. When administered subcutaneously HS-599, a new didehydroderivative of buprenorphine (18,19-dehydrobuprenorphine), produced a long-lasting antinociceptive response in rats. Its potency exceeded twice that of buprenorphine. In the tail-flick test it acted as a full agonist but in the plantar test only as a partial agonist. Whereas the mu-opioid antagonists naloxone and naltrexone antagonized HS-599 antinociception the delta-opioid antagonist naltrindole and the kappa-opioid antagonist nor-binaltorphimine did not. 2. Unlike buprenorphine and morphine, HS-599 never induced conditioned place-preference in rats. 3. In radioligand binding assays, compared with buprenorphine HS-599 had 3 fold higher mu-opioid receptor affinity but lower delta- and kappa-opioid receptor affinity. 4. In isolated guinea-pig ileum preparations, HS-599 only partially inhibited the electrically-stimulated contraction, acting as a partial opioid agonist. When tested against the mu-opioid receptor agonist dermorphin, it behaved as a non-equilibrium antagonist. Conversely, in mouse vas deferens (rich in delta-opioid receptors) and rabbit vas deferens preparations (rich in kappa-opioid receptors) HS-599 acted as a pure equilibrium antagonist, shifting the log-concentration-response curves of the delta-opioid agonist deltorphin I and the kappa-opioid agonist U-69593 to the right. 5. In conclusion, HS-599 is a novel buprenorphine derivative with higher affinity, selectivity and potency than the parent compound, for mu-opioid receptors. It produces intense and long-lasting antinociception and does not induce place-preference in rats.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Benzeneacetamides; Binding, Competitive; Buprenorphine; Dose-Response Relationship, Drug; Guinea Pigs; Ileum; Male; Membranes; Mice; Morphine; Oligopeptides; Pain; Pyrrolidines; Rabbits; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Vas Deferens

Topics: Acetaminophen; Analgesics, Non-Narcotic; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Antidepressive Agents; Aspirin; Asthma; Buprenorphine; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Tolerance; Fentanyl; Humans; Injections; Isoenzymes; Ketorolac; Membrane Proteins; Narcotic Antagonists; Pain; Prostaglandin-Endoperoxide Synthases; Substance-Related Disorders; Tramadol

This study was designed to determine the magnitude and duration of the analgesic effect of three commonly used opioids: buprenorphine (0.5 mg/kg for rats; 2.0 mg/kg for mice), butorphanol (2.0 mg/kg for rats; 5.0 mg/kg for mice), and morphine (10 mg/kg for rats and mice). We used two standard tests, the hot plate and tail flick assays, to measure opioid analgesia in 62 male, 200 to 300 g Sprague-Dawley rats and 61 male, 25 to 35 g ICR mice. We obtained five baseline measurements then administered the drugs subcutaneously. Morphine gave the highest analgesic effect and was intermediate in duration (2 to 3 h in rats and mice) of analgesia. Butorphanol provided the lowest level of and shortest (1 to 2 h in rats and mice) analgesia. Buprenorphine had an intermediate analgesic effect and the longest duration (6 to 8 h in rats and 3 to 5 h in mice). In light of our results, we recommend the use of morphine (with frequent redosing) for severe pain, butorphanol for mild pain of short duration, and buprenorphine for mild to moderate pain of increased duration. The dosing intervals suggested by our study are 2 to 3 h for morphine in both rats and mice, 1 to 2 h for butorphanol in both rats and mice; and 6 to 8 h in rats and 3 to 5 h in mice for buprenorphine.

Topics: Analgesia; Analgesics, Opioid; Animal Welfare; Animals; Buprenorphine; Butorphanol; Drug Administration Schedule; Injections, Subcutaneous; Male; Mice; Mice, Inbred ICR; Morphine; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Tail; Time Factors

We examined the effects of several opioids that vary in intrinsic efficacy at the mu-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50 degrees C and 52 degrees C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids.. Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.

Topics: Analgesics, Opioid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Buprenorphine; Butorphanol; Cycloparaffins; Dose-Response Relationship, Drug; Drug Combinations; Levorphanol; Morphine; Nalbuphine; Narcotics; Nociceptors; Pain; Physical Stimulation; Rats; Rats, Long-Evans; Receptors, Opioid, mu; Tetrahydronaphthalenes

An experimental paradigm, based on the microcrystalline sodium urate-induced arthritis pain model, was used to investigate the potential peripheral analgesic properties of a variety of opioid agonists. The response criteria were changes in behavioral profiles and pain-related behaviors over 60 min commencing 1 h after intraarticular injection. The testing system was used to determine the potential optimum dose of intraarticular application of morphine sulphate (1-3 mg), fentanyl citrate (0.5-3 mg), and buprenorphine hydrochloride (0.05-1 mg). None of the opioid analgesics used had any effect on pain behavior, and it was concluded that opioids with a high affinity for the mu receptor when injected intraarticularly were unlikely to be of use in the treatment or diagnosis of inflammatory arthritic pain in the strain of domestic fowl chosen.

Topics: Analgesia; Analgesics; Animals; Arthritis, Gouty; Buprenorphine; Chickens; Disease Models, Animal; Fentanyl; Injections, Intra-Articular; Male; Morphine; Motor Activity; Narcotics; Pain; Receptors, Opioid, mu; Uric Acid

There is very little research into the problem of chronic pain in dialysed patients, despite the fact that pain is a widely diffused phenomena amongst these patients. This work proposes to evaluate the intensity of pain, supply a scale of levels of intervention, with an indication of the consumption and relative costs of pharmacological therapies.. 37 out of 100 patients undergoing haemodialysis suffer chronic pain. Aetiological research has shown that osteoarticular pain (24 cases), is the most common, peripheral vascular pain (3 cases), is subjectively and indirectly considered to be the most serious form. Nine cases have presented pain of a neuromuscular origin, whilst one case of a neoplastic origin. The degree of personal invalidism shows serious invalidism in 11 cases.. The therapeutic file that forsaw four levels of pharmacological intervention (1st levels: FANS, 2nd level: Codeine+paracetamol, 3rd level: Buprenorphine, 4th level: Morphine for os), accompanied by instrumental and pharmacological support intervention, has proved to be indispensable in confronting the problem. Through pharmacy data, we have noticed a progressive increase over the year in the use of analgesic medicines, of which we can confirm the effectiveness, tolerability, low level of side-effects, at low costs.. In our opinion chronic pain in dialysed patients should not be neglected. The perfection of diagnostic techniques, the discovery of pain-killers with reduced side-effects, the multidisciplinary approach, and reduced costs of treatment, are all valid arguments in favour of an intervention that improves the quality of life of these patients, already so compromised by the nature of the illness itself.

Topics: Acetaminophen; Analgesics; Arthralgia; Buprenorphine; Chronic Disease; Codeine; Disability Evaluation; Drug Costs; Drug Therapy, Combination; Humans; Italy; Morphine; Neuromuscular Diseases; Pain; Pain Measurement; Renal Dialysis; Vascular Diseases

The effects of bupivacaine, a long-acting local anaesthetic, and buprenorphine, an opioid analgesic, administered either pre- or post-operatively, were investigated in a rat laparotomy model. Surgical anaesthesia was induced and maintained with halothane. The type of analgesic treatment was a significant factor in the reduction in body weight and food and water intake which occurred following surgery. The largest reductions were seen in the bupivacaine-treated groups and those animals which received no analgesics. The timing of administration of analgesics had no influence on the effect of bupivacaine administration. The group receiving buprenorphine before surgery showed less depression in food intake than the group receiving buprenorphine at the end of surgery. Animals which received buprenorphine showed less depression of activity than those receiving saline or bupivacaine.

Topics: Analgesics, Opioid; Anesthetics, Local; Animals; Body Weight; Bupivacaine; Buprenorphine; Drinking; Eating; Laparotomy; Male; Motor Activity; Pain; Postoperative Care; Preoperative Care; Random Allocation; Rats; Rats, Wistar; Reference Values; Specific Pathogen-Free Organisms

Pain control (PC) in laboratory animals is supported by ethical as well as methodological considerations, aimed at preventing an interfering reduction in food and water intake and normalizing stress hormone levels. However, little is known about the immunomodulatory attributes of analgesics, which putatively prevents the routine implementation of PC in immunological research. In an established murine model of endotoxemia we investigated the immunomodulatory properties of common clinical analgesics (the opioids fentanyl and buprenorphine). Additionally, a literature study was conducted to investigate the frequency of PC in laboratory animals used for immunological experimentation. In line with various reports, we observed interactions between the opioid analgesics and the immune system that altered the outcome of performed in vivo immunological experiments. Of 100 evaluated publications, none mentioned the use of PC, indicating its uncommon implementation. In conclusion, more studies on the interactions between the immune system and analgesics are needed to establish better criteria for adequate implementation. Finally, we propose that methodological sections in scientific journals should clearly document whether or not PC was employed. If PC is not used, the reason for not using it should be stated.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Fentanyl; Lipopolysaccharides; Male; Mice; Pain; Tumor Necrosis Factor-alpha

To develop a technique for objective assessment of modulation of nociperception in conscious perching birds.. 31 adult African grey parrots.. Birds were randomly assigned to receive saline (0.9% NaCl) solution (n = 10), butorphanol tartrate (11), or buprenorphine hydrochloride (10), i.m. Birds were fitted with a surface electrode on the medial metatarsus of 1 leg. An electrical stimulus was delivered to the bird's foot through an aluminum surface on half of the perch. The alternate side of the perch delivered a noxious thermal stimulus. A withdrawal response to either stimulus was recorded when the bird lifted its foot or vigorously flinched its wings.. Responses to thermal stimuli were extremely variable during baseline testing and after administration of drugs. Thus, significant differences were not detected after drug injection. In contrast, responses to an electrical stimulus were predictable with much less variation.. This method and device allowed for the reliable determination of withdrawal threshold in perching birds. Use of this technique for objective assessment of modulation of nociperception in conscious perching birds will enable assessment of analgesic drugs.

Topics: Analgesia; Animals; Bird Diseases; Buprenorphine; Butorphanol; Consciousness; Electric Stimulation; Hot Temperature; Pain; Pain Measurement; Parrots; Random Allocation

To evaluate effects of butorphanol tartrate and buprenorphine hydrochloride on withdrawal threshold to a noxious stimulus in conscious African grey parrots.. 29 African grey parrots (Psittacus erithacus erithacus and Psittacus erithacus timneh).. Birds were fitted with an electrode on the medial metatarsal region of the right leg, placed into a test box, and allowed to acclimate. An electrical stimulus (range, 0.0 to 1.46 mA) was delivered to each bird's foot through an aluminum perch. A withdrawal response was recorded when the bird lifted its foot from the perch or vigorously flinched its wings. Baseline threshold to a noxious electrical stimulus was determined. Birds then were randomly assigned to receive an i.m. injection of saline (0.9% NaCl) solution, butorphanol (1.0 mg/kg of body weight), or buprenorphine (0.1 mg/kg), and threshold values were determined again.. Butorphanol significantly increased threshold value, but saline solution or buprenorphine did not significantly change threshold values.. Butorphanol had an analgesic effect, significantly increasing the threshold to electrical stimuli in African grey parrots. Buprenorphine at the dosage used did not change the threshold to electrical stimulus. Butorphanol provided an analgesic response in half of the birds tested. Butorphanol would be expected to provide analgesia to African grey parrots in a clinical setting.

Topics: Analgesia; Animals; Bird Diseases; Buprenorphine; Butorphanol; Consciousness; Electric Stimulation; Pain; Pain Measurement; Pain Threshold; Parrots; Species Specificity

During the last decades, an increase is apparent in the use of analgesics for laboratory animals in situations where this was previously considered unnecessary. Mice with advanced tumours often show clear signs of discomfort which may be a result of chronic pain or a result of general ill-being. The syngeneic murine tumour model most frequently used in our experiments was used to investigate whether this discomfort can be reduced with an analgesic. Twenty DBA/2 mice bearing SL2 lymphoma were given 0.5 mg/kg buprenorphine (Temgesic) in food gel twice daily, 20 tumour-bearing mice were given control food gel at the same times. Indicators of well-being were monitored daily. These included behavioural parameters such as exploration, grooming, and posture; food and water consumption and fur quality. All mice showed a clear increase of discomfort with time: explorative behaviours and grooming decreased, while sitting in hunched posture increased. Food and water consumption and fur quality also decreased. Major significant differences between the buprenorphine treated group and the control group were not apparent. In conclusion, we could not document a positive effect or buprenorphine on discomfort in mice as evaluated by our scoring system. It remains possible that pain itself was not the primary cause of the discomfort in mice bearing these tumours, or that the analgesic effect of buprenorphine was insufficient under these circumstances.

Topics: Analgesia; Analgesics, Opioid; Animal Welfare; Animals; Behavior, Animal; Buprenorphine; Drinking; Eating; Female; Hair; Mice; Mice, Inbred DBA; Neoplasm Transplantation; Neoplasms, Experimental; Pain; Sleep Stages

Topics: Analgesics, Opioid; Bile Ducts; Buprenorphine; Chronic Disease; Codeine; Humans; Morphine; Pain; Pancreatitis; Pentazocine; Sphincter of Oddi; Tramadol

Pain is a significant health problem, and there is considerable need for clinical and epidemiological research in this topic. A prerequisite for doing research on patients treated with strong analgesics is that it is possible to identify the patients. We assessed two Danish population-based information systems, in which patients treated with strong analgesics are registered by using the patients' personal registration numbers as identifier. The two systems, which we compared, were (1) a surveillance system administered by the National Board of Health, and (2) the drug prescription register in the Danish National Health Service. During August 1994, 3787 patients were registered in the surveillance system and 3812 in the National Health Service in North Jutland County. Ninety-five persons were registered only in the surveillance system, and 120 only in the National Health Service register. A capture-recapture analysis showed a coverage of 96.9% for the surveillance system and 97.5% for the National Health Service. We thus conclude that the two systems form a valuable study base of patients treated with strong analgesics in epidemiological research.

Topics: Adult; Aged; Analgesics, Opioid; Bias; Buprenorphine; Denmark; Drug Prescriptions; Epidemiologic Methods; Female; Humans; Male; Medical Record Linkage; Middle Aged; Pain; Patient Identification Systems; Registries; Reproducibility of Results; Tramadol

A 46-year-old man involved in a traffic accident was admitted to our university hospital for treatment of acute subdural hematoma of the brain, multiple rib fractures and hemothorax. On admission, he manifested disturbance of consciousness, and his left upper and lower extremities were paralyzed. Blood gas analysis revealed hypoxia, and he was nasotracheally intubated. He was mechanically ventilated with 10 cmH2O positive end-expiratory pressure for treatment of rib fractures following surgical removal of the subdural hematoma and insertion of a sensor into the epidural space for measurement of intracranial pressure. Despite continuous intravenous infusion of midazolam and buprenorphine, he was agitated and thrashed from side to side, probably due to severe chest pain caused by rib fractures. Agitation was effectively controlled by continuous thoracic epidural administration of morphine and bupivacaine. Intracranial pressure did not increase, and epidural analgesia was without sequelae. The patient's level of consciousness gradually improved, rib fractures were treated and he was extubated on the 25th hospital day. These findings indicate that epidural analgesia is useful for controlling pain-related agitation caused by head and chest injuries if increased intracranial pressure is not present.

Topics: Accidents, Traffic; Analgesia, Epidural; Analgesics, Opioid; Bupivacaine; Buprenorphine; Craniocerebral Trauma; Fractures, Bone; Hematoma, Subdural; Humans; Intracranial Pressure; Male; Middle Aged; Monitoring, Physiologic; Morphine; Pain; Ribs

A C-fibre reflex elicited by electrical stimulation within the territory of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anaesthetised rats. Such reflex responses can be inhibited by applying noxious conditioning stimuli to heterotopic areas of the body. These inhibitory processes have been termed diffuse noxious inhibitory controls. The responses were recorded before, during and after the immersion of the tail in a thermoregulated waterbath (at 50 degrees C) for 1 min. The C-fibre reflex responses were depressed by a maximum of 71 +/- 3% at 45 s after the start of such conditioning stimuli. A dose of 3 mu g/kg buprenorphine completely blocked the inhibition and post-stimulus effects triggered by the heterotopic noxious stimuli. In the 0.3-3 mu g/kg range, buprenorphine increased, in a dose-dependent manner, the magnitude of the inhibition. These doses did not produce any changes in the C-fibre reflex itself. The results are discussed in terms of the mechanisms underlying the analgesic properties of buprenorphine.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Nerve Fibers; Pain; Rats; Rats, Sprague-Dawley; Reflex

Topics: Administration, Sublingual; Adult; Ankle Injuries; Buprenorphine; Epilepsy, Generalized; Humans; Joint Dislocations; Male; Pain

Naloxone is known to decrease, increase or have no effect on nociceptive thresholds. Here, using two commonly accepted pain-related behaviors (licking and flinching) associated with injection of noxious formalin into a hind paw in rats, naloxone (0.1-1 mg/kg s.c.) simultaneously decreases and increases nociceptive responding in the same animal. Licking, which is reduced by naloxone, is enhanced by low doses but attenuated by high doses of morphine. However, although licking initially increases with a rise in formalin concentration, at higher concentrations the time spent licking the injected paw actually declines. By contrast, flinching, which is enhanced by naloxone, is only antagonized by morphine and increases linearly with formalin concentration. Both actions of naloxone can be interpreted in terms of a leftward shift in the formalin concentration-response curves. This study demonstrates that naloxone can increase formalin-induced flinching while simultaneously decreasing licking behavior. These findings suggest that, on its own, an unexpected decrease in a single nociceptive index may be an inadequate criterion for demonstrating antinociception.

Topics: Animals; Behavior, Animal; Buprenorphine; Dose-Response Relationship, Drug; Formaldehyde; Injections, Subcutaneous; Male; Morphine; Naloxone; Pain; Rats; Rats, Sprague-Dawley

Tablet buprenorphine hydrochloride when administered to 34 primigravida women sublingually in a dose of 6 micrograms/kg body weight during the first stage of labour, the analgesic action started 30 minutes after administration of drug and the analgesic action increased gradually and reached its peak level 3 hours after administration of drug. Analgesic action continued throughout the first stage of labour when the duration after administration of drug was 9 hours. In one case maximum analgesic action did not persist after 9 hours. The average time of delivery was 5.88 hours having cervical dilatation of 3.1 (+/- 0.13) cm and the progress of labour was not delayed by the drug. There was no cardiorespiratory depression of the subjects. None complained of nausea or vomiting. There was no change in foetal heart rate and Apgar scoring of neonates revealed the average value of 9.71 at 1 minute and 9.94 at 5 minutes.

Topics: Administration, Sublingual; Adult; Analgesia, Obstetrical; Buprenorphine; Female; Humans; Labor, Obstetric; Pain; Pregnancy; Tablets

Buprenorphine is a mixed opioid agonist/antagonist which appears to produce less physical dependence and respiratory depression than typical mu-agonist opioids. These effects suggest its use for analgesia for drug abusers. However, buprenorphine may precipitate withdrawal from other opioids. The present case illustrates the utility of buprenorphine and describes a method to transfer a patient from a mu-agonist to buprenorphine without precipitating withdrawal or interrupting analgesia.

Topics: Adult; Buprenorphine; Crohn Disease; Drug Administration Schedule; Humans; Male; Morphine; Morphine Dependence; Naloxone; Neurologic Examination; Pain; Pain Measurement; Single-Blind Method; Substance Withdrawal Syndrome

This study assessed the relationship between autotomy and opioid systems following brachial nerve sections in the rat. Morphine, buprenorphine and/or naloxone were self-administered orally to rats following nerve sections. Oral morphine and buprenorphine increased the severity of autotomy. Naloxone alone had no effect, but reversed oral morphine effect on autotomy. These results suggest that mu-receptor activation by morphine and buprenorphine can increase the severity of autotomy.

Topics: Administration, Oral; Animals; Body Weight; Brachial Plexus; Buprenorphine; Denervation; Dose-Response Relationship, Drug; Drug Administration Schedule; Male; Morphine; Naloxone; Pain; Rats; Rats, Inbred F344; Self Mutilation

Topics: Anesthesia, Dental; Anesthesia, Local; Buprenorphine; Clorazepate Dipotassium; Diazepam; Flunitrazepam; Humans; Lorazepam; Meperidine; Midazolam; Morphine; Oxazepam; Pain; Pentazocine; Pirinitramide; Preanesthetic Medication

Topics: Buprenorphine; Costs and Cost Analysis; Humans; Morphine; Pain

Topics: Analgesics, Opioid; Animals; Buprenorphine; Butorphanol; Dose-Response Relationship, Drug; Formaldehyde; Male; Morphine; Nalbuphine; Nociceptors; Pain; Pentazocine; Rats; Rats, Inbred Strains; Sensory Thresholds

During a trimester time-course, pain and the efficiency of analgesic interventions were carefully analyzed over 4 weeks in 50 consecutive medical oncology patients with chronic cancer pain. Pain self-assessment was performed with help of a semi-verbal linear analogue scale (VAS). During the initial hospital stay a mean reduction in pain intensity of "40-50%" on VAS in (largely insufficiently pretreated) cancer patients was recorded within 3-7 days. Optimizing pain therapy was not accompanied by more prominent side-effects from more potent analgesic measures, which consisted in regular "pain prophylaxis" instead of PRN-orders, more frequent use of analgesics with a central analgesic action, combination of analgesics with antidepressants or neuroleptic agents and diligent use of still available potentially effective causal pain relief from palliative chemo-hormonotherapy, irradiation and supportive surgery. The (most frequent) skeletal pain situations were usually managed effectively by prostaglandin-synthetase inhibitors, and also by liberal use of palliative antitumor therapy. Visceral cancer pain was more effectively controlled by analgesics only (opiates/opioids). Strong emphasis is placed on critical interpretation of VAS pain scores and on concomitant psychosocial issues.

Topics: Adult; Aged; Analgesics; Buprenorphine; Chronic Disease; Female; Humans; Male; Middle Aged; Morphine; Neoplasms; Pain; Pain Measurement; Prospective Studies

A retrospective study was undertaken at Morristown Memorial Hospital to evaluate the cost impact of buprenorphine HCl, a Schedule V injectable analgesic, versus the Schedule II drugs morphine and meperidine HCl. Time-and-motion studies were conducted in the pharmacy and nursing units. Algorithms were used to determine the cost of auditing, ordering, dispensing, recording, and administering a single dose of Schedule II and Schedule V injectable analgesics. Based on acquisition costs and duration of analgesia, total 24-hour dose costs were calculated for buprenorphine, morphine, and meperidine. The resultant cost comparisons demonstrated that the use of buprenorphine as an alternative to morphine and meperidine for moderate to severe postoperative pain is highly cost-effective and, in this hospital, resulted in a total cost avoidance of up to 67% of analgesic cost per patient per day.

Topics: Buprenorphine; Cost-Benefit Analysis; Hospital Bed Capacity, 500 and over; Humans; Medication Systems, Hospital; New Jersey; Nurses; Pain; Pharmacists; Task Performance and Analysis; Time and Motion Studies

Topics: Animals; Buprenorphine; Humans; Pain; Scorpion Stings; Scorpions

The effects on respiration and pain perception of giving 0.6 mg buprenorphine alone and of giving the same dose after the administration of pethidine intravenously to achieve a steady-state blood pethidine level (mean blood level 0.29-0.47 microgram/ml) were studied in 3 healthy male volunteers. Depression of ventilation occurred with both pethidine and buprenorphine, and the combination produced greater depression than did either drug alone. Times to onset of, and tolerance to, experimental pain increased with pethidine and buprenorphine, a greater increase occurring when both drugs were combined. There was no evidence that buprenorphine reversed the respiratory depression produced by pethidine, while maintaining analgesia.

Topics: Adult; Buprenorphine; Drug Interactions; Humans; Male; Meperidine; Middle Aged; Pain; Reaction Time; Respiration

Topics: Buprenorphine; Chronic Disease; Humans; Narcotics; Pain

Topics: Adult; Aged; Buprenorphine; Chronic Disease; Evoked Potentials, Somatosensory; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Pain; Time Factors

The analgesic, hemodynamic and respiratory effects of buprenorphine (0.3 mg i.v.) were monitored in 15 coronary care unit-admitted patients presenting with myocardial infarction who were in functional class I according to the Killip classification. At the time of the study, 8 of them had unequivocal precordial pain (group 1); the remaining 7 were painfree (group 2). The agent showed a prompt and potent analgesic action. It also induced a slight decrease in mean aortic pressure associated with a reduction in systemic vascular resistance and an increase in cardiac index, a rise in the pulmonary arterial pressure and arteriolar resistance and right atrial pressure, a reduction in arterial pO2 and pH and an increase in pCO2. Tension-time-indices of the left and right ventricles varied in parallel with variations in aortic and pulmonary artery pressure, respectively. These responses were probably unrelated to analgesia since they were similar in groups 1 and 2. Changes in systemic circulation were such as to possibly decrease the contractile effort and the oxygen need of the left ventricle and the size of infarction. On the contrary, the rise in pulmonary arterial pressure imposes a hemodynamic burden on the right ventricle that, depending on the patient's condition, may assume clinical importance. It is felt that the use of buprenorphine in myocardial infarction should be restricted to uncomplicated and selected cases.

Topics: Buprenorphine; Drug Evaluation; Hemodynamics; Humans; Myocardial Infarction; Pain; Pulmonary Circulation; Time Factors

Buprenorphine (15 micrograms/kg b.wt. per hour) distinctly reduced pain sensitivity in acute 3% sodium-taurocholate pancreatitis in male Wistar rats without interfering with the course of the disease. This was seen by assessment of enzyme elevation in serum and ascites and by histological evaluation of the pancreas. Buprenorphine is therefore recommended for animal experiments to study the effect of therapeutic principles in acute pancreatitis.

Topics: Acute Disease; Animals; Buprenorphine; Male; Pain; Pancreatitis; Rats; Rats, Inbred Strains; Taurocholic Acid

Epidural administration of opiates as a long-term treatment of cancer pain, even for out-patients, is now well established. Most reports describe intermittent injections given several times a day, which may have technical and personal disadvantages. Continuous epidural infusion may be preferable. This report describes 16 patients who were treated with epidural opiates delivered by plastic infusion pumps. Pain relief was effective, the equipment was inexpensive and home treatment was easily accomplished.

Topics: Anesthesia, Epidural; Buprenorphine; Catheters, Indwelling; Humans; Infusion Pumps; Meperidine; Morphine; Neoplasms; Pain

The effect of the irreversible opioid receptor antagonist, beta-funaltrexamine (beta-FNA), on antinociception produced by mu- and kappa-receptor agonists was studied in the rat. beta-FNA, 20 to 80 mg kg-1, s.c., given 24 h before testing, produced a dose-related antagonism of the effects of morphine in the paw pressure, hotplate and tail-flick tests. Following the 80 mg kg-1 dose, the degree of antagonism of morphine was stable for up to 48 h after dosing, but was reduced by 5 days and had disappeared by 8 days. In the paw pressure test, beta-FNA, 40 mg kg-1, s.c., antagonized the effects of fentanyl, buprenorphine, tifluadom, ethylketocyclazocine and proxorphan; it was without effect against the highly selective kappa-agonist, U-50,488. In light of these results, the possible opioid receptor selectivities of both the agonists and beta-FNA are reassessed.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Buprenorphine; Cyclazocine; Ethylketocyclazocine; Fentanyl; Male; Naltrexone; Pain; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

During a 2-year period, 150 patients were treated with epidural opioids for more than 7 days; 89 received morphine and 61 buprenorphine. In 16 cases, medication was changed from morphine to buprenorphine, and in 6 from buprenorphine to morphine. In 19 patients in each group, the disease process was benign. The median daily dose of morphine was 17 mg given by an average of 2.9 injections; the corresponding figures in the buprenorphine group were 1.3 mg and 2.6 injections. The mean duration of treatment was 49 days (7-397) in the morphine group and 53 days (7-262) in the buprenorphine group. Satisfactory pain relief was achieved in 40 (45%) patients who received morphine and 41 (67%) patients given buprenorphine. Altering medication from morphine to buprenorphine improved analgesia in 32% of patients, while the reverse improved pain relief in a further 46% of the patients. Side effects were reported in 46% of patients given morphine and 20% given buprenorphine. Seventy-one patients were treated on an outpatient basis. In these cases, buprenorphine was administered for 89% of the total duration of treatment and morphine chloride for 52%.

Topics: Buprenorphine; Chronic Disease; Epidural Space; Humans; Injections; Morphinans; Morphine; Pain; Retrospective Studies

Topics: Acute Disease; Alfentanil; Analgesics, Opioid; Buprenorphine; Fentanyl; Humans; Infusions, Parenteral; Intraoperative Period; Pain; Postoperative Period; Sufentanil

Topics: Buprenorphine; Humans; Morphinans; Pain; Terminal Care

Topics: Adult; Buprenorphine; Evoked Potentials, Somatosensory; Humans; Morphine; Naloxone; Pain; Recruitment, Neurophysiological; Sensory Thresholds; Suprofen; Transcutaneous Electric Nerve Stimulation

Topics: Adult; Antidepressive Agents; Buprenorphine; Chronic Disease; Humans; Male; Middle Aged; Morphine; Pain; Pancreatitis; Pyridoxine; Thiamine

Buprenorphine was administered as sublingual tablets to 70 patients suffering from chronic pain of malignant or non-malignant origin. Daily doses ranging from 0.4 mg to 3.2 mg were administered and good analgesia was reported by the majority of patients. The most common unwanted effects were drowsiness/sleepiness, nausea and/or vomiting and sweating which appeared to be dose related but the incidence of dizziness was not related to daily dose. The incidence of all these unwanted effects except drowsiness/sleepiness decreased after the first week's treatment. No buprenorphine related changes in vital signs or laboratory values were observed and no signs of tolerance or physical dependence were seen in the short term period after discontinuation of treatment. A significant positive correlation between buprenorphine plasma concentration and daily dose was observed but there was no correlation between plasma levels and pain relief.

Topics: Administration, Oral; Adult; Aged; Buprenorphine; Chronic Disease; Evaluation Studies as Topic; Female; Humans; Kinetics; Male; Middle Aged; Morphinans; Pain

Topics: Adolescent; Buprenorphine; Child; Child, Preschool; Female; Humans; Male; Morphinans; Neoplasms; Pain; Retrospective Studies

Topics: Buprenorphine; Butorphanol; Drug Evaluation; Humans; Nalbuphine; Narcotic Antagonists; Pain; Receptors, Opioid

Systemic administration of opioids is one of the traditional, but by no means optimized therapeutic procedures in cancer pain. Besides the underlying pathophysiology, appropriate treatment has to take into account the psychodynamics and behavior of the patient as well as his life expectancy. In view of this, therapy with centrally acting analgesics can be considered after administration of analgesics with peripheral action first and then of psychoactive agents. Nefopam is a centrally (but not spinally) acting analgesic with a novel activity profile. Its advantages and disadvantages in the treatment of carcinoma pain are outlined. The opiate agonist-antagonist principle has the advantage of a lower dependence and tolerance potential. In addition, the preparations pentazocine, tilidine plus naloxone, and buprenorphine deviate from the morphine derivatives in various constituent effects. Their actions and side effects are outlined. The optimization of control of cancer pain is not possible without taking into account the time dimension. In 50 pain patients with advanced cancer, the following main errors were observed in previous treatment of pain syndromes: (1) too early parenteral administration in the course of the disease; (2) underdosage; (3) application intervals that were too long; and (4) use of analgesics as needed by the patient or on request and not according to a time schedule.

Topics: Adult; Aged; Analgesics, Opioid; Buprenorphine; Female; Humans; Male; Middle Aged; Morphine; Nefopam; Neoplasms; Pain; Pentazocine; Tilidine; Tramadol

Topics: Adult; Buprenorphine; Drug Tolerance; Epidural Space; Female; Humans; Injections; Morphinans; Pain; Spinal Neoplasms; Uterine Neoplasms

This case-report of a 78-year old patient, suffering from extreme pain caused by metastatic formation and pathological bone fractures, shows, that the epidural injection of buprenorphine is a good alternative compared to other means of pain-treatment. During almost four days heart rate, blood pressure and breathing frequency, as well as the general reactions of the patient, were observed. Few side effects and little discomfort make the method advisable for patients in poor general condition.

Topics: Aged; Anesthesia, Epidural; Breast Neoplasms; Buprenorphine; Chronic Disease; Epidural Space; Female; Femoral Neck Fractures; Humans; Injections; Morphinans; Neoplasm Metastasis; Pain

Topics: Adult; Buprenorphine; Humans; Male; Middle Aged; Morphinans; Pain; Substance-Related Disorders

Topics: Buprenorphine; Humans; Morphinans; Pain; Palliative Care

Topics: Buprenorphine; Humans; Morphinans; Pain; Pentazocine

Topics: Administration, Oral; Blood Gas Analysis; Buprenorphine; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Morphinans; Mouth Floor; Pain; Time Factors

Topics: Buprenorphine; Endorphins; Humans; Morphinans; Pain; Pentazocine

Topics: Buprenorphine; Humans; Injections; Morphinans; Pain; Pain, Postoperative

1 The treatment of pain of cardiac origin requires a knowledge of the haemodynamic action of the analgesic agents used. 2 The haemodynamic effects of morphine, diamorphine, pavaveretum, pethidine and pentazocine are reviewed. 3 Clinical experience with the new antagonist analgesic buprenorphine is reported. 4 These studies indicate that buprenorphine may be the agent of choice for the relief of severe pain in patients with unstable circulation.

Topics: Buprenorphine; Heart Diseases; Humans; Myocardial Infarction; Narcotic Antagonists; Pain; Structure-Activity Relationship

In that study we compared the analgesic effects of equianalgesic doses of buprenorphine and morphine taken as the narcotic of reference. The experiment has been undertaken in ten adults having severe cancer pain. The results have been analysed by statistical non parametric tests. We found that buprenorphine and morphine have the same pattern of action despite the fact that intramuscular buprenorphine has a clinical duration of approximately 9 hours.

Topics: Adolescent; Adult; Analgesics; Buprenorphine; Female; Humans; Male; Middle Aged; Morphinans; Morphine; Neoplasms; Pain; Statistics as Topic; Time Factors

1. The opioid antagonists, naloxone, GPA 2163, levallorphan and Mr-2266 reduced the latency of the jumping reaction of mice in the hot plate test. The (+)-isomers of levallorphan and Mr-2266 which are devoid of antagonistic activity did not increase this latency. 2. In the same nociceptive reaction test, the enhancing effect of naloxone progressed in a dose-range similar to that required for the antagonism by naloxone of the depressive action of morphine. 3. The facilitatory effect of naloxone was not blocked by the previous administration of morphine or etorphine but it was prevented by pretreatment with a high dose of buprenorphine. 4. The antagonism by naloxone of morphine and of buprenorphine did not follow the same pattern. 5. The factors which are or may be involved in the efficacy of naloxone in enhancing nociceptive reactions are discussed. 6. The enhancing effect of naloxone may be due to an antagonism of endogenous ligands for the opiate receptor. If so, these ligands would be involved in reaction to but not in perception of nociceptive stimuli which need not be harmful ones.

Topics: Animals; Buprenorphine; Etorphine; Male; Mice; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Pain; Stereoisomerism