tapentadol and Pain

Tapentadol is the first of a new class of analgesics, having synergistic µ-opioid receptor agonist and noradrenaline reuptake inhibitory actions. It has been widely researched in many areas of pain, often in noninferiority studies against potent opioids. This review describes all randomized and recent nonrandomized studies of tapentadol in adults with cancer pain.. Tapentadol has been shown to be at least as effective as morphine and oxycodone in five randomized (two of which were multicenter and double-blind) and a range of nonrandomized trials, although caution is needed when interpreting these results. It is effective in both opioid-naive patients and those already taking opioids. By having a lower µ-opioid receptor binding affinity, it has fewer opioid-related toxicities such as constipation and nausea. A recent randomized trial comparing tapentadol to tapentadol plus duloxetine in patients with chemotherapy-induced peripheral neuropathy shows similar improvement in both groups in a range of pain relieving and quality of life measures, with similar adverse effects.. Tapentadol has been shown in a range of studies to be an effective analgesic and thus should be considered as an alternative to morphine and oxycodone, especially when opioid toxicities are an issue.

Topics: Adult; Analgesics; Analgesics, Opioid; Cancer Pain; Humans; Morphine; Multicenter Studies as Topic; Neoplasms; Oxycodone; Pain; Phenols; Quality of Life; Randomized Controlled Trials as Topic; Receptors, Opioid; Tapentadol

Painful diabetic peripheral neuropathy (painful-DPN) is a highly prevalent and disabling condition, affecting up to one-third of patients with diabetes. This condition can have a profound impact resulting in a poor quality of life, disruption of employment, impaired sleep, and poor mental health with an excess of depression and anxiety. The management of painful-DPN poses a great challenge. Unfortunately, currently there are no Food and Drug Administration (USA) approved disease-modifying treatments for diabetic peripheral neuropathy (DPN) as trials of putative pathogenetic treatments have failed at phase 3 clinical trial stage. Therefore, the focus of managing painful- DPN other than improving glycaemic control and cardiovascular risk factor modification is treating symptoms. The recommended treatments based on expert international consensus for painful- DPN have remained essentially unchanged for the last decade. Both the serotonin re-uptake inhibitor (SNRI) duloxetine and α2δ ligand pregabalin have the most robust evidence for treating painful-DPN. The weak opioids (e.g. tapentadol and tramadol, both of which have an SNRI effect), tricyclic antidepressants such as amitriptyline and α2δ ligand gabapentin are also widely recommended and prescribed agents. Opioids (except tramadol and tapentadol), should be prescribed with caution in view of the lack of definitive data surrounding efficacy, concerns surrounding addiction and adverse events. Recently, emerging therapies have gained local licenses, including the α2δ ligand mirogabalin (Japan) and the high dose 8% capsaicin patch (FDA and Europe). The management of refractory painful-DPN is difficult; specialist pain services may offer off-label therapies (e.g. botulinum toxin, intravenous lidocaine and spinal cord stimulation), although there is limited clinical trial evidence supporting their use. Additionally, despite combination therapy being commonly used clinically, there is little evidence supporting this practise. There is a need for further clinical trials to assess novel therapeutic agents, optimal combination therapy and existing agents to determine which are the most effective for the treatment of painful-DPN. This article reviews the evidence for the treatment of painful-DPN, including emerging treatment strategies such as novel compounds and stratification of patients according to individual characteristics (e.g. pain phenotype, neuroimaging and genotype) to improve treatment responses.

Topics: Analgesics, Opioid; Diabetes Mellitus; Diabetic Neuropathies; Humans; Ligands; Pain; Quality of Life; Serotonin and Noradrenaline Reuptake Inhibitors; Tapentadol; Tramadol

The global epidemic of diabetes has led to an epidemic of diabetes complications. Diabetic neuropathy is the most common microvascular complication, of which diabetic peripheral neuropathy (DPN) and autonomic neuropathy (AN) are the most prevalent, affecting ~50% of patients. DPN results in pain with a poor quality of life and a loss of sensation with an increased risk of foot ulceration. Autonomic neuropathy can cause significant morbidity in a minority and is associated with increased mortality. The cornerstone of treatment to prevent or limit the progression of DPN/AN is multifactorial risk factor modification including treatment of glycemia, lipids and blood pressure. Whilst, there are no FDA-approved disease-modifying therapies, there are a number of therapies to relieve symptoms in DPN and AN.. The authors discuss current approved therapies for painful diabetic neuropathy and autonomic neuropathy. They also address the potential role of improving risk factors to limit the development and progression of diabetic neuropathy and new pathogenetic and pain-relieving treatments.. The FDA-approved Pregabalin and Duloxetine over 25 years ago and Tapentadol, 6 years ago for painful diabetic neuropathy. There are currently no FDA-approved disease-modifying treatments for diabetic neuropathy which has been attributed to inappropriate models of the disease with limited translational capacity and major limitations of trial designs and endpoints in clinical trials.

Topics: Diabetic Neuropathies; Humans; Pain; Quality of Life; Risk Factors; Tapentadol

We conducted a narrative review of the literature to compare the pharmacological, efficacy and safety profiles of tapentadol and tramadol, and to assess the clinical interest of tapentadol in adult patients. Tapentadol and tramadol share a mixed mechanism of action, including both mu-agonist and monoaminergic properties. Tapentadol is approximately two to three times more potent than tramadol and two to three times less potent than morphine. It has no identified analgesically active metabolite and is not significantly metabolised by cytochrome P450 enzymes, thus overcoming some limitations of tramadol, including the potential for pharmacokinetic drug-drug interactions and interindividual variability due to genetic polymorphisms of cytochrome P450 enzymes. The toxicity profiles of tramadol and tapentadol are similar; however tapentadol is likely to result in less exposure to serotoninergic adverse effects (nausea, vomiting, hypoglycaemia) but cause more opioid adverse effects (constipation, respiratory depression, abuse) than tramadol. The safety of tapentadol in real-world conditions remains poorly documented, particularly in at-risk patient subgroups and also in the ability to assess the risk associated with its residual serotonergic activity (serotonin syndrome, seizures). Because of an earlier market introduction, more real-world safety data are available for tramadol, including data from at-risk patient subgroups. The level of evidence on the efficacy of both tramadol and tapentadol for the treatment of chronic pain is globally low. The trials published to date show overall that tapentadol does not provide a clinically significant analgesic improvement compared to existing treatments, for which the safety profile is much better known. In conclusion, tapentadol is not a first-line opioid but represents an additional analgesic in the therapeutic choices, which some patients may benefit from after careful examination of their clinical situation, co-morbidities and co-medications.

Topics: Analgesics, Opioid; Cytochrome P-450 CYP2D6; Dose-Response Relationship, Drug; Humans; Liver Failure; Pain; Renal Insufficiency; Tapentadol; Tramadol

Tapentadol is a centrally acting analgesic that has been available for the management of acute and chronic pain in routine clinical practice since 2009.. This is the first integrated descriptive analysis of post-marketing safety data following the use of tapentadol in a broad range of pain conditions relating to the topics overall safety, dose administration above approved dosages, administration during pregnancy, serotonin syndrome, respiratory depression, and convulsion. The data analyzed pertain to spontaneous reports from healthcare and non-healthcare professionals and were put in the context of safety information known from interventional and non-interventional trials.. The first years of routine clinical practice experience with tapentadol have confirmed the tolerability profile that emerged from the clinical trials. Moreover, the reporting of expected side effects such as respiratory depression and convulsion was low and no major risks were identified. The evaluation of available post-marketing data did not confirm the theoretical risk of serotonin syndrome nor did it reveal unexpected side effects with administration of higher than recommended doses.. More than 8 years after its first introduction, the favorable overall safety profile of tapentadol in the treatment of various pain conditions is maintained in the general population.. Grünenthal GmbH.

Topics: Analgesics, Opioid; Chronic Pain; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Pain; Product Surveillance, Postmarketing; Respiratory Insufficiency; Seizures; Serotonin Syndrome; Tapentadol

Moderate-to-severe pain represents a heavy burden in patients' quality of life, and ultimately in the society and in healthcare costs. The aim of this review was to summarize data on tramadol and tapentadol adverse effects, toxicity, potential advantages and limitations according to the context of clinical use. We compared data on the pharmacological and toxicological profiles of tramadol and tapentadol, after an extensive literature search in the US National Library of Medicine (PubMed). Tramadol is a prodrug that acts through noradrenaline and serotonin reuptake inhibition, with a weak opioid component added by its metabolite O-desmethyltramadol. Tapentadol does not require metabolic activation and acts mainly through noradrenaline reuptake inhibition and has a strong opioid activity. Such features confer tapentadol potential advantages, namely lower serotonergic, dependence and abuse potential, more linear pharmacokinetics, greater gastrointestinal tolerability and applicability in the treatment of chronic and neuropathic pain. Although more studies are needed to provide clear guidance on the opioid of choice, tapentadol shows some advantages, as it does not require CYP450 system activation and has minimal serotonergic effects. In addition, it leads to less side effects and lower abuse liability. However, in vivo and in vitro studies have shown that tramadol and tapentadol cause similar toxicological damage. In this context, it is important to underline that the choice of opioid should be individually balanced and a tailored decision, based on previous experience and on the patient's profile, type of pain and context of treatment.. This review underlines the need for a careful prescription of tramadol and tapentadol. Although both are widely prescribed synthetic opioid analgesics, their toxic effects and potential dependence are not completely understood yet. In particular, concerning tapentadol, further research is needed to better assess its toxic effects.

Topics: Analgesics, Opioid; Humans; Pain; Quality of Life; Tapentadol; Tramadol

Tapentadol is a centrally acting analgesic with a dual mode of action as a μ-opioid receptor (MOR) agonist and a noradrenaline reuptake inhibitor (NRI). It was initially approved by the US Food and Drug Administration in November 2008 for the treatment of moderate-to-severe acute pain in adult patients, and in August 2011, for chronic pain in an prolonged release form in the same population. Due to its limited protein binding capacity, the absence of active metabolites and significant microsomal enzyme induction or inhibition, tapentadol has a limited potential for drug-drug interactions. It appears to be well-tolerated and effective in the treatment of moderate-to severe acute and chronic pain. Owing to its dual mechanism of action, it is hypothesized to be good option in the treatment of both nociceptive and neuropathic pain.

Topics: Analgesics; Humans; Norepinephrine Plasma Membrane Transport Proteins; Pain; Phenols; Receptors, Opioid, mu; Tapentadol

Chronic pain is now recognized as a neural disease, which results from a maladaptive functional and structural transformation process occurring over time. In its chronic phase, pain is not just a symptom but also a disease entity. Therefore, pain must be properly addressed, as many patients still report unsatisfactory pain control despite on-going treatment. The selection of the therapy - taking into account the pathophysiological mechanisms of pain - and the right timing can result in a successful analgesic outcome. This review will present the functional and structural modifications leading to chronification of pain, focusing on the role of tapentadol in this setting.. For inclusion in this review, research studies were retrieved via a keyword-based query of multiple databases (MEDLINE, Embase, Cochrane). The search was last updated in November 2016; no limitations were applied.. Functional and structural abnormalities of the nervous system associated with pain chronification have been reported in several conditions, including osteoarthritis, chronic back pain, chronic pelvic pain and fibromyalgia. Correct identification and treatment of pain in recurrent/progressive stage is crucial to prevent chronification and related changes in neural structures. Among analgesic drugs, tapentadol, with its dual mechanism of action (opioid agonist and noradrenaline reuptake blocker), has recently resulted active in pain control at both central and spinal level.. Tapentadol represents a suitable candidate for patients at early progressive stage of pain who have developed neuroplasticity with modification of pain pathways. The availability of different doses of tapentadol may help clinicians to tailor treatment based on the individual need of each patient, with the aim to enhance therapeutic appropriateness in the treatment of musculoskeletal and neuropathic pain.

Topics: Analgesics; Analgesics, Opioid; Chronic Pain; Humans; Neuralgia; Pain; Phenols; Tapentadol

Pain remains a tremendous burden on patients and for the health care system, with uncontrolled pain being the leading cause of disability in this country. There are a variety of medications that can be used in the treatment of pain, including ketorolac, oxymorphone, tapentadol, and tramadol. Depending on the clinical situation, these drugs can be used as monotherapy or in conjunction with other types of medications in a multimodal approach. A strong appreciation of pharmacologic properties of these agents and potential side effects is warranted for clinicians.

Topics: Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Humans; Ketorolac; Oxymorphone; Pain; Pain Measurement; Phenols; Tapentadol; Tramadol

To assess the efficacy and safety of tapentadol IR for moderate to severe pain compared to oxycodone IR.. A search was carried out up to July 2015 for randomized controlled trials (RCTs) of tapentadol IR compared to placebo or oxycodone HCL IR 10 mg for moderate to severe pain. Studies were pooled by risk ratio (RR) and weighted mean differences (WMD) with 95% confidence interval (CI).. Nine RCTs (n = 3,961) were analyzed. In this meta-analysis, tapentadol IR (50-, 75-, and 100-mg doses) showed significant improvements in moderate to severe pain relief on the sum of pain intensity difference over 48 hours (SPID 48 ) scores ( P  <   0.00001 or P  =   0.01). No statistically significant difference among all three doses of tapentadol IR and oxycodone HCL IR 10 mg on both SPID 48 and total pain relief over 48 hours (TOTPAR 48 ) scores (all P  >   0.05) was found. Compared with tapentadol IR 50 mg, tapentadol IR 75 mg demonstrated significant improvement in moderate to severe pain relief based on both SPID 48 and TOTPAR 48 scores (all P  <   0.05). For total adverse events (AEs) incidence, tapentadol IR 50 and 75 mg were significantly lower than oxycodone HCL IR 10 mg. Incidence of nausea and constipation were significantly lower with either tapentadol IR 50 or 75 mg compared with oxycodone HCL IR 10 mg (all P  <   0.05).. Tapentadol IR 75 mg might be an optimal dose for moderate to severe pain control with fewer side effects. All three doses of tapentadol IR could provide comparable efficacy to oxycodone HCL IR 10 mg.

Topics: Analgesics; Humans; Pain; Phenols; Randomized Controlled Trials as Topic; Tapentadol

Persistent pain affects the elderly disproportionally, occurring in 50% of elderly community-dwelling patients and 80% of aged care residents. The management of pain in the elderly and frail patient is complicated because of the risks posed by changes in pharmacokinetics and pharmacodynamics, polypharmacy, and drug-disease interactions. Trials evaluating the efficacy of analgesics have often excluded elderly patients and universally excluded frail patients; therefore, the true efficacy and side-effect profiles in these population groups are largely unknown, especially for long-term use. A stepwise approach is recommended to managing pain, commencing with paracetamol and adding on opioids when needed to manage pain. However, because of the short duration of clinical trials, exclusion of frail patients, and minimal inclusion of elderly patients, the decision as to which opioid should be added on to paracetamol is a difficult one. This article reviews the evidence surrounding a newer opioid, tapentadol. Tapentadol acts on both the mu receptors and on neuronal reuptake of noradrenaline, and has no significant analgesically active metabolites, which theoretically presents some advantages, particularly in comparison with tramadol. However, the evidence to support tapentadol is weak and the trials were often methodologically poor and sponsored almost universally by the drug company. Currently, there is insufficient evidence to support the use of tapentadol over other opioids, which have been on the market longer, are less expensive, and have better established safety profiles. As a first-line agent after the failure of paracetamol alone, morphine, oxycodone, fentanyl, or buprenorphine are still the preferred evidence-based choices for add-on opioid therapy for elderly or frail patients.

Topics: Age Factors; Aged; Analgesics; Frail Elderly; Humans; Pain; Pain Management; Phenols; Receptors, Opioid, mu; Tapentadol

A large proportion of people with advanced cancer will experience moderate to severe pain. Tapentadol is a novel, centrally acting analgesic medicine acting at the μ-opioid receptor and inhibiting noradrenaline reuptake. The efficacy of tapentadol is stated to be comparable to morphine and oxycodone.. To assess the analgesic efficacy of tapentadol for the relief of cancer pain in adults, and the adverse events associated with its use in clinical trials.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from January 2005 to July 2015, together with reference lists of retrieved papers and review articles, and two clinical trial registries. Searches started from 2005 because this covered the period during which clinical trials were conducted. We contacted the manufacturer of tapentadol in the UK to find additional trials not identified by electronic searches. We did not restrict searches by language.. We included randomised controlled trials (RCTs) of tapentadol compared with placebo or active controls in adults with moderate to severe cancer pain. Pain had to be measured using a validated assessment tool, and studies had to include at least 10 participants per treatment arm.. Two review authors independently extracted data using a standard form and assessed risk of bias. We extracted available data on study design, participant details, interventions, and outcomes, including analgesic outcome measures, withdrawals, and adverse events.. We included four studies with 1029 participants. All the studies used a parallel-group design, and included an initial titration phase to determine the maximum effective and tolerated dose, followed by a maintenance phase. Tapentadol medication was taken twice daily and doses ranged from 50 to 500 mg per day. Rescue medication (morphine or oxycodone immediate-release) was available to participants in all studies.Overall, 440 participants were randomised in classically designed RCTs, and 589 participants were enrolled in enriched-enrolment, randomised-withdrawal (EERW) trials. A total of 476 participants were randomised to titration with tapentadol and 338 participants took tapentadol throughout the maintenance phase of their trial.All studies used numerical rating scores, Patient Global Impression of Change scores, and use of rescue medication as measures of efficacy, and all reported on adverse events and withdrawals.All studies enrolled fewer than 200 participants per treatment arm and were therefore at risk of overestimating efficacy. One study was terminated early due to problems with supply of rescue medication, with fewer than 20 participants enrolled per treatment arm in the maintenance phase of the trial. We judged another study at high risk of bias due to an open-label design.There were insufficient data for pooling and statistical analysis. Response rates for pain intensity were comparable across treatment groups in each study. In one EERW study, response rates were high across both treatment and placebo arms during the maintenance phase (62% tapentadol, 69% morphine, 50% placebo). For pain relief, tapentadol is no more and no less effective than oxycodone or morphine (low quality evidence).Treatment emergent adverse event rates were high, approximately 50% to 90%. The most common adverse events were gastrointestinal (nausea, vomiting, constipation) (low quality evidence). There was no advantage of tapentadol over morphine or oxycodone in terms of serious adverse events. The number of people experiencing effects on consciousness, appetite, or thirst was low.. Information from RCTs on the effectiveness and tolerability of tapentadol was limited. The available studies were of moderate or small size and used different designs, which prevented pooling of data. Pain relief and adverse events were comparable between the tapentadol and morphine and oxycodone groups.

Topics: Adult; Humans; Neoplasms; Pain; Phenols; Randomized Controlled Trials as Topic; Receptors, Opioid, mu; Tapentadol

Tapentadol is a novel, centrally-acting analgesic drug, with an analgesic efficacy comparable to that of strong opioids such as oxycodone and morphine. Its high efficacy has been demonstrated in a range of animal models of acute and chronic, nociceptive, inflammatory, and neuropathic pain as well as in clinical studies with moderate to severe pain arising from a number of different etiologies. At the same time, a favorable gastrointestinal tolerability has been demonstrated in rodents and humans, and advantages over morphine regarding tolerance development and physical dependence were shown in animal studies. Furthermore, a low level of abuse and diversion is beginning to emerge from first post-marketing data. Tapentadol acts as a μ-opioid receptor (MOR) agonist and noradrenaline reuptake inhibitor (NRI). Both mechanisms of action have been shown to contribute to the analgesic activity of tapentadol and to produce analgesia in a synergistic manner, such that relatively moderate activity at the two target sites (MOR and noradrenaline reuptake transporter) is sufficient to produce strong analgesic effects. It has been suggested that tapentadol is the first representative of a proposed new class of analgesics, MOR-NRI. This review presents the evidence that has led to this suggestion, and outlines how the pharmacology of tapentadol can explain its broad analgesic activity profile and high analgesic potency as well as its favorable tolerability.

Topics: Adrenergic Uptake Inhibitors; Analgesia; Animals; Drug Therapy, Combination; Humans; Pain; Phenols; Receptors, Opioid, mu; Tapentadol

Decades after the publication of the World Health Organization's analgesic ladder, cancer pain is still a major cause of suffering for patients with cancer and affects millions of people worldwide. Owing to the increasing incidence of cancer, cancer-related pain is a major public health problem worldwide. Unfortunately, current research revealed that available options for the successful treatment of cancer pain is still massively underutilized by physicians, and many patients suffer from insufficiently controlled pain despite available treatment options. This review aims to present a concise update about new data or treatment recommendations from the field of cancer pain management. Therefore, information from guidelines, systematic reviews, and original articles that were published in the year 2012 are presented. Specifically, the publication covers information on tapentadol, fixed oxycodone/naloxone combinations, rapid onset fentanyl, nabiximols, ketamine, denusomab, and specialized psychosocial interventions including early palliative care.

Topics: Analgesics; Animals; Chemistry, Pharmaceutical; Humans; Neoplasms; Pain; Pain Management; Pain Measurement; Phenols; Receptors, Opioid, mu; Tapentadol

Tapentadol is a new centrally acting analgesic with a dual mode of action as an agonist of the µ-opioid receptor and as a norepinephrine reuptake inhibitor. The aim of the present study was to evaluate the results from randomized controlled trials investigating the relative amount of adverse effects using tapentadol or oxycodone for the treatment of pain.. A quantitative systematic review was carried out according to the PRISMA recommendations on randomized controlled trials comparing tapentadol and oxycodone in pain treatment. The incidences of typical adverse side effects of opioid-based analgesic therapy (e.g. nausea, vomiting, obstipation or pruritus) were extracted and the pooled relative risks (RR) with corresponding 95% confidence intervals (CI) were calculated.. A total of 9 trials involving 7,948 patients were included and of these 2,810 patients were treated with oxycodone and 5,138 were treated with tapentadol in equivalent analgesic dosages as documented by an equivalent analgesic effect. The risk of typical opioid-based adverse effects, such as nausea (RR 0.61; 95% CI 0.57-0.66), vomiting (RR 0.50, 95% CI: 0.41-0.60), obstipation (RR 0.47, 95%-CI 0.40-0.56), dizziness (RR 0.86, 95% CI 0.78-0.95), somnolence (RR 0.76, 95% CI 0.67-0.86) and pruritus (RR 0.46, 95% CI 0.37-0.58) was reduced when tapentadol was used for analgesic treatment. These adverse effects were investigated in all nine trials. The risk for dryness of the mouth (6 trials, 6,218 patients, RR 1.79, 95% CI 1.40-2.29) and dyspepsia (1 trial, 646 patients, RR 2.75, 95% CI 1.09-6.94) was increased when tapentadol was used instead of oxycodone. There were no significant differences in the relative risk for any other investigated adverse effect such as dysentery, headache or fatigue.. The results show that using tapentadol significantly reduces the risk of the typical opioid-based adverse effects compared with oxycodone while providing equivalent analgesic treatment.

Topics: Adverse Drug Reaction Reporting Systems; Analgesics, Opioid; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Humans; Oxycodone; Pain; Phenols; Randomized Controlled Trials as Topic; Risk; Tapentadol

Many opioid analgesics share common structural elements; however, minor differences in structure can result in major differences in pharmacological activity, pharmacokinetic profile, and clinical efficacy and tolerability.. This review compares and contrasts the chemistry, pharmacodynamics, pharmacokinetics, and CNS 'functional activity' of tapentadol and tramadol, responsible for their individual clinical utilities.. The distinct properties of tapentadol and tramadol generate different CNS functional activities, making each drug the prototype of different classes of opioid/nonopioid analgesics. Tramadol's analgesia derives from relatively weak µ-opioid receptor (MOR) agonism, plus norepinephrine and serotonin reuptake inhibition, provided collectively by the enantiomers of the parent drug and a metabolite that is a stronger MOR agonist, but has lower CNS penetration. Tapentadol's MOR agonist activity is several-fold greater than tramadol's, with prominent norepinephrine reuptake inhibition and minimal serotonin effect. Accordingly, tramadol is well-suited for pain conditions for which a strong opioid component is not needed-and it has the benefit of a low abuse potential; whereas tapentadol, a schedule-II controlled substance, is well-suited for pain conditions requiring a strong opioid component-and it has the benefit of greater gastrointestinal tolerability compared to classical strong opioids. Both drugs offer distinct and complementary clinical options.

Topics: Analgesics, Opioid; Animals; Humans; Pain; Phenols; Receptors, Opioid, mu; Tapentadol; Tramadol

There has been an alarming increase in the prescription of opiates and opioids for chronic non-cancer pain in the past 15 years. It is estimated that opiate-induced constipation (OIC) is experienced by ~40% of these patients, and that constipation and other gastrointestinal symptoms may dissuade patients from using the required analgesic dose to achieve effective pain relief. Opiates have several effects on gastrointestinal functions, and the inhibition of colonic transit and intestinal and colonic secretion results in constipation. Several different pharmacological approaches are being developed to prevent or treat OIC: prolonged release formulations that contain naloxone (a less specific opiate antagonist that is widely distributed) and a new class of peripherally restricted μ-opiate receptor antagonists, including methylnaltrexone, alvimopan, tapentadol, NKTR-118, and TD-1211. Novel patient response outcomes have been developed to facilitate demonstration of efficacy and safety of drugs in development for OIC.

Topics: Analgesics, Opioid; Constipation; Humans; Naloxone; Narcotic Antagonists; Pain; Phenols; Receptors, Opioid, mu; Tapentadol

Several mechanisms can be proposed to explain an apparent synergistic analgesic action between μ-opioid and α(2)-adrenergic receptor agonists. Combining both effects in a single molecule eliminates the potential for drug-drug interactions inherent in multiple drug therapy. Tapentadol is the first US FDA-approved centrally acting analgesic having both μ-opioid receptor agonist and noradrenaline (norepinephrine) reuptake inhibition activity with minimal serotonin reuptake inhibition. This dual mode of action may make tapentadol particularly useful in the treatment of neuropathic pain. Having limited protein binding, no active metabolites and no significant microsomal enzyme induction or inhibition, tapentadol has a limited potential for drug-drug interactions. Clinical trial evidence in acute and chronic non-cancer pain and neuropathic pain supports an opioid-sparing effect that reduces some of the typical opioid-related adverse effects. Specifically, the reduction in treatment-emergent gastrointestinal adverse effects for tapentadol compared with equianalgesic pure μ-opioid receptor agonists results in improved tolerability and adherence to therapy for both the immediate- and extended-release formulations of tapentadol.

Topics: Adrenergic alpha-2 Receptor Agonists; Analgesics, Opioid; Delayed-Action Preparations; Drug Interactions; Humans; Neuralgia; Pain; Phenols; Receptors, Opioid, mu; Tapentadol

Opioids are among the most effective and potent analgesics currently available. Their utility in the management of pain associated with cancer, acute injury, or surgery is well recognized. However, extending the application of opioids to the management of chronic non-cancer pain has met with considerable resistance. This resistance is due in part to concerns related to gastrointestinal and central nervous system-related adverse events as well as issues pertaining to regulatory affairs, the development of tolerance, incorrect drug usage, and addiction. This review focuses on the incidence of opioid-related side effects and the patient and physician barriers to opioid therapy for chronic non-cancer pain. Tapentadol, a centrally acting analgesic with two mechanisms of action, micro-opioid agonism and norepinephrine reuptake inhibition, may be considered to be a partial solution to some of these issues.. MEDLINE was searched for English-language articles from 1950 to February 2010 using the terms chronic non-cancer pain and opioids together and in combination with undertreatment, adherence, and compliance.. The majority of patients treated with traditional opioids experience gastrointestinal- or central nervous system-related adverse events, most commonly constipation, nausea, and somnolence. These side effects often lead to discontinuation of opioid therapy. Concerns about side effects, analgesic tolerance, dependence, and addiction limit the use of opioids for the management of chronic pain. Treatment with tapentadol appears to provide several advantages of an analgesic with a more favorable side-effect profile than the classic micro-opioid receptor agonist oxycodone (especially related to gastrointestinal tolerability).. The pervasiveness of opioid-associated side effects and concerns related to tolerance, dependence, and addiction present potential barriers to the approval and use of opioids for the management of chronic non-cancer pain. The lower incidence of opioid-associated adverse events and possibly fewer withdrawal symptoms, combined with a satisfactory analgesic profile associated with tapentadol, suggest its potential utility for the management of chronic non-cancer pain. This review will focus on the incidence of opioid-related side effects and barriers to opioid therapy that are available as English-language articles in the MEDLINE index, and as such, it is a representative but not an exhaustive review of the current literature.

Topics: Analgesics, Opioid; Chronic Disease; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Humans; Neoplasms; Opioid-Related Disorders; Pain; Phenols; Severity of Illness Index; Tapentadol

Tapentadol is a novel opioid agent with a dual mode of analgesic action. The inhibition of norepinephrine combined with moderate opioid agonist activity results in fewer gastrointestinal adverse effects compared with equianalgesic doses of oxycodone. Having no active metabolites and minimal protein binding, tapentadol provides improved tolerability with a lower potential for pharmacokinetic drug-drug interactions or accumulation with impaired renal or hepatic function when compared with oxycodone. Tapentadol immediate-release is currently US FDA approved for moderate-to-severe acute pain in adults.

Topics: Clinical Trials as Topic; Drug Interactions; Humans; Pain; Phenols; Receptors, Opioid, mu; Tapentadol; Treatment Outcome

Tapentadol (Nucynta) is an orally active, centrally acting synthetic analgesic that is thought to exert its analgesic effects via two mechanisms of action (mu-opioid receptor agonism and norepinephrine reuptake inhibition). In the US, the immediate-release (IR) formulation of the drug is approved for the relief of moderate to severe acute pain in patients aged > or =18 years. In the EU, the drug is currently in the marketing authorization process. In clinical trials in patients with moderate to severe acute (postorthopaedic surgical or musculoskeletal) pain, recommended regimens of tapentadol IR (50-100 mg every 4-6 hours) provided an analgesic effect that was superior to that of placebo, and noninferior or similar to that of oxycodone IR (10 or 15 mg every 4-6 hours). Tapentadol IR therapy was generally well tolerated; it was associated with significant reductions in the incidences of nausea, vomiting and constipation compared with oxycodone IR therapy. Thus, tapentadol IR is an effective treatment option for the management of moderate to severe acute pain. However, further studies evaluating its clinical utility in relation to that of tramadol and opioids other than oxycodone are warranted. Because tapentadol IR offers the prospect of reduced opioid-related gastrointestinal adverse events while maintaining adequate analgesia, it is a potentially valuable addition to the analgesic armamentarium.

Topics: Analgesics; Analgesics, Opioid; Animals; Clinical Trials as Topic; Drug Interactions; Humans; Oxycodone; Pain; Phenols; Receptors, Opioid, mu; Severity of Illness Index; Tapentadol

Topics: Adrenergic Uptake Inhibitors; Analgesics, Opioid; Chronic Disease; Drug Interactions; Humans; Neuralgia; Pain; Phenols; Tapentadol

Tapentadol is a novel, centrally acting analgesic with two mechanisms of action: micro-opioid receptor agonism and norepinephrine reuptake inhibition. It has demonstrated broad analgesic efficacy across multiple pain models. This article reviews the clinical development of tapentadol immediate release (IR), including results from Phase II and III clinical trials that evaluated the efficacy and safety of tapentadol IR in patients with moderate-to-severe acute pain. In clinical studies in patients with moderate-to-severe acute postoperative pain, osteoarthritis pain and/or low back pain, tapentadol IR 50, 75 or 100 mg every 4 - 6 h has demonstrated analgesic efficacy similar to that observed with the micro-opioid receptor agonist oxycodone HCl IR 10 or 15 mg every 4 - 6 h. However, at doses providing comparable analgesic efficacy, tapentadol IR has been associated with significantly lower incidences of nausea and/or vomiting and constipation, and a significantly lower rate of treatment discontinuation compared with oxycodone IR. The observed efficacy across different pain models and favorable gastrointestinal tolerability profile associated with tapentadol IR indicate that this novel analgesic is an attractive treatment option for the relief of moderate-to-severe acute pain.

Topics: Analgesics; Clinical Trials as Topic; Humans; Pain; Phenols; Receptors, Opioid, mu; Tapentadol

Tapentadol exerts its analgesic effects through micro opioid receptor agonism and noradrenaline reuptake inhibition in the central nervous system. Preclinical studies demonstrated that tapentadol is effective in a broad range of pain models, including nociceptive, inflammatory, visceral, mono- and polyneuropathic models. Moreover, clinical studies showed that tapentadol effectively relieves moderate to severe pain in various pain care settings. In addition, it was reported to be associated with significantly fewer treatment discontinuations due to a significantly lower incidence of gastrointestinal-related adverse events compared with equivalent doses of oxycodone. The combination of these reduced treatment discontinuation rates and tapentadol efficacy for the relief of moderate to severe nociceptive and neuropathic pain may offer an improvement in pain therapy by increasing patient compliance with their treatment regimen.

Topics: Adrenergic Uptake Inhibitors; Analgesics; Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Pain; Phenols; Receptors, Opioid, mu; Tapentadol

To review the pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, dosing, and administration of tapentadol, a combination mu-opioid-receptor agonist and monoamine-reuptake inhibitor, and compare it with tramadol, the first drug in this class.. MEDLINE/PUBMED and EMBASE searches (1986 through March 2009) were conducted to identify pertinent English-language papers. In addition, meeting abstracts from multiple pain specialty organizations were searched (2000 through 2008).. All papers/abstracts evaluating any aspect of tapentadol.. Oral tapentadol hydrochloride (HCl) is the second combination mu-opioid-receptor agonist and monoamine-reuptake inhibitor to be approved by the Food and Drug Administration (approved for treatment of moderate-to-severe acute pain in adults). It was active in a wide variety of pain states in animals and humans. It behaved in a similar fashion to morphine and hydromorphone in animal and human models of physical/psychological dependence. Oral tapentadol HCI is administered in doses of 50 to 100 mg every four to six hours (dose and dosing interval being selected on the basis of pain intensity). No specific recommendations have been made for elders.. Tapentadol overcomes some of the liabilities of tramadol. However, it still has some liabilities: its potential to contribute to/precipitate serotonin syndrome and anticholinergic/5-HT3 antagonist effects and to induce physical/psychological dependence (similar to schedule II opioids). There is also a dearth of information in terms of efficacy/tolerability in chronic pain states, clinical data in frail elders, and details of drug-drug interaction potential vis-à-vis glucuronidation and quantitation of the risk of serotonin syndrome.

Topics: Adrenergic Uptake Inhibitors; Analgesics, Opioid; Animals; Clinical Trials as Topic; Humans; Pain; Phenols; Receptors, Opioid, mu; Tapentadol; Tramadol

Tapentadol hydrochloride is a centrally acting oral analgesic approved by the US Food and Drug Administration in November 2008 for the treatment of moderate to severe acute pain. It is available as immediate-release 50-, 75-, and 100-mg tablets.. The purpose of this article is to review animal studies, pharmacokinetic studies, drug-drug interaction studies, and Phase II/III trials of tapentadol in various conditions producing moderate to severe pain. Efficacy and tolerability data from these studies are summarized.. A search of MEDLINE and International Pharmaceutical Abstracts was conducted from January 2005 through June 30, 2009. Search terms included tapentadol, tapentadol hydrochloride, and (-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride. Relevant information was extracted from the identified articles, and the reference lists of these articles were reviewed for additional pertinent publications. The manufacturer was contacted for clinical trials, abstracts, and poster presentations that were not identified by the literature search. ClinicalTrials.gov was searched to identify recently completed studies.. Tapentadol produces analgesia through a dual mechanism of action: mu-opioid-receptor activation and norepinephrine reuptake inhibition. Its efficacy has been reported in a number of animal studies, as well as in Phase II/III clinical trials. Primary pain disorders in which efficacy has been reported include dental extraction pain, pain after bunionectomy surgery, osteoarthritis pain of the knee and hip, and low back pain. Major adverse effects reported in Phase II/III trials primarily involved the gastrointestinal system (2%-66% of subjects) and the central nervous system (4%-65% of subjects). The occurrence of gastrointestinal adverse effects appeared to be less frequent in tapentadol recipients than in those receiving oxycodone.. Tapentadol appears to be a well-tolerated and effective analgesic for the treatment of moderate to severe acute pain. Although not currently approved for the management of chronic pain, tapentadol has been reported to be effective in managing pain associated with osteoarthritis and low back pain.

Topics: Acute Disease; Administration, Oral; Adrenergic Uptake Inhibitors; Analgesics; Animals; Clinical Trials as Topic; Drug Interactions; Humans; Pain; Pain Measurement; Phenols; Receptors, Opioid, mu; Severity of Illness Index; Tapentadol; Treatment Outcome

Pain sensitization, in the form of knee tenderness and anatomically spread hyperalgesia, is notably common in patients with knee OA and is often refractory to conventional interventions. Tapentadol, as an opioid receptor agonist and noradrenaline reuptake inhibitor, has been proposed as a potentially effective symptomatic treatment for pain-sensitized OA patients. We empirically tested whether tapentadol could attenuate brain response to painful stimulation on the tender knee using functional MRI.. Painful pressure stimulation was applied to the articular interline and the tibial surface, a commonly sensitized site surrounding the joint. Thirty patients completed the crossover trial designed to compare prolonged release tapentadol and placebo effects administered over 14 days.. We found no effects in the direction of the prediction. Instead, patients administered with tapentadol showed stronger activation in response to pressure on the tender site in the right prefrontal cortex and somatosensory cortices. The somatosensory effect was compatible with the spread of neural activation around the knee cortical representation. Consistent with the functional MRI findings, the patients showed higher clinical ratings of pain sensitization under tapentadol and a significant positive association was identified between the number of tapentadol tablets and the evoked subjective pain.. The tapentadol effect paradoxically involved both the spread of the somatosensory cortex response and a stronger activation in prefrontal areas with a recognized role in the appraisal of pain sensations. Further studies are warranted to explore how OA patients may benefit from powerful analgesic drugs without the associated risks of prolonged use.. EudraCT, https://eudract.ema.europa.eu, 2016-005082-31.

Topics: Analgesics; Analgesics, Opioid; Brain; Chronic Pain; Cross-Over Studies; Humans; Osteoarthritis, Knee; Pain; Tapentadol

Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system.. This is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na. Measurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.. This trial was registered 25/06/2019 in EudraCT ( 2019-000942-36 ).

Topics: Biomarkers; Double-Blind Method; Healthy Volunteers; Humans; Lacosamide; Multicenter Studies as Topic; Pain; Peripheral Nerves; Pregabalin; Randomized Controlled Trials as Topic; Tapentadol

IMI2-PainCare-BioPain-RCT2 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on specific compartments of the nociceptive system that could serve to accelerate the future development of analgesics. IMI2-PainCare-BioPain-RCT2 will focus on human spinal cord and brainstem activity using biomarkers derived from non-invasive neurophysiological measurements.. This is a multisite, single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Neurophysiological biomarkers of spinal and brainstem activity (the RIII flexion reflex, the N13 component of somatosensory evoked potentials (SEP) and the R2 component of the blink reflex) will be recorded before and at three distinct time points after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol), and placebo, given as a single oral dose in separate study periods. Medication effects on neurophysiological measures will be assessed in a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin), and in a non-sensitized normal condition. Patient-reported outcome measures (pain ratings and predictive psychological traits) will also be collected; and blood samples will be taken for pharmacokinetic modelling. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between the two primary endpoints, namely the percentage amplitude changes of the RIII area and N13 amplitude under tapentadol. Remaining treatment arm effects on RIII, N13 and R2 recovery cycle are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modelling are exploratory.. The RIII component of the flexion reflex is a pure nociceptive spinal reflex widely used for investigating pain processing at the spinal level. It is sensitive to different experimental pain models and to the antinociceptive activity of drugs. The N13 is mediated by large myelinated non-nociceptive fibers and reflects segmental postsynaptic response of wide dynamic range dorsal horn neurons at the level of cervical spinal cord, and it could be therefore sensitive to the action of drugs specifically targeting the dorsal horn. The R2 reflex is mediated by large myelinated non-nociceptive fibers, its circuit consists of a polysynaptic chain lying in the reticular formation of the pons and medulla. The recovery cycle of R2 is widely used for assessing brainstem excitability. For these reasons, IMI2-PainCare-BioPain-RCT2 hypothesizes that spinal and brainstem neurophysiological measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.. This trial was registered on 02 February 2019 in EudraCT ( 2019-000755-14 ).

Topics: Analgesics; Biomarkers; Brain Stem; Cross-Over Studies; Double-Blind Method; Healthy Volunteers; Humans; Lacosamide; Multicenter Studies as Topic; Pain; Pregabalin; Randomized Controlled Trials as Topic; Spinal Cord; Tapentadol

IMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nociceptive signal processing in human volunteers. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity.. This is a multisite single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from scalp EEG measurements (laser-evoked brain potentials [LEPs], pinprick-evoked brain potentials [PEPs], resting EEG) will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose in separate study periods. Medication effects will be assessed concurrently in a non-sensitized normal condition and a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin). Patient-reported outcomes will also be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between LEP and PEP under tapentadol. Remaining treatment arm effects on LEP or PEP or effects on EEG are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modeling are exploratory.. LEPs and PEPs are brain responses related to the selective activation of thermonociceptors and mechanonociceptors. Their amplitudes are dependent on the responsiveness of these nociceptors and the state of the pathways relaying nociceptive input at the level of the spinal cord and brain. The magnitude of resting EEG oscillations is sensitive to changes in brain network function, and some modulations of oscillation magnitude can relate to perceived pain intensity, variations in vigilance, and attentional states. These oscillations can also be affected by analgesic drugs acting on the central nervous system. For these reasons, IMI2-PainCare-BioPain-RCT3 hypothesizes that EEG-derived measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.. This trial was registered 25/06/2019 in EudraCT ( 2019%2D%2D001204-37 ).

Topics: Biomarkers; Cross-Over Studies; Double-Blind Method; Electroencephalography; Healthy Volunteers; Humans; Lacosamide; Pain; Pain Measurement; Pregabalin; Tapentadol

Tapentadol is effective in the treatment of neuropathic and nociceptive pain and in acute and chronic pain conditions; two mechanisms combining opioid µ-receptor agonism and noradrenergic reuptake inhibition underlie its analgesic effect.. With this single-center, placebo-controlled, double-blind, cross-over pilot-study, we investigated the antihyperalgesic effect of a single oral dose of 100 mg immediate-release tapentadol on thermal and mechanical hyperalgesia in two human models (i.e. 0.6 % topical capsaicin and 40% topical menthol) of evoked neuropathic pain signs in healthy volunteers.. No significant differences regarding experimentally induced heat or cold and mechanical (pinprick) hyperalgesia, as assessed by quantitative sensory testing, could be observed between a single dose of drug and placebo (thermal pain thresholds p>0.4, mechanical pain sensitivity p>0.1). Only few mild side effects of tapentadol were reported.. The discrepancy between pain models using healthy volunteers and drug trials under real acute and chronic pain conditions in patients as well as methodological aspects may have contributed to this result. The impact of these findings questions the general use of pain models as predictors for early decision making during drug development. The study was registered in ClinicalTrials.gov (NCT01615510).

Topics: Adult; Capsaicin; Cross-Over Studies; Double-Blind Method; Female; Humans; Hyperalgesia; Male; Neuralgia; Pain; Pain Measurement; Pain Threshold; Phenols; Pilot Projects; Tapentadol; Young Adult

The goal of this analysis was to develop and evaluate integrated measures of benefit and tolerability of analgesic drugs in clinical trials. We evaluated an efficacy-tolerability composite (ETC) measure combining different cutoff values for daily pain reduction (≥20%, ≥30%, or ≥50% pain reduction) and adverse events (AEs) (no AE, no or mild AEs, no or mild drug-related AEs). Nine ETC cutoff values (3 × 3) were tested using data from a randomized double-blind trial comparing tapentadol extended release (ER) (n = 310), oxycodone controlled release (CR) (n = 322), and placebo (n = 314) in subjects with chronic low back pain. Efficacy-tolerability composite scores were calculated as the mean number of days a subject met the ETC criterion divided by the number of days the subject was expected to be in study; ETC scores were then averaged in each treatment group. For all 9 ETC measures, validity was demonstrated by significant correlation of ETC scores with patients' Global Impression of change and with change from baseline in pain scores. Tapentadol ER ETC scores were statistically significantly higher than oxycodone CR ETC scores for 4 of the ETC measures. "No/mild drug-related AE and ≥20% pain reduction" demonstrated the best overall validity (correlation with patients' global impression of change) and responsiveness (discrimination between treatment groups), yielding a higher standardized effect size for tapentadol ER compared with placebo (0.19 [95% confidence interval: 0.031-0.346]) and with oxycodone CR (0.23 [95% confidence interval: 0.070-0.383]) than other cutoff values. Thus, we have identified herein a composite measure that seems to be a valid and responsive measure of the overall efficacy and tolerability of analgesics in clinical trials.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics; Double-Blind Method; Female; Humans; Male; Middle Aged; Pain; Pain Measurement; Phenols; Tapentadol; Treatment Outcome; Young Adult

To evaluate the analgesic potential of the centrally acting analgesics tramadol, morphine and the novel analgesic tapentadol in a pre-clinical research model of acute nociceptive pain, the tail-flick model in dogs.. Prospective part-randomized pre-clinical research trial.. Fifteen male Beagle dogs (HsdCpb:DOBE), aged 12-15 months.. On different occasions separated by at least 1 week, dogs received intravenous (IV) administrations of tramadol (6.81, 10.0 mg kg(-1) ), tapentadol (2.15, 4.64, 6.81 mg kg(-1) ) or morphine (0.464, 0.681, 1.0 mg kg(-1) ) with subsequent measurement of tail withdrawal latencies from a thermal stimulus (for each treatment n = 5). Blood samples were collected immediately after the pharmacodynamic measurements of tramadol to determine pharmacokinetics and the active metabolite O-demethyltramadol (M1).. Tapentadol and morphine induced dose-dependent antinociception with ED50-values of 4.3 mg kg(-1) and 0.71 mg kg(-1) , respectively. In contrast, tramadol did not induce antinociception at any dose tested. Measurements of the serum levels of tramadol and the M1 metabolite revealed only marginal amounts of the M1 metabolite, which explains the absence of the antinociceptive effect of tramadol in this experimental pain model in dogs.. Different breeds of dogs might not or only poorly respond to treatment with tramadol due to low metabolism of the drug. Tapentadol and morphine which act directly on μ-opioid receptors without the need for metabolic activation are demonstrated to induce potent antinociception in the experimental model used and should also provide a reliable pain management in the clinical situation. The non-opioid mechanisms of tramadol do not provide antinociception in this experimental setting. This contrasts to many clinical situations described in the literature, where tramadol appears to provide useful analgesia in dogs for post-operative pain relief and in more chronically pain states.

Topics: Analgesics, Opioid; Animals; Disease Models, Animal; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Male; Morphine; Pain; Pain Measurement; Phenols; Receptors, Opioid, mu; Tapentadol; Tramadol

Constipation is a common side effect of opioid therapy. Tapentadol immediate release (IR) was better tolerated than oxycodone IR in 2 clinical trials involving patients with low back or osteoarthritis pain. The objective of this study was to examine patient-reported bowel function during those trials.. Bowel function was assessed during secondary post hoc analyses using: the bowel movement questionnaire (BMQ; 10-d trial); the Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM; 90-day trial); and laxative use (both trials). Random effects maximum likelihood regressions were run to examine PAC-SYM data. BMQ data were analyzed using 1-way analyses of variance and a multinomial logistic regression. Rates of laxative use were compared using χ(2) statistics.. The 10- and 90-day trials consistently showed that tapentadol IR caused less impairment of bowel function than oxycodone IR. BMQ data were comparable between patients receiving tapentadol IR and placebo, and better versus oxycodone IR including: lower proportion of days where bowel movement was absent (P<0.05); lower risks of reporting hard stools (P<0.001); and moderate or severe straining (P<0.001). All PAC-SYM summary scores (abdominal, rectal, stool, overall) indicated fewer symptoms among patients receiving tapentadol IR versus oxycodone IR (P<0.001). In both trials, rates of laxative use was lower for tapentadol IR treatment groups versus oxycodone IR (P<0.001).. Patient-reported bowel function associated with tapentadol IR treatment was similar to that associated with placebo (10-d trial) and significantly better than that associated with oxycodone IR treatment (10- and 90-d trials).

Topics: Adolescent; Adult; Analgesics, Opioid; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Gastroenteritis; Humans; Laxatives; Low Back Pain; Male; Osteoarthritis; Oxycodone; Pain; Phenols; Surveys and Questionnaires; Tapentadol; Time Factors; Young Adult

The aim of this prospective, open-label study was to evaluate the efficacy and tolerability of tapentadol (TP) in the management of cancer pain.. A 4 weeks' prospective study was carried out in 50 opioid-naive cancer patients with moderate-severe pain. Each patient initially received twice-daily doses of slow-release TP 50 mg. Doses were then managed to maintain adequate relief or dose-limiting toxicity, on the basis of the clinical response. The following parameters were recorded at weekly intervals for 4 weeks: pain and opioid-related adverse effects, quality of life measured with the Spitzer score, TP escalation index percent (TPEI%) and TP escalation index in mg (TPEImg), calculated at the end of the study, pain mechanisms, and PainDETECT at baseline.. Of 50 patients, 39 completed the entire study and 11 discontinued the treatment for different reasons. Pain intensity significantly decreased from baseline to all the week intervals (p < 0.0005), and adverse effects did not changed significantly, while quality of life improved. TP escalation indexes were low and no relationship was found with age, gender, and pain mechanisms.. Tapentalol started in doses of 100 mg/day was well-tolerated and effective in opioid-naive patients with cancer pain, regardless of the pain mechanism. It can be considered as a flexible drug to be used in patients with moderate-severe pain.. This was an open-label study for exploratory purposes. Data should be confirmed in controlled studies with a larger number of patients.

Topics: Aged; Analgesics; Female; Humans; Male; Middle Aged; Neoplasms; Pain; Pain Measurement; Phenols; Prospective Studies; Tapentadol

Painful diabetic peripheral neuropathy (DPN) may not be adequately managed with available therapeutic options. This phase III, randomized-withdrawal, placebo-controlled trial evaluated the safety and efficacy of tapentadol extended release (ER) for relieving painful DPN.. Patients (n = 588) with at least a 3-month history of opioid and/or non-opioid analgesic use for DPN, dissatisfaction with current treatment, and an average pain intensity score of at least 5 on an 11-point numerical rating scale (NRS; 0 = 'no pain,' 10 = 'pain as bad as you can imagine') were titrated to an optimal dose of tapentadol ER (100-250 mg bid) during a 3-week open-label phase. Subsequently, patients (n = 395) with at least a 1-point reduction in pain intensity were randomized 1:1 to receive placebo or the optimal fixed dose of tapentadol ER determined during the open-label phase for a 12-week double-blind phase.. NCT00455520.. The primary efficacy outcome was the change in average pain intensity from randomization, determined by twice-daily NRS measurements. Safety was assessed throughout the study.. The least-squares mean difference between groups in the change in average pain intensity from the start of double-blind treatment to week 12 was -1.3 (95% confidence interval, -1.70 to -0.92; p < 0.001, tapentadol ER vs. placebo). A total of 60.5% (356/588) of patients reported at least a 30% improvement in pain intensity from the start to the end of the open-label titration phase; of the patients who were randomized to tapentadol ER, 53.6% (105/196) reported at least a 30% improvement from pre-titration to week 12 of the double-blind phase. The most common treatment-emergent adverse events that occurred during double-blind treatment with tapentadol ER included nausea, anxiety, diarrhea, and dizziness. Potential limitations of this study are related to the enriched enrollment randomized-withdrawal trial design, which may result in a more homogeneous patient population during double-blind treatment and may present a risk of unblinding because of changes in side effects from the open-label to the double-blind phase.. Compared with placebo, tapentadol ER 100-250 mg bid provided a statistically significant difference in the maintenance of a clinically important improvement in pain 1 , 2 and was well-tolerated by patients with painful DPN.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Analgesics, Opioid; Delayed-Action Preparations; Diabetic Neuropathies; Double-Blind Method; Female; Humans; Male; Middle Aged; Pain; Pain Measurement; Phenols; Placebos; Tapentadol; Treatment Outcome; Withholding Treatment

Two randomized, double-blind, placebo-controlled studies in acute and chronic pain treatment, powered to assess noninferiority of the efficacy of tapentadol immediate release (IR) (50 mg, 75 mg) versus oxycodone hydrochloride (HCl) IR (10 mg), established comparable efficacy of tapentadol IR with oxycodone HCl IR, and suggested tapentadol IR's improved gastrointestinal tolerability. The impact of these equianalgesic doses of tapentadol and oxycodone HCl on bowel function and gastrointestinal tolerability was then directly assessed in the current study, using a validated bowel function diary to comprehensively assess opioid-induced constipation symptoms and outcomes.. In this double-blind study, patients with end-stage joint disease were randomized to tapentadol IR (50 mg or 75 mg), oxycodone HCl IR 10 mg, or placebo. Treatment with IR formulations (14 days) was followed by treatment (28 days) with extended-release (ER) formulations of active drugs (or placebo).. Oxycodone HCl IR treatment significantly decreased (P<0.001) mean (SD) number of spontaneous bowel movements over the 14-day period (average per week: [6.7 (5.44)] versus tapentadol IR 50 mg [9.0 (4.04)], tapentadol IR 75 mg [8.6 (4.65)], and placebo [9.9 (5.16)]) (primary measure), confirming the tolerability findings of the earlier studies. Additionally, incidences of nausea and vomiting were significantly lower over the 14-day period (nominal P<0.001) for tapentadol IR 50 and 75 mg, versus oxycodone HCl IR 10 mg. Results with ER formulations of tapentadol and oxycodone HCl over a longer treatment period were consistent with those of IR formulations.. Tapentadol IR (50 mg, 75 mg) consistently demonstrated superior gastrointestinal tolerability, including for the most commonly reported events, such as nausea, vomiting, and constipation at doses that provide comparable efficacy with oxycodone HCl IR 10 mg. These findings validate and extend the tolerability findings of the two earlier studies that established comparable efficacy of these tapentadol and oxycodone HCl doses.

Topics: Aged; Analgesics, Opioid; Chronic Disease; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Joint Diseases; Male; Middle Aged; Nausea; Oxycodone; Pain; Phenols; Tapentadol; Vomiting

Tapentadol is a novel, centrally acting analgesic with mu-opioid receptor agonist and norepinephrine reuptake inhibitor activity.. to evaluate the efficacy and safety of Tapentadol extended release (ER) compared with oxycodone controlled release (CR) for management of moderate to severe chronic osteoarthritis-related knee pain.. this was a randomized, double-blind, active- and placebo-controlled, parallel-arm, multicentre, phase III study during which patients received Tapentadol ER, oxycodone CR or placebo for a 3-week titration period followed by a 12-week maintenance period. The study was carried out at sites in Australia, Canada, New Zealand and the US. A total of 1030 patients with chronic osteoarthritis-related knee pain were randomized to receive Tapentadol ER 100-250 mg twice daily, oxycodone HCl CR 20-50 mg twice daily or placebo. Primary endpoints (as determined prior to initiation of the study) were the changes from baseline in average daily pain intensity (rated by patients on an 11-point numerical rating scale) over the last week of maintenance and over the entire 12-week maintenance period; last observation carried forward was used to impute missing values after early treatment discontinuation.. efficacy and safety were evaluated for 1023 patients. Tapentadol ER significantly reduced average pain intensity from baseline to week 12 of the maintenance period versus placebo (least squares mean [LSM] difference [95% CI], -0.7 [-1.04, -0.33]), and throughout the maintenance period (-0.7 [-1.00, -0.33]). Oxycodone CR significantly reduced average pain intensity from baseline throughout the maintenance period versus placebo (LSM difference [95% CI], -0.3 [-0.67, -0.00]) but not at week 12 (-0.3 [-0.68, 0.02]). A significantly higher percentage of patients achieved > or =50% improvement in pain intensity in the Tapentadol ER group (32.0% [110/344]) compared with the placebo group (24.3% [82/337]; p = 0.027), indicating a clinically significant improvement in pain intensity, while a significantly lower percentage of patients achieved > or =50% improvement in pain intensity in the oxycodone CR group (17.3% [59/342]; p = 0.023 vs placebo). In the placebo, Tapentadol ER and oxycodone CR groups, respectively, 61.1% (206/337), 75.9% (261/344) and 87.4% (299/342) of patients reported at least one treatment-emergent adverse event (TEAE); incidences of gastrointestinal-related TEAEs were 26.1% (88/337), 43.0% (148/344) and 67.3% (230/342).. treatment with Tapentadol ER 100-250 mg twice daily or oxycodone HCl CR 20-50 mg twice daily was effective for the management of moderate to severe chronic osteoarthritis-related knee pain, with substantially lower incidences of gastrointestinal-related TEAEs associated with treatment with Tapentadol ER than with oxycodone CR.

Topics: Aged; Analgesics; Chronic Disease; Delayed-Action Preparations; Double-Blind Method; Female; Humans; Male; Middle Aged; Osteoarthritis, Knee; Oxycodone; Pain; Phenols; Tapentadol

Tapentadol is a new, centrally active analgesic agent with two modes of action--mu opioid receptor agonism and norepinephrine reuptake inhibition--and the immediate-release (IR) formulation is approved in the US for the relief of moderate to severe acute pain. The aims of this analysis were to develop a population pharmacokinetic model to facilitate the understanding of the pharmacokinetics of tapentadol IR in healthy subjects and patients following single and multiple dosing, and to identify covariates that might explain variability in exposure following oral administration.. The analysis included pooled data from 11,385 serum pharmacokinetic samples from 1827 healthy subjects and patients with moderate to severe pain. Population pharmacokinetic modelling was conducted using nonlinear mixed-effects modelling (NONMEM) software to estimate population pharmacokinetic parameters and the influence of the subjects' demographic characteristics, clinical laboratory chemistry values and disease status on these parameters. Simulations were performed to assess the clinical relevance of the covariate effects on tapentadol exposure.. A two-compartment model with zero-order release followed by first-order absorption and first-order elimination best described the pharmacokinetics of tapentadol IR following oral administration. The interindividual variability (coefficient of variation) in apparent oral clearance (CL/F) and the apparent central volume of distribution after oral administration were 30% and 29%, respectively. An additive error model was used to describe the residual variability in the log-transformed data, and the standard deviation values were 0.308 and 0.314 for intensively and sparsely sampled data, respectively. Covariate analysis showed that sex, age, bodyweight, race, body fat, hepatic function (using total bilirubin and total protein as surrogate markers), health status and creatinine clearance were statistically significant factors influencing the pharmacokinetics of tapentadol. Total bilirubin was a particularly important factor that influenced CL/F, which decreased by more than 60% in subjects with total bilirubin greater than 50 micromol/L.. The population pharmacokinetic model for tapentadol IR identified the relationship between pharmacokinetic parameters and a wide range of covariates. The simulations of tapentadol exposure with identified, statistically significant covariates demonstrated that only hepatic function (as characterized by total bilirubin and total protein) may be considered a clinically relevant factor that warrants dose adjustment. None of the other covariates are of clinical relevance, nor do they necessitate dose adjustment.

Topics: Administration, Oral; Adolescent; Adult; Aged; Analgesics; Area Under Curve; Biological Availability; Computer Simulation; Disease Progression; Drug Administration Schedule; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Monte Carlo Method; Pain; Phenols; Tapentadol; Young Adult

Tapentadol is a novel, centrally acting analgesic with two mechanisms of action, mu-opioid receptor agonism and norepinephrine reuptake inhibition, in a single molecule. This phase III, randomized, double-blind, active-controlled study evaluated the tolerability of tapentadol immediate release (IR) and oxycodone IR for low back pain or osteoarthritis pain (hip or knee), using flexible dosing over 90 days.. Patients (N = 878) were randomly assigned (4:1 ratio) to receive tapentadol IR (50 or 100 mg, q4-6h, p.o.) or oxycodone IR (10 or 15 mg, q4-6h, p.o.). Tapentadol IR was evaluated for tolerability over 90 days, tolerability relative to oxycodone IR, withdrawal symptoms, and pain intensity. This study was not placebo-controlled, which limited efficacy evaluations.. In total, 849 intent-to-treat patients received tapentadol IR (n = 679) or oxycodone IR (n = 170), and among these, 391 patients (57.6%) in the tapentadol IR group and 86 patients (50.6%) in the oxycodone IR group completed the study. Gastrointestinal events, including nausea (18.4% vs 29.4%), vomiting (16.9% vs 30.0%), and constipation (12.8% vs 27.1%), were reported by 44.2% of patients receiving tapentadol IR and 63.5% of patients receiving oxycodone IR, respectively. Nervous system events, including dizziness (18.1% vs 17.1%), headache (11.5% vs 10.0%), and somnolence (10.2% vs 9.4%), were reported by 36.7% of patients receiving tapentadol and 37.1% of patients receiving oxycodone, respectively. Odds ratios (tapentadol:oxycodone) showed that the incidences of somnolence and dizziness were similar; however, nausea, vomiting, and constipation were significantly less likely with tapentadol IR compared with oxycodone IR. The pattern of withdrawal symptoms suggests that drug tapering may not be necessary after tapentadol IR treatment of this duration. Pain intensity measurements showed similar efficacy for tapentadol and oxycodone.. During this 90-day study, tapentadol IR was associated with improved gastrointestinal tolerability compared with oxycodone IR while providing similar pain relief. Trial registration information: NCT00364546.

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Double-Blind Method; Drug Administration Schedule; Drug Compounding; Female; Humans; Low Back Pain; Male; Middle Aged; Models, Biological; Osteoarthritis, Hip; Osteoarthritis, Knee; Oxycodone; Pain; Phenols; Tapentadol; Time Factors; Treatment Outcome

The primary objective of this study was to assess the efficacy and tolerability of tapentadol immediate release (IR) in patients who were candidates for joint replacement surgery due to end-stage joint disease. A secondary objective was to compare tapentadol IR with oxycodone HCl IR with respect to efficacy and prespecified tolerability end points.. This 10-day, Phase III, randomized, double-blind, active- and placebo-controlled study compared the efficacy and tolerability of tapentadol IR, oxycodone HCl IR, and placebo in patients with uncontrolled osteoarthritis pain who were candidates for primary replacement of the hip or knee as a result of end-stage degenerative joint disease. Patients received tapentadol IR 50 mg, tapentadol IR 75 mg, oxycodone HCl IR 10 mg, or placebo every 4 to 6 hours during waking hours. The primary end point was the sum of pain intensity difference (SPID) over 5 days. Secondary efficacy end points included 2- and 10-day SPID; 2-, 5-, and 10-day total pain relief (TOTPAR); and the sum of total pain relief and pain intensity difference (SPRID). Prespecified noninferiority comparisons with oxycodone HCl IR were performed with respect to efficacy (based on 5-day SPID) and tolerability (based on incidence of the reported adverse events (AEs) of nausea and/or vomiting and constipation).. Of 666 patients originally enrolled, 659 were included in the efficacy analysis (51% male; 91% white; mean age, 61.2 years; mean weight, 97 kg). Five-day SPID was significantly lower in those treated with tapentadol IR (tapentadol IR 50 mg: least squares mean difference [LSMD] = 101.2 [95% CI, 54.58- 147.89]; tapentadol IR 75 mg: LSMD = 97.5 [95% CI, 51.81-143.26]) or oxycodone HCl IR (LSMD = 111.9 [95% CI, 66.49-157.38]) (all, P < 0.001). Tapentadol IR 50 and 75 mg and oxycodone HCl IR 10 mg were associated with significant reductions in pain intensity compared with placebo, based on 2- and 10-day SPID and 2-, 5-, and 10-day TOTPAR and SPRID (all, P < 0.001). The efficacy of tapentadol IR 50 and 75 mg was noninferior to that of oxycodone HCl IR 10 mg; however, the incidence of selected gastrointestinal AEs (nausea, vomiting, and constipation) was significantly lower for both doses of tapentadol IR compared with oxycodone HCl IR 10 mg (nominal P < 0.001). The odds ratios for nausea and/or vomiting for tapentadol IR 50 and 75 mg relative to oxycodone HCl IR 10 mg were 0.21 (95% CI, 0.128-0.339) and 0.32 (95% CI, 0.204-0.501), respectively; for constipation, the corresponding odds ratios were 0.13 (95% CI, 0.057-0.302) and 0.20 (95% CI, 0.098-0.398). Rates of treatment discontinuation were 18% (28/157) in the tapentadol IR 50-mg group, 26% (43/168) in the tapentadol IR 75-mg group, 35% (60/172) in the oxycodone HCl IR 10-mg group, and 10% (17/169) in the placebo group. In a post hoc analysis, tapentadol IR 50 mg was associated with a significantly lower incidence of treatment discontinuation than was oxycodone HCl IR 10 mg (P < 0.001).. In these patients with uncontrolled osteoarthritis pain who were awaiting joint replacement surgery, tapentadol IR 50 and 75 mg were associated with analgesia that was noninferior to that provided by oxycodone HCl IR 10 mg. Tapentadol treatment was associated with improved gastrointestinal tolerability.

Topics: Adult; Aged; Analgesics, Opioid; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Nausea; Osteoarthritis, Hip; Osteoarthritis, Knee; Oxycodone; Pain; Phenols; Tapentadol; Vomiting; Young Adult

To evaluate the relative efficacy and tolerability of tapentadol immediate release (IR) and oxycodone IR for management of moderate to severe pain following orthopedic surgery (bunionectomy).. Randomized patients (N = 901) received oral tapentadol IR 50 or 75 mg, oxycodone HCl IR 10 mg, or placebo every 4-6 h over a 72-h period following surgery. Acetaminophen (< or =2 g) was allowed in the first 12 h after the first dose of study drug. In the primary analysis, tapentadol IR (50 and 75 mg) was evaluated for efficacy superior to placebo and non-inferior to oxycodone HCl IR 10 mg (using sum of pain intensity difference [SPID] over 48 h), and tolerability superior to oxycodone IR (using incidence of treatment-emergent adverse events [TEAEs] of nausea and/or vomiting).. Statistically significantly higher mean SPID(48) values were observed with tapentadol IR (50 and 75 mg) and oxycodone HCl IR 10 mg than placebo (all p < 0.001). The efficacy of tapentadol IR 50 mg and 75 mg was non-inferior to oxycodone HCl IR 10 mg. The incidence of TEAEs of nausea and/or vomiting was statistically significantly lower with tapentadol IR 50 mg versus oxycodone IR 10 mg (35 vs. 59%; p < 0.001). No statistically significant difference in the incidence of nausea and/or vomiting was observed between tapentadol IR 75 mg and oxycodone IR 10 mg (51 vs. 59%; p = 0.057). A possible limitation of this study was that the intense dose and patient monitoring may not represent real-world situations and may result in higher incidences of TEAEs than expected in a practice setting; this bias would be similar for all treatment groups.. Clinically meaningful and statistically significant improvements were observed with tapentadol IR 50 mg and 75 mg compared with placebo for the relief of moderate-to-severe acute pain after orthopedic surgery. Tapentadol IR 50 mg and 75 mg were non-inferior to oxycodone HCl IR 10 mg for the treatment of acute pain based on the primary efficacy endpoint of SPID(48) and the pre-specified margin of 48 points. The incidence of nausea and/or vomiting was statistically significantly lower for tapentadol IR 50 mg and numerically lower for tapentadol IR 75 mg than for oxycodone HCl IR 10 mg.

Topics: Acute Disease; Adult; Aged; Algorithms; Analgesics, Opioid; Dosage Forms; Double-Blind Method; Female; Humans; Male; Middle Aged; Oxycodone; Pain; Phenols; Placebos; Tapentadol; Treatment Outcome

This is a case report of a patient with sleepwalking likely caused by tapentadol ER secondary to higher than the recommended dose for the treatment of pain.. This report presents the relevant patient history, laboratory data and literature review on possible causes of this patient's sleepwalking.. A 39-year-old female reported sleepwalking as the dose of tapentadol increased above the recommended maximum provided in the package insert. The mechanism of action of tapentadol involving norepinephrine reuptake inhibition affecting the central nervous system, higher dosage and drug interactions with other home medications likely contributed to her sleepwalking.. This case highlights the importance of adhering to the recommended dosage of a medication and if it is clinically warranted to exceed the maximum recommended dose, the importance of diligent monitoring for any adverse effects.

Topics: Adult; Analgesics, Opioid; Drug Interactions; Female; Humans; Pain; Phenols; Somnambulism; Tapentadol

This pilot study evaluated the short-term analgesic effect of oral tapentadol hydrochloride (tapentadol) in dogs with unilateral hind limb lameness secondary to naturally occurring cranial cruciate ligament rupture. Baseline data including pharmacodynamic parameters, sedation scores, lameness scores, and objective gait analyses were collected. Tapentadol was administered orally (30 mg/kg body weight). Four hours following administration of tapentadol all data were collected again. Plasma concentrations of tapentadol 4 hours after administration were assessed using high performance liquid chromatography tandem mass spectrometry. No significant side effects were noted. All dogs had measurable plasma concentrations of tapentadol (mean concentration: 18.9 ng/mL). There were no significant differences in pharmacodynamic parameters or sedation over time. Subjective lameness scores were significantly lower than baseline at 4 hours post-drug administration. No significant improvement was seen in objective gait analysis. Further studies are needed to assess dosing regimens which may lead to effective treatment of acute pain and long-term use.

Topics: Analgesics, Opioid; Animals; Anterior Cruciate Ligament Injuries; Dog Diseases; Dogs; Pain; Phenols; Pilot Projects; Tapentadol

Despite growing concerns over the extramedical use of pharmaceutical opioids, few studies have focused on the contexts that shape this use or how it might lead to harm. There is also limited research examining how contexts might vary across different opioids, such as those with well-established abuse liabilities (e.g. oxycodone) and newer 'atypical' opioids (e.g. tapentadol). We aimed to address these gaps.. We analysed Australian paramedic case descriptions for tapentadol cases (n = 82) and a representative sample of oxycodone cases (n = 82) from a 6-year period (2013-2018). We used framework analysis to identify 'contexts' shaping extramedical use from cases where use of tapentadol or oxycodone was assessed to have significantly contributed to the attendances.. Demographically, case descriptions from both drug types were broadly similar (approximately 55% female, 44% were 35-54 years old), as were the contextual factors. The most prevalent contexts common to both oxycodone and tapentadol cases were psychological distress, physical pain and social stressors. Suicidal intent was present across multiple contexts.. This study is one of the first to explore the contexts of extramedical pharmaceutical opioid use leading to acute harm. Our analysis found patients in complex, emergency situations, seeking rapid relief from physical pain, psychological distress, social issues and/or suicidal thoughts. These data highlight the complex needs of those experiencing harm from extramedical pharmaceutical opioid use, regardless of opioid type, and the importance of contextual factors shaping both use and subsequent harm.

Topics: Adult; Allied Health Personnel; Analgesics, Opioid; Australia; Female; Humans; Male; Middle Aged; Oxycodone; Pain; Prescription Drug Misuse; Social Environment; Stress, Psychological; Tapentadol

Topics: Central Nervous System Sensitization; Humans; Osteoarthritis; Pain; Pregabalin; Tapentadol

This study has been performed in diabetic type 2 patients with pain due to peripheral artery disease (PAD) in order to evaluate the efficacy and tolerability of tapentadol prolonged release (PR).

Topics: Aged; Aged, 80 and over; Analgesics; Chronic Pain; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Male; Middle Aged; Pain; Pain Measurement; Peripheral Arterial Disease; Phenols; Quality of Life; Tapentadol; Treatment Outcome

The distinct properties of the centrally-acting analgesic tapentadol derive from the combined contributions of an opioid component and a nonopioid component. However, the opioid component's relative contribution to analgesic and adverse effects has not previously been elucidated. Tapentadol's analgesic effect derives from the combined contribution of an opioid mechanism and a nonopioid mechanism, the extent of which can vary for different pains. Likewise, the interaction can vary for various adverse effects. Hence, the contribution of each mechanism to adverse effects can be different from the contribution to analgesia. We here estimate the percent contribution of each component of the mechanism of action to analgesia and to adverse effects.. Several approaches to in vitro and in vivo data to estimate the contribution of tapentadol's opioid component to analgesia and to the two important opioid adverse effects, respiratory depression and constipation. The results are then compared with clinical data.. Traditional opioids, such as morphine, oxycodone, and others, produce their analgesic effects primarily through a single mechanism-the activation of µ-opioid receptors (MOR). Therefore, the contribution of the opioid component to adverse effects is 100%. In contrast, the newer strong analgesic tapentadol produces its analgesic effect via two separate and complementary analgesic mechanisms, only one of which is µ-opioid. We applied standard drug-receptor theory and novel techniques to in vitro and in vivo data to estimate by several different ways the μ-load of tapentadol (the % contribution of the opioid component to the adverse effect magnitude relative to a pure/classical µ-opioid at equianalgesia) in respiratory depression and constipation, and we compared the results to clinical evidence. The estimate is remarkably consistent over the various approaches and indicates that the μ-load of tapentadol is ≤ 40% (relative to pure MOR agonists, which have, by definition, a µ-load of 100%).. Grünenthal GmbH.

Topics: Analgesia; Analgesics, Opioid; Animals; Constipation; Humans; Mathematical Concepts; Pain; Pain Management; Pain Measurement; Receptors, Opioid, mu; Respiratory Insufficiency; Tapentadol; Treatment Outcome

Topics: Acetaminophen; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; KATP Channels; Male; Mice; Pain; Pain Measurement; Receptors, Opioid, mu; Tapentadol

Topics: Analgesics; Animals; Biological Availability; Biological Transport; Chitosan; Drug Carriers; Drug Compounding; Drug Liberation; Factor Analysis, Statistical; Half-Life; Hot Temperature; Male; Nanoparticles; Pain; Particle Size; Phenols; Polyphosphates; Polysorbates; Rats; Rats, Wistar; Tapentadol

More than 50% of oncohematological patients suffer from pain syndrome, mostly originating from the bone, which often include nociceptive and neuropathic complaints. Tapentadol, a recently available treatment option for cancer pain, exerts a dual analgesic mechanisms (opioid and noradrenergic), allowing for a high clinical efficacy as well as for a reduction in adverse events compared to traditional opioids.. To explore the safety and efficacy of tapentadol as a suitable agent for the pain management in the setting of oncohematology.. Our observational study included 36 patients with basal pain intensity (NRS) ranging from 5 to 10. Tapentadol prolonged release (PR) was given at the initial dose of 50 mg BID and careful titrated according to the achieved pain control.. Tapentadol PR was given at the dosages ranging from 200 and 260 mg/day after a careful titration, allowed for a clinically (-7 points NRS) remarkable reduction of pain intensity without any significant side effects.. In oncohematological patients on pain, tapentadol PR was effective and well tolerated, so representing a suitable treatment option in this difficult setting.

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; Female; Hematologic Neoplasms; Humans; Male; Middle Aged; Pain; Pain Management; Phenols; Retrospective Studies; Tapentadol

Nitric oxide synthases (NOSs) have been shown to participate in the mechanism of the antinociceptive action of tapentadol. The results obtained in this study indicate that tapentadol administered intrathecally at a range of doses (30-100 µg) increased nociceptive thresholds in the Randall-Selitto and tail-flick tests in rats; however, this effect was significant only for the higher doses. After intracerebroventricular administration of tapentadol at the same dose range, an antinociceptive effect was observed only in response to mechanical stimuli. In coadministration studies, L-N-nitro arginine (L-NOArg) - a nonselective NOS inhibitor as well as selective inhibitors: 7-Nitroindazole (7-NI), L-N(1-iminoethyl)lysine (L-NIL) or N-(1-iminoethyl)-L-ornithine (L-NIO) for the respective neuronal, inducible, and endothelial NOSs enhanced the antinociceptive activity of intrathecally administered tapentadol in the Randall-Selitto test and to a lesser extent in the tail-flick test. A similar, although less pronounced effect of intracerebroventricular tapentadol was also observed after previous administration of NOS inhibitors in the Randall-Selitto test, but not in the tail-flick test. In conclusion, neuronal NOS, inducible NOS, and endothelial NOS influence the antinociceptive action of tapentadol at the spinal level and to a much lesser extent at the supraspinal level.

Topics: Analgesics, Opioid; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Injections, Spinal; Male; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pain; Pain Threshold; Phenols; Rats; Tapentadol

Pain is a common and highly debilitating complication for cancer patients significantly compromising their quality of life. Cancer-induced bone pain involves a complex interplay of multiple mechanisms including both inflammatory and neuropathic processes and also some unique changes. Strong opioids are a mainstay of treatments but side effects are problematic and can compromise optimal pain control. Tapentadol is a novel dual-action drug, both stimulating inhibitory μ-opioid receptors (MOR) and mediating noradrenaline reuptake inhibition (NRI) leading to activation of the inhibitory α-2 adrenoceptor. It has been demonstrated to treat effectively both acute and chronic pain. We here demonstrate the efficacy in a model of cancer-induced bone pain.. MRMT-1 mammary carcinoma cells were inoculated into the tibia of 6-week-old rats and 2 weeks after, the neuronal responses to a wide range of peripheral stimulation were evaluated. The recordings were made from wide-dynamic range neurons in lamina V of the dorsal horn before and after administration of tapentadol as well as antagonists of the two mechanisms, naloxone or atipamezole.. We found marked inhibitions of the neuronal activity with efficacy against mechanical, thermal and electrically evoked activity following tapentadol administration. In addition, the effects of the drug were fully reversible by naloxone and partly by atipamezole, supporting the idea of MOR-NRI dual actions.. These findings add to the mechanistic understanding of cancer-induced bone pain and support the sparse clinical data indicating a possible use of the drug as a therapeutic alternative for cancer patients with metastatic pain complication.

Topics: Adrenergic alpha-2 Receptor Antagonists; Analgesia; Animals; Cell Line, Tumor; Disease Models, Animal; Electrophysiology; Male; Neoplasms; Pain; Pain Measurement; Phenols; Quality of Life; Rats, Sprague-Dawley; Receptors, Opioid, mu; Tapentadol

Tapentadol, a new analgesic drug with a dual mechanism of action (μ-opioid receptor agonism and norepinephrine reuptake inhibition), is indicated for the treatment of moderate to severe acute and chronic pain. In this paper, the possible additional involvement of the nitric oxide synthase (NOS) system in the antinociceptive activity of tapentadol was investigated using an unspecific inhibitor of NOS, L-NOArg, a relatively specific inhibitor of neuronal NOS, 7-NI, a relatively selective inhibitor of inducible NOS, L-NIL, and a potent inhibitor of endothelial NOS, L-NIO. Tapentadol (1-10 mg/kg, intraperitoneal) increased the threshold for mechanical (Randall-Selitto test) and thermal (tail-flick test) nociceptive stimuli in a dose-dependent manner. All four NOS inhibitors, administered intraperitoneally in the dose range 0.1-10 mg/kg, potentiated the analgesic action of tapentadol at a low dose of 2 mg/kg in both models of pain. We conclude that NOS systems participate in tapentadol analgesia.

Topics: Analgesics, Opioid; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Nitric Oxide Synthase; Pain; Phenols; Rats; Receptors, Opioid, mu; Tapentadol

Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action, MOR agonism and noradrenaline (NA) reuptake inhibition in a single molecule. It is the first member of a new therapeutic class, MOR-NRI. A high throughput liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay was developed and validated for the quantitative analysis of tapentadol and its O-glucuronide metabolite in human serum. Simultaneous quantification was deemed to be challenging because of the large difference in concentrations between tapentadol and its O-glucuronide metabolite in clinical samples. Therefore, a method was established using a common processed sample, but with different injection volumes and chromatographic conditions for each analyte. Tapentadol and tapentadol-O-glucuronide were determined by protein precipitation of 0.100ml of the samples with acetonitrile. The internal standards used are D₆-tapentadol and D₆-tapentadol-O-glucuronide. The validated concentration range was 0.200-200 ng/ml (tapentadol) and 10.0-10,000 ng/ml (tapentadol-O-glucuronide). Chromatographic separation was achieved by gradient elution on a Waters Acquity UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) column, with mobile phase consisting of 0.01 M ammonium formate (adjusted to pH 4 using formic acid) (A) and methanol (B). A separate injection was done for measurement of each analyte, with a different gradient and run time. The analytes were detected by using an electrospray ion source on a triple quadrupole mass spectrometer operating in positive ionization mode. The run time was 1.6 min for tapentadol and 1.5 min for tapentadol-O-glucuronide. The high sensitivity and acceptable performance of the assay allowed its application to the analysis of serum samples in clinical trials. The validated method was used for analysis of tapentadol in over 17,000 samples.

Topics: Analgesics; Chromatography, High Pressure Liquid; Glucuronides; Humans; Linear Models; Neoplasms; Pain; Phenols; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry; Tapentadol

Opioid analgesics are widely used for managing moderate to severe pain. In cancer pain management sustained-release opioids are used for continuous pain as well as immediate-release opioids for breakthrough pain. Sustained-release drugs have the advantage of stabilizing the blood concentration, although it takes some time to exert their effects. In Japan, the currently available oral sustained-release opioids include six types of sustained-release morphine (three are once-a-day formulations, while the rest are twice-a-day), one type of oxycodone and tapentadol. In this article, we will discuss the pharmacokinetic properties of MS Contin, Morphes, Kadian, P guard and Pacif as sustained-release morphine, Oxycontin as sustained-release oxycodone and Tapenta as sustained-release tapentadol.

Topics: Analgesics, Opioid; Delayed-Action Preparations; Drug Delivery Systems; Humans; Japan; Morphine; Oxycodone; Pain; Phenols; Tapentadol

Tapentadol(TP)is a new strong opioid analgesicthat has both m-opioid receptor(MOR)effects and norepinephrine reuptake inhibitor(NRI)effects. In comparison with the existing strong opioid analgesics, the mechanism of action suitable for palliation of neuropathic pain is expected to be better for TP. The analgesic effect and side effects of this drug were tested in 10 cases of exacerbation of neuropathic pain at our hospital, and the sedative response rate was 70%. The main side effects were somnolence 44.4%, nausea 33.4%, and constipation 11.1%. The side effects on the digestive system were considered minimal. Although it is speculated that opioids would be useful as an outpatient treatment, few case reports are available regarding their use for cancer pain; therefore, further investigation is necessary. Generally, numerous social issues that would increase the likelihood of drug adherence failure must be addressed in order to expand the use of strong opioid analgesics such as TP. Both the patients and the healthcare worker should be involved when addressing these issues in Japan, and the measures should include instructions for appropriate reporting and for using such drugs.

Topics: Aged; Analgesics, Opioid; Female; Humans; Male; Middle Aged; Neoplasms; Pain; Pain Management; Pain Measurement; Palliative Care; Phenols; Tapentadol

Topics: Analgesics, Opioid; Humans; Pain; Phenols; Tapentadol

Prescription opioid analgesics play an important role in managing moderate to severe pain. An unintended consequence of the availability of these drugs is nonmedical use. We report rates and methods of nonmedical use of the analgesic tapentadol immediate release (IR) and other commonly prescribed opioid analgesics among US college students following the launch of tapentadol IR in June 2009.. The Researched Abuse, Diversion and Addiction-Related Surveillance System College Survey Program collects data from approximately 2000 self-identified college students throughout the United States during fall, spring, and summer terms using a web-based questionnaire. Responses from July 2009 through September 2011 were analyzed for the rate of nonmedical use of tapentadol IR.. Nonmedical use of prescription opioids was reported by 1626 of 13,514 respondents (12.0%); tapentadol IR use was reported by 101 respondents (0.7%). The rate of nonmedical tapentadol IR use per 100,000 population was highest in 4Q2009 (0.013 per 100,000 population) and decreased over the subsequent 2 years to 0.004 per 100,000 population. Similarly, the rate per 1000 unique recipients of dispensed drug (URDD) was highest in 4Q2009 (0.66 per 1000 URDD) and decreased to 0.06 per 1000 URDD. The primary route of administration endorsed for nonmedical tapentadol IR use was intact swallow (49.5%), chewed and swallowed (41.6%), followed by inhalation (20.8).. Since its launch, rates of nonmedical tapentadol IR use by college students have been low and have decreased over time. The initial levels of reported nonmedical use may represent a brief period of experimentation after introduction.

Topics: Adolescent; Analgesics, Opioid; Female; Humans; Male; Pain; Phenols; Prescription Drugs; Retrospective Studies; Students; Surveys and Questionnaires; Tapentadol; United States; Universities; Young Adult

The aim of this study was to assess the efficacy and tolerability of tapentadol (TP) for a period of 4 weeks in patients who were already treated by opioids.. A convenience sample of 30 patients was selected for a prospective observational cohort study. Cancer patients who were receiving at least 60 mg of oral morphine equivalents were selected. Patients discontinued their previous opioid analgesics before starting TP, in doses calculated according the previous opioid consumption (1:3.3 ratio with oral morphine equivalents). The subsequent doses were changed according to the patients' needs for a period of 4 weeks. Oral morphine was offered as a breakthrough pain medication. Pain and symptom intensity were recorded at weekly intervals. Distress score (DS) was calculated from the sum of symptom intensities. TP opioid escalation indexes (TPEI) for the study period were calculated.. Nineteen patients were male, and the mean age was 63.5 years (±11.5). The mean Karnofsky status was 62.9 (±10). The mean dose of oral morphine equivalents before switching to TP was 112 mg (±57) and the initial mean dose of TP was 343 mg (±150). Pain intensity significantly decreased. Tapentadol escalation index in percentage was 1.26 (TPEI% ± 2.6) and Tapentadol escalation index in mg was 2.76 (TPEImg ± 4.96). No significant relationships were found with primary tumor (TPEI%, p = 0.204; TPEImg, p = 0.180), pain mechanism (TPEI%, p = 0.863; TPEImg, p = 0.846), age (TPEI%, p = 0.882; TPEImg, p = 0.884), or gender (TPEI%, p = 0.287; TPEImg, p = 0.325). DS decreased, but non-significantly (p = 0.1). Ten patients did not complete the study period: five patients discontinued TP for uncontrolled pain, despite increasing doses of TP over 600 mg/day. Two patients discontinued TP for adverse effects and three patients dropped out, one patient for poor compliance and two patients for unrecorded reasons.. In our sample, TP used in doses of 350-450 mg/day was well tolerated and effective in opioid tolerant patients with cancer pain and could be considered as a flexible drug to be used for the management of moderate to severe cancer pain. Like most studies in patients with cancer pain, it was limited by its open-label, uncontrolled design, the number of patients lost in follow-up, and discontinuation of the treatment for several reasons. Further studies in a large number of patients should confirm these preliminary results.

Topics: Aged; Analgesics, Opioid; Cohort Studies; Dose-Response Relationship, Drug; Drug Dosage Calculations; Drug Monitoring; Female; Humans; Italy; Karnofsky Performance Status; Male; Middle Aged; Morphine; Neoplasms; Pain; Pain Management; Pain Measurement; Phenols; Prospective Studies; Receptors, Opioid, mu; Tapentadol; Treatment Outcome

Although norepinephrine transporter (NET) inhibition has an additional effect on μ-opioid receptor (MOR)-mediated anti-nociception in inflammatory and neuropathic pain, its effect on cancer pain is not well characterized. We investigated the additional effect of NET inhibition on MOR activation using a mouse femur bone cancer (FBC) pain model by comparing the anti-nociceptive effect of the dual-acting opioids tramadol and tapentadol and the clinically used MOR-targeted opioids oxycodone and morphine. The anti-nociceptive effects of subcutaneously administered opioids were assessed using the von-Frey filament test. Oxycodone (1 - 10 mg/kg) and morphine (5 - 50 mg/kg) dose-dependently exhibited potent anti-nociceptive effects, whereas tramadol (10 - 56 mg/kg) and tapentadol (10 - 30 mg/kg) exhibited partial effects. Rota-rod analyses of tapentadol at a higher dose (> 30 mg/kg) showed a significant decrease in motor coordination, which was partially recovered by pretreatment with MOR or α(1)-adrenoceptor antagonists. The partial anti-nociceptive effect of tapentadol (30 mg/kg) was completely suppressed by a MOR antagonist, but not by α(1)- or α(2)-adrenoceptor antagonists, suggesting that neither α(1)-adrenoceptor- nor α(2)-adrenoceptor-mediated pathways are involved in anti-nociception in the FBC model. We conclude that addition of NET inhibition does not contribute to MOR-mediated anti-nociception in bone cancer pain.

Topics: Analgesics, Opioid; Animals; Bone Neoplasms; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice, Inbred C3H; Morphine; Neoplasm Transplantation; Norepinephrine Plasma Membrane Transport Proteins; Oxycodone; Pain; Phenols; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Receptors, Opioid, mu; Tapentadol; Tramadol; Tumor Cells, Cultured

To evaluate differences in patient characteristics, healthcare resource utilization, and healthcare costs among patients receiving immediate release (IR) formulations of tapentadol (TAP IR) or oxycodone (OXY IR).. Patients (≥18 years) who took TAP IR or OXY IR (6/1/2009-7/31/2011) were selected from the OptumInsight Clinformatics Data Mart claims database. Patients were assigned to the TAP IR or OXY IR cohort based on initial drug usage (index event). Continuous health plan coverage 60 days before (baseline period) and after (follow-up period) the index event was required. TAP IR patients were matched to OXY IR patients (1:1) using exact match of key patient characteristics and propensity score matching with patient demographics and clinical characteristics as covariates. T-test and chi-squared test were utilized to evaluate differences in patient characteristics, healthcare utilization and charges among cohorts.. Patient profiles during the baseline period significantly differed among TAP IR users (n = 17,539) and OXY IR users (n = 85,821) in the overall study population. The matched sample of TAP IR and OXY IR patients (n = 10,185 in both cohorts) had similar patient characteristics. During the 60-day follow-up period, patients who took TAP IR had a shorter mean hospital LOS (0.21 vs 0.35 days, p < 0.0001), a lower mean number of hospitalizations (0.07 vs 0.10, p < 0.0001), and lower mean inpatient ($2900 vs $4382, p < 0.001) and outpatient healthcare charges ($10,550 vs $11,084, p = 0.047). The higher index opioid prescription charge of TAP IR ($190 vs $150, p < 0.0001) was offset by other lower healthcare charges.. The characteristics of patients who took TAP IR were different from patients who took OXY IR in many respects. In the sub-set of patients matched on demographic and clinical characteristics, those who took TAP IR used healthcare resources to a lesser extent, which was reflected in their lower healthcare charges, relative to OXY IR users.

Topics: Adult; Aged; Analgesics, Opioid; Female; Health Expenditures; Health Services; Humans; Length of Stay; Male; Middle Aged; Oxycodone; Pain; Phenols; Retrospective Studies; Tapentadol

The aim of this exploratory study was to assess the conversion ratios between tapentadol and other opioids in patients requiring an opioid switching.. A prospective study was carried out in a convenience sample of consecutive patients admitted to an acute palliative care unit and a home care unit for a period of 1 year. Patients who were switched from/to tapentadol were selected. The initial ratio between tapentadol and other opioids, expressed as oral morphine equivalents was 1:3.3. The subsequent doses were flexible and were changed to fit the patients' needs. Pain intensity and distress score were recorded until opioid doses were stable. In all, 37 patients were examined; 24 and 13 patients were switched from and to tapentadol, respectively.. The most frequent sequences were tapentadol-morphine (18 patients) in one direction, and morphine-tapentadol (8 patients) in the other direction. In the sequence tapentadol-morphine and morphine-tapentadol, the mean final tapentadol-morphine ratios were 3.9:1 (SD 2.3), and 1:4.5 (SD 3.2), respectively, which did not differ significantly from the initial established conversion ratio. A minority of patients were switched from/to tapentadol to/from other opioids. Globally, the initial ratio did not change after switching took place.. Data suggest that a conversion ratio between tapentadol and other opioids, expressed in oral morphine equivalents could be 1:3.3 in both direction, particularly in patients who are switched in conditions of equianalgesia. The limited number of patients prevents a definitive conclusion to be drawn, and data should be interpreted with caution, given the exploratory nature of the study and the question of the low number of patients should be addressed in future studies.

Topics: Analgesics, Opioid; Delayed-Action Preparations; Humans; Morphine; Narcotics; Neoplasms; Pain; Palliative Care; Phenols; Prospective Studies; Receptors, Opioid, mu; Tapentadol

Tapentadol may have a lower abuse risk than other opioids because it has a relatively low affinity for the mu-opioid receptor. The aim of this retrospective cohort study was to compare the risk of opioid abuse between tapentadol immediate release (IR) and oxycodone IR using 2 claims databases (Optum and MarketScan). Subjects with no recent opioid use exposed to tapentadol IR or oxycodone IR in 2010 were followed for 1 year. The outcome was the proportion of subjects who developed opioid abuse, defined as subjects with International Classification of Diseases, 9th revision, codes for opioid abuse, addiction, or dependence. The relative odds of abuse were estimated using a logistic regression model with propensity-score stratification. The estimates from the 2 databases were pooled using a random effects model. There were 13,814 subjects in Optum (11,378 exposed to oxycodone, 2,436 exposed to tapentadol) and 25,553 in MarketScan (21,728 exposed to oxycodone, 3,825 exposed to tapentadol). The risk of abuse was higher in the oxycodone group than in the tapentadol group in each database. The pooled adjusted estimate for the odds of abuse was 65% lower with tapentadol than with oxycodone (odds ratio = .35, 95% confidence interval = .21-.58). The risk of receiving an abuse diagnosis with tapentadol was lower than the risk with oxycodone. Continued monitoring is warranted because opioid desirability can change over time.. This study compared the risk of receiving an opioid abuse diagnosis between tapentadol and oxycodone in 2 U.S. claims databases. The risk of receiving an abuse diagnosis was lower with tapentadol during the year of follow-up. Opioid prescribers and patients must be aware of the risk of abuse associated with all opioids.

Topics: Adult; Aged; Analgesics, Opioid; Cohort Studies; Databases, Factual; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; International Classification of Diseases; Male; Middle Aged; Odds Ratio; Opioid-Related Disorders; Oxycodone; Pain; Phenols; Propensity Score; Retrospective Studies; Risk; Sample Size; Tapentadol

Topics: Adult; Humans; Pain; Pain Management; Phenols; Tapentadol

Topics: Aged; Analgesics, Opioid; Female; Humans; Methadone; Multiple Myeloma; Neoplasms; Pain; Phenols; Tapentadol

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

Topics: Anticoagulants; Enoxaparin; Heart Valve Prosthesis Implantation; Humans; Pain; Phenols; Tapentadol; Thromboembolism

The novel analgesic tapentadol HCl [(-)-(1R,2R)-3-(3-dimethylamino)-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in a single molecule and shows a broad efficacy profile in various preclinical pain models. This study analyzed the analgesic activity of tapentadol in experimental inflammatory pain. Analgesia was evaluated in the formalin test (pain behavior, rat and mouse), carrageenan-induced mechanical hyperalgesia (paw-pressure test, rat), complete Freund's adjuvant (CFA)-induced paw inflammation (tactile hyperalgesia, rat), and CFA knee-joint arthritis (weight bearing, rat). Tapentadol showed antinociceptive activity in the rat and mouse formalin test with an efficacy of 88 and 86% and ED(50) values of 9.7 and 11.3 mg/kg i.p., respectively. Tapentadol reduced mechanical hyperalgesia in carrageenan-induced acute inflammatory pain by 84% with an ED(50) of 1.9 mg/kg i.v. In CFA-induced tactile hyperalgesia, tapentadol showed 71% efficacy with an ED(50) of 9.8 mg/kg i.p. The decrease in weight bearing after CFA injection in one knee joint was reversed by tapentadol by 51% with an ED(25) of 0.9 mg/kg i.v. Antagonism studies were performed with the MOR antagonist naloxone and the α(2)-noradrenergic receptor antagonist yohimbine in the carrageenan- and CFA-induced hyperalgesia model. In the CFA model, the serotonergic receptor antagonist ritanserin was also tested. The effect of tapentadol was partially blocked by naloxone and yohimbine and completely blocked by the combination of both, but it was not affected by ritanserin. In summary, tapentadol showed antinococeptive/antihyperalgesic analgesic activity in each model of acute and chronic inflammatory pain, and the antagonism experiments suggest that both MOR activation and NRI contribute to its analgesic effects.

Topics: Adrenergic alpha-2 Receptor Antagonists; Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Freund's Adjuvant; Hyperalgesia; Inflammation; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Phenols; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Serotonin 5-HT2 Receptor Antagonists; Tapentadol

Topics: Analgesics, Opioid; Chronic Disease; Cross-Sectional Studies; General Practice; Germany; Health Services Needs and Demand; Humans; Pain; Palliative Care; Phenols; Tapentadol

Topics: Analgesics; Humans; Pain; Phenols; Receptors, Opioid, mu; Tapentadol

Topics: Analgesics, Opioid; Chronic Disease; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Humans; Pain; Phenols; Randomized Controlled Trials as Topic; Receptors, Opioid, mu; Tapentadol

Topics: Acute Disease; Chronic Disease; Humans; Pain; Phenols; Receptors, Opioid, mu; Tapentadol

Topics: Analgesics; Humans; Pain; Phenols; Receptors, Opioid, mu; Tapentadol

Tapentadol immediate-release (IR) tablets are indicated for the treatment of moderate to severe acute pain. In clinical trials, tapentadol IR effectively reduced moderate to severe pain with improved tolerability compared with oxycodone IR at doses providing comparable analgesia.. This analysis compared the cost-effectiveness of tapentadol IR with doses of oxycodone IR providing comparable analgesia in the outpatient treatment of acute postsurgical and nonsurgical pain. The perspective was that of a US managed care health plan as third-party payer.. A Markov model was developed to simulate clinical-economic outcomes for tapentadol IR 100 mg compared with oxycodone IR 15 mg in the treatment of acute postsurgical pain (3 days) and for tapentadol IR 50 mg compared with oxycodone IR 10 mg in the treatment of acute nonsurgical pain (10 days). The model simulated changes in pain relief; occurrence of opioid-related adverse events (AEs); opioid switching, discontinuation, and dose change; and number of quality-adjusted life-days (QALDs). Data inputs for the model were obtained from clinical trials, claims databases, surveys, Medicare fee schedules, and other published sources. Only direct costs were included. Drug costs were based on the wholesale acquisition cost. Prescription copayments were set at $5 for oxycodone IR and $25 for tapentadol IR. All costs were in 2008 US dollars. Sensitivity analyses were conducted on key model parameters.. The cost of pain medication per patient was higher for tapentadol IR than for oxycodone IR in both the surgical pain setting ($15.23 vs $9.57, respectively) and the nonsurgical pain setting ($57.17 vs $21.31). However, this cost difference was offset by reductions in pharmacy and medical costs associated with the treatment of AEs and opioid switching/discontinuation, resulting in a lower mean treatment cost per patient for tapentadol IR 100 mg compared with oxycodone IR 15 mg in the treatment of acute surgical pain ($52.90 vs $55.99) and for tapentadol IR 50 mg compared with oxycodone IR 10 mg in the treatment of acute nonsurgical pain ($139.48 vs $144.79). Tapentadol IR also was associated with a greater mean number of treatment days with ≥30% improvement in pain intensity without opioid-related AEs compared with oxycodone IR and a greater mean number of QALDs (surgical pain: 1.73 vs 1.68; nonsurgical pain: 6.03 vs 4.92). Because both doses of tapentadol IR were dominant (ie, lower treatment costs and greater effectiveness) relative to the corresponding doses of oxycodone IR providing com- parable analgesia, incremental cost-effectiveness ratios were not calculated.. The results of this model suggest that at doses providing comparable analgesia, tapentadol IR is a cost-effective alternative to oxycodone IR for the treatment of acute surgical and nonsurgical pain.

Topics: Acute Disease; Analgesics, Opioid; Computer Simulation; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Humans; Markov Chains; Models, Econometric; Oxycodone; Pain; Pain Measurement; Pain, Postoperative; Phenols; Quality-Adjusted Life Years; Solubility; Tablets; Tapentadol

Topics: Adult; Analgesics; Drug Approval; Humans; Pain; Phenols; Tapentadol; United States; United States Food and Drug Administration

The FDA has approved tapentadol hydrochloride (Nucynta--Ortho-McNeil Janssen) for oral treatment of moderate to severe acute pain in patients >18 years old. It has been classified as a Schedule II controlled substance. Tapentadol (Nucynta) is a centrally acting oral analgesic with opioid and adrenergic activity. In studies published to date, it was as effective as oxycodone or morphine with a lower incidence of gastrointestinal adverse effects, but until more data become available, older analgesics are preferred.

Topics: Analgesics; Clinical Trials as Topic; Drug Interactions; Humans; Pain; Phenols; Tapentadol

Topics: Analgesics; Chronic Disease; Clinical Trials, Phase III as Topic; Humans; Pain; Phenols; Severity of Illness Index; Tapentadol

(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl) is a novel micro-opioid receptor (MOR) agonist (Ki = 0.1 microM; relative efficacy compared with morphine 88% in a [35S]guanosine 5'-3-O-(thio)triphosphate binding assay) and NE reuptake inhibitor (Ki = 0.5 microM for synaptosomal reuptake inhibition). In vivo intracerebral microdialysis showed that tapentadol, in contrast to morphine, produces large increases in extracellular levels of NE (+450% at 10 mg/kg i.p.). Tapentadol exhibited analgesic effects in a wide range of animal models of acute and chronic pain [hot plate, tail-flick, writhing, Randall-Selitto, mustard oil colitis, chronic constriction injury (CCI), and spinal nerve ligation (SNL)], with ED50 values ranging from 8.2 to 13 mg/kg after i.p. administration in rats. Despite a 50-fold lower binding affinity to MOR, the analgesic potency of tapentadol was only two to three times lower than that of morphine, suggesting that the dual mode of action of tapentadol may result in an opiate-sparing effect. A role of NE in the analgesic efficacy of tapentadol was directly demonstrated in the SNL model, where the analgesic effect of tapentadol was strongly reduced by the alpha2-adrenoceptor antagonist yohimbine but only moderately attenuated by the MOR antagonist naloxone, whereas the opposite was seen for morphine. Tolerance development to the analgesic effect of tapentadol in the CCI model was twice as slow as that of morphine. It is suggested that the broad analgesic profile of tapentadol and its relative resistance to tolerance development may be due to a dual mode of action consisting of both MOR activation and NE reuptake inhibition.

Topics: Acute Disease; Analgesics, Opioid; Animals; Behavior, Animal; Brain; Chronic Disease; Disease Models, Animal; Guinea Pigs; Humans; Male; Mice; Mice, Inbred Strains; Microdialysis; Norepinephrine; Pain; Pain Measurement; Phenols; Protein Binding; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Opioid, mu; Synaptosomes; Tapentadol