buprenorphine and Respiratory-Insufficiency

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

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

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

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

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

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

Opioid treatment of pain is generally safe with 0.5% or less events from respiratory depression. However, fatalities are regularly reported. The only treatment currently available to reverse opioid respiratory depression is by naloxone infusion. The efficacy of naloxone depends on its own pharmacological characteristics and on those (including receptor kinetics) of the opioid that needs reversal. Short elimination of naloxone and biophase equilibration half-lives and rapid receptor kinetics complicates reversal of high-affinity opioids. An opioid with high receptor affinity will require greater naloxone concentrations and/or a continuous infusion before reversal sets in compared with an opioid with lower receptor affinity. The clinical approach to severe opioid-induced respiratory depression is to titrate naloxone to effect and continue treatment by continuous infusion until chances for renarcotization have diminished. New approaches to prevent opioid respiratory depression without affecting analgesia have led to the experimental application of serotinine agonists, ampakines, and the antibiotic minocycline.

Topics: Buprenorphine; Humans; Minocycline; Naloxone; Narcotic Antagonists; Postoperative Complications; Respiratory Insufficiency; Serotonin Agents

Topics: Analgesia, Epidural; Analgesia, Patient-Controlled; Analgesics, Opioid; Anesthetics, Local; Buprenorphine; Hematoma, Epidural, Spinal; Humans; Morphine; Nausea; Pain, Postoperative; Respiratory Insufficiency; Urination Disorders

Buprenorphine is an opioid agonist-antagonist with a 'ceiling effect' for respiratory depression. Compared with methadone, its unique pharmacology offers practical advantages and enhanced safety when prescribed as recommended and supervised by a physician. Buprenorphine has been approved in several countries as an efficient and safe maintenance therapy for heroin addiction. Its use resulted in a salutary effect with a reduction in heroin overdose-related deaths in countries that implemented office-based buprenorphine maintenance. In France, however, where high-dose buprenorphine has been marketed since 1996, several cases of asphyxic deaths were reported among addicts treated with buprenorphine. Death resulted from buprenorphine intravenous misuse or concomitant sedative drug ingestion, such as benzodiazepines. In these situations of abuse, misuse, or in association with elevated doses of psychotropic drugs, buprenorphine may cause severe respiratory depression. Unlike other opiates, the respiratory effects from buprenorphine are not responsive to naloxone. However, the exact mechanism of buprenorphine-induced effects on ventilation is still unknown. The role of norbuprenorphine, the main N-dealkylated buprenorphine metabolite with potent respiratory depressor activity, also remains unclear. Experimental studies investigating the respiratory effects of combinations of high doses of buprenorphine and benzodiazepines suggested that this drug-drug interaction may result from a pharmacodynamic interaction. A pharmacokinetic interaction between buprenorphine and flunitrazepam is also considered. As there are many questions regarding the possible dangers of death or respiratory depression associated with buprenorphine use, we aimed to present a comprehensive critical review of the published clinical and experimental studies on buprenorphine respiratory effects.

Topics: Analgesics, Opioid; Anti-Anxiety Agents; Asphyxia; Benzodiazepines; Buprenorphine; Drug Interactions; Heroin Dependence; Humans; Respiratory Insufficiency

There is an unmet need for therapeutics with greater efficacy and tolerability for the treatment of opioid use disorder (OUD). ASP8062 is a novel compound with positive allosteric modulator activity on the γ-aminobutyric acid type B receptor under development for use with standard-of-care treatment for patients with OUD.. To investigate the safety, tolerability, interaction potential, and pharmacokinetics (PK) of ASP8062 in combination with buprenorphine/naloxone (B/N; Suboxone. In this phase 1, randomized, double-masked, placebo-controlled study, patients with OUD began B/N (titrated to 16/4 mg/day) treatment upon enrollment (induction, Days 1-4; maintenance, Days 5-18; downward titration, Days 19-26; and discharge, Day 27). On Day 12, patients received a single dose of ASP8062 60 mg or placebo with B/N and underwent safety and PK assessments. Primary endpoints included frequency and severity of treatment-emergent adverse events (TEAEs), clinical laboratory tests, respiratory depression, and suicidal ideation. Secondary endpoints investigated the impact of ASP8062 on B/N PK.. In this phase 1 study, ASP8062 was safe, well tolerated, and did not enhance respiratory suppression induced by buprenorphine.. Clinicaltrials.gov identifier: NCT04447287.

Topics: Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Double-Blind Method; Humans; Narcotic Antagonists; Opioid-Related Disorders; Respiratory Insufficiency

Opioid-induced respiratory depression driven by ligand binding to mu-opioid receptors is a leading cause of opioid-related fatalities. Buprenorphine, a partial agonist, binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects. The authors examined whether sustained buprenorphine plasma concentrations similar to those achieved with some extended-release injections used to treat opioid use disorder could reduce the frequency and magnitude of fentanyl-induced respiratory depression.. In this two-period crossover, single-centre study, 14 healthy volunteers (single-blind, randomized) and eight opioid-tolerant patients taking daily opioid doses ≥90 mg oral morphine equivalents (open-label) received continuous intravenous buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma concentrations of 0.2 or 0.5 ng/mL in healthy volunteers and 1.0, 2.0 or 5.0 ng/mL in opioid-tolerant patients. Upon reaching target concentrations, participants received up to four escalating intravenous doses of fentanyl. The primary endpoint was change in isohypercapnic minute ventilation (VE). Additionally, occurrence of apnea was recorded.. Fentanyl-induced changes in VE were smaller at higher buprenorphine plasma concentrations. In healthy volunteers, at target buprenorphine concentration of 0.5 ng/mL, the first and second fentanyl boluses reduced VE by [LSmean (95% CI)] 26% (13-40%) and 47% (37-59%) compared to 51% (38-64%) and 79% (69-89%) during placebo infusion (p = 0.001 and < .001, respectively). Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection. In opioid-tolerant patients, fentanyl reduced VE up to 49% (21-76%) during buprenorphine infusion (all concentration groups combined) versus up to 100% (68-132%) during placebo infusion (p = 0.006). In opioid-tolerant patients, the risk of experiencing apnea requiring verbal stimulation following fentanyl boluses was lower with buprenorphine than with placebo (odds ratio: 0.07; 95% CI: 0.0 to 0.3; p = 0.001).. Results from this proof-of-principle study provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids like fentanyl.

Topics: Adult; Buprenorphine; Cross-Over Studies; Delayed-Action Preparations; Female; Fentanyl; Healthy Volunteers; Humans; Infusions, Intravenous; Male; Middle Aged; Opioid-Related Disorders; Proof of Concept Study; Respiratory Insufficiency; Single-Blind Method; Young Adult

BACKGROUNDPotent synthetic opioids, such as fentanyl, are increasingly abused, resulting in unprecedented numbers of fatalities from respiratory depression. Treatment with the high-affinity mu-opioid receptor partial agonist buprenorphine may prevent fatalities by reducing binding of potent opioids to the opioid receptor, limiting respiratory depression.METHODSTo characterize buprenorphine-fentanyl interaction at the level of the mu-opioid receptor in 2 populations (opioid-naive individuals and individuals who chronically use high-dose opioids), the effects of escalating i.v. fentanyl doses with range 0.075-0.35 mg/70 kg (opioid naive) and 0.25-0.70 mg/70 kg (chronic opioid use) on iso-hypercapnic ventilation at 2-3 background doses of buprenorphine (target plasma concentrations range: 0.2-5 ng/mL) were quantified using receptor association/dissociation models combined with biophase distribution models.RESULTSBuprenorphine produced mild respiratory depression, while high doses of fentanyl caused pronounced respiratory depression and apnea in both populations. When combined with fentanyl, buprenorphine produced a receptor binding-dependent reduction of fentanyl-induced respiratory depression in both populations. In individuals with chronic opioid use, at buprenorphine plasma concentrations of 2 ng/mL or higher, a protective effect against high-dose fentanyl was observed.CONCLUSIONOverall, the results indicate that when buprenorphine mu-opioid receptor occupancy is sufficiently high, fentanyl is unable to activate the mu-opioid receptor and consequently will not cause further respiratory depression in addition to the mild respiratory effects of buprenorphine.TRIAL REGISTRATIONTrialregister.nl, no. NL7028 (https://www.trialregister.nl/trial/7028)FUNDINGIndivior Inc., North Chesterfield, Virginia, USA.

Topics: Analgesics, Opioid; Buprenorphine; Fentanyl; Humans; Receptors, Opioid; Respiratory Insufficiency

Naloxone is the usual drug used in opioid-induced respiratory depression but it has a short half-life, precipitates withdrawal in dependent patients, and thus for persistent reversal of long-acting opioids has to be given by titrated doses and infusions. The partial agonist buprenorphine has a much longer duration of action and causes less severe withdrawal, but still should largely reverse respiratory depression induced by full agonist opioids. We aimed to compare the efficacy/safety of buprenorphine and naloxone in reversing respiratory depression in methadone-poisoned opioid-dependent patients.. Patients with methadone-induced respiratory depression were randomized to receive naloxone (titrated doses), or lower or higher doses of buprenorphine (10 μg/kg or 15 μg/kg). The primary outcome was immediate reversal of respiratory depression. We also recorded acute opioid withdrawal, need for intubation/recurrent apnea, repeated doses of opioid antagonists, length of hospital stay, other morbidity, and mortality. The study was registered with the Iranian Registry of Clinical Trials (Trial ID: 18265; Approval code: IRCT2015011020624N1).. Eighty-five patients were randomized; 55/56 patients who received buprenorphine had rapid reversal of respiratory depression, which persisted for at least 12 h. Naloxone was effective in 28/29 patients, but often required very high titrated doses (thus delaying time to respond) and prolonged infusions. Intubation (8/29 vs 5/56) and opioid withdrawal (15/29 vs 7/56) were less common with buprenorphine. There were no serious complications or deaths in those receiving buprenorphine. The 15-μg/kg buprenorphine dose appeared to provide a longer duration of action, but precipitated withdrawal more frequently than the 10-μg/kg dose.. Buprenorphine appears to be a safe and effective substitute for naloxone in overdosed opioid-dependent patients. Further studies are warranted to explore the optimal dosing strategy for buprenorphine to consistently maintain reversal of respiratory depression but not precipitate withdrawal.. IRCT2015011020624N1. Registered 30 September 2015.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Drug Overdose; Female; Humans; Male; Methadone; Middle Aged; Naloxone; Narcotic Antagonists; Respiratory Insufficiency; Young Adult

To investigate plasma levels of buprenorphine and norbuprenorphine and their relationship to respiratory depression.. Opioid-dependent subjects were randomized 2 : 1 to novel lyophilized rapid-disintegrating tablet ("bup-lyo") or standard sublingual buprenorphine tablet ("bup-SL"). Measurements included oximetry scores and linked plasma buprenorphine and norbuprenorphine levels.. Exploratory investigation found respiratory depression more strongly associated with norbuprenorphine than with buprenorphine. This accords with animal studies.
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Topics: Administration, Sublingual; Analgesics, Opioid; Biological Availability; Biotransformation; Buprenorphine; Drug Compounding; Freeze Drying; Humans; Lung; Opiate Substitution Treatment; Opioid-Related Disorders; Respiration; Respiratory Insufficiency; Risk Factors; Solubility; Tablets; Treatment Outcome

The objective of this study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of buprenorphine and fentanyl for the respiratory depressant effect in healthy volunteers. Data on the time course of the ventilatory response at a fixed P(ET)CO(2) of 50 mm Hg and P(ET)O(2) of 110 mm Hg following intravenous administration of buprenorphine and fentanyl were obtained from two phase I studies (50 volunteers received buprenorphine: 0.05-0.6 mg/70 kg and 24 volunteers received fentanyl: 0.075-0.5 mg/70 kg). The PK/PD correlations were analyzed using nonlinear mixed effects modeling. A two- and three-compartment pharmacokinetic model characterized the time course of fentanyl and buprenorphine concentration, respectively. Three structurally different PK/PD models were evaluated for their appropriateness to describe the time course of respiratory depression: (1) a biophase distribution model with a fractional sigmoid E(max) pharmacodynamic model, (2) a receptor association/dissociation model with a linear transduction function, and (3) a combined biophase distribution-receptor association/dissociation model with a linear transduction function. The results show that for fentanyl hysteresis is entirely determined by the biophase distribution kinetics, whereas for buprenorphine hysteresis is caused by a combination of biophase distribution kinetics and receptor association/dissociation kinetics. The half-time values of biophase equilibration (t(1/2, k(eo))) were 16.4 and 75.3 min for fentanyl and buprenorphine, respectively. In addition, for buprenorphine, the value of k(on) was 0.246 ml/ng/min and the value of k(off) was 0.0102 min(-1). The concentration-effect relationship of buprenorphine was characterized by a ceiling effect at higher concentrations (intrinsic activity alpha=0.56, 95% confidence interval (CI): 0.50-0.62), whereas fentanyl displayed full respiratory depressant effect (alpha=0.91, 95% CI: 0.19-1.62).

Topics: Adult; Analgesics, Opioid; Buprenorphine; Double-Blind Method; Female; Fentanyl; Half-Life; Humans; Male; Metabolic Clearance Rate; Models, Biological; Respiratory Insufficiency

Respiratory depression is a potentially life-threatening adverse effect of opioid therapy. It has been postulated that the difficulty of reversing buprenorphine-induced respiratory depression is caused by slow receptor association-dissociation kinetics at the opioid mu receptor. The aim of this study was to characterise the pharmacodynamic interaction between buprenorphine and naloxone in healthy volunteers.. A competitive pharmacodynamic interaction model was proposed to describe and predict the time course of naloxone-induced reversal of respiratory depression. The model was identified using data from an adaptive naloxone dose-selection trial following intravenous administration of buprenorphine 0.2mg/70kg or 0.4mg/70kg.. The pharmacokinetics of naloxone and buprenorphine were best described by a two-compartment model and a three-compartment model, respectively. A combined biophase equilibration-receptor association-dissociation pharmacodynamic model described the competitive interaction between buprenorphine and naloxone at the opioid mu receptor. For buprenorphine, the values of the rate constants of receptor association (k(on)) and dissociation (k(off)) were 0.203 mL/ng/min and 0.0172 min(-)(1), respectively. The value of the equilibrium dissociation constant (K(D)) was 0.18 nmol/L. The half-life (t((1/2))) of biophase equilibration was 173 minutes. These estimates of the pharmacodynamic parameters are similar to values obtained in the absence of naloxone co-administration. For naloxone, the half-life of biophase distribution was 6.5 minutes.. Because of the slow receptor association-dissociation kinetics of buprenorphine in combination with the fast elimination kinetics of naloxone, naloxone is best administered as a continuous infusion for reversal of buprenorphine-induced respiratory depression.

Topics: Adolescent; Adult; Algorithms; Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Drug Interactions; Female; Half-Life; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Models, Biological; Naloxone; Narcotic Antagonists; Respiratory Function Tests; Respiratory Insufficiency

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

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

The objective of this investigation was to examine the ability of the opioid antagonist naloxone to reverse respiratory depression produced by the mu-opioid analgesic, buprenorphine, in healthy volunteers. The studies were designed in light of the claims that buprenorphine is relatively resistant to the effects of naloxone.. In a first attempt, the effect of an intravenous bolus dose of 0.8 mg naloxone was assessed on 0.2 mg buprenorphine-induced respiratory depression. Next, the effect of increasing naloxone doses (0.5-7 mg, given over 30 min) on 0.2 mg buprenorphine-induced respiratory depression was tested. Subsequently, continuous naloxone infusions were applied to reverse respiratory depression from 0.2 and 0.4 mg buprenorphine. All doses are per 70 kg. Respiration was measured against a background of constant increased end-tidal carbon dioxide concentration.. An intravenous naloxone dose of 0.8 mg had no effect on respiratory depression from buprenorphine. Increasing doses of naloxone given over 30 min produced full reversal of buprenorphine effect in the dose range of 2-4 mg naloxone. Further increasing the naloxone dose (doses of 5 mg or greater) caused a decline in reversal activity. Naloxone bolus doses of 2-3 mg, followed by a continuous infusion of 4 mg/h, caused full reversal within 40-60 min of both 0.2 and 0.4 mg buprenorphine-induced respiratory depression.. Reversal of buprenorphine effect is possible but depends on the buprenorphine dose and the correct naloxone dose window. Because respiratory depression from buprenorphine may outlast the effects of naloxone boluses or short infusions, a continuous infusion of naloxone may be required to maintain reversal of respiratory depression.

Topics: Adult; Buprenorphine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Naloxone; Receptors, Opioid, mu; Respiratory Insufficiency

There is evidence from animal studies suggesting the existence of a ceiling effect for buprenorphine-induced respiratory depression. To study whether an apparent ceiling effect exists for respiratory depression induced by buprenorphine, we compared the respiratory effects of buprenorphine and fentanyl in humans and rats.. In healthy volunteers, the opioids were infused i.v. over 90 s and measurements of minute ventilation at a fixed end-tidal PCO2 of 7 kPa were obtained for 7 h. Buprenorphine doses were 0.7, 1.4, 4.3 and 8.6 microg kg(-1) (n=20 subjects) and fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 microg kg(-1) (n=21). Seven subjects received placebo. In rats, both opioids were infused i.v. over 20 min, and arterial PCO2 was measured 5, 10, 15 and 20 min after the start of fentanyl infusion and 30, 150, 270 and 390 min after the start of buprenorphine infusion. Doses tested were buprenorphine 0, 100, 300, 1000 and 3000 microg kg(-1) and fentanyl 0, 50, 68 and 90 microg kg(-1).. In humans, fentanyl produced a dose-dependent depression of minute ventilation with apnoea at doses > or = 2.9 microg kg(-1); buprenorphine caused depression of minute ventilation which levelled off at doses > or = 3.0 microg kg(-1) to about 50% of baseline. In rats, the relationship of arterial PCO2 and fentanyl dose was linear, with maximum respiratory depression at 20 min (maximum PaCO2 8.0 kPa). Irrespective of the time at which measurements were obtained, buprenorphine showed a non-linear effect on PaCO2, with a ceiling effect at doses > 1.4 microg kg(-1). The effect on PaCO2 was modest (maximum value measured, 5.5 kPa).. Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.

Topics: Adult; Analgesics, Opioid; Animals; Buprenorphine; Carbon Dioxide; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fentanyl; Humans; Male; Partial Pressure; Rats; Rats, Wistar; Respiratory Insufficiency

Although in most of the cases the placebo response appears to be unpredictable, several factors have been considered in order to explain the placebo analgesic effect. For example, it is widely recognized, albeit with little empirical evidence, that placebo analgesia is more likely to occur after a successful analgesic therapy. On the basis of this assumption, we tested the placebo response in a population of patients who were treated with buprenorphine the day before for relieving postoperative pain. However, due to the high variability of opioid responsiveness, buprenorphine was effective in some patients and poorly effective in some others. Similarly, buprenorphine produced respiratory depression with a large variability, ranging from mild depression to no effect. We found that the placebo analgesic response depended on the buprenorphine analgesic effectiveness of the previous day. Analogously, we found that a placebo respiratory depressant response was more pronounced in those patients with a respiratory depressant response to buprenorphine on the day before, irrespective of the analgesic effectiveness. These specific effects suggest that (1) the placebo effect is experience-dependent; (2) the mechanisms underlying placebo analgesia and placebo respiratory depression are independent from each other and, by considering the role of endogenous opioids in placebo analgesia, might involve different subpopulations of opioid receptors.

Topics: Analgesia; Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Placebos; Respiratory Insufficiency; Retreatment

In order to compare the effect of buprenorphine and naloxone on respiratory depression after fentanyl anaesthesia (25 micrograms/kg), 32 women scheduled for elective abdominal hysterectomy participated in a double-blind randomized investigation. At termination of anaesthesia, after antagonizing residual neuromuscular blockade, 20 normocapnic patients with a respiratory rate of 4 breaths/min or less entered the study, receiving either buprenorphine (0.6 mg in 20 ml NaCl) or naloxone (0.4 mg in 20 ml NaCl) 2 ml/min until 20 ml was given or until the respiratory rate exceeded 8 breaths/min. Respiratory rate, PaCO2, sedation score, and pain intensity were evaluated during a 3-h study period. Fifteen min after beginning the treatment, all the patients in both groups had their ventilatory depression antagonized. There were no statistically significant differences in respiratory rates between groups except at 15 min. On no occasion did either PaCO2 or a sedation score differ statistically significantly between the groups. At 15 min all patients in the buprenorphine group had no or mild pain, compared to the patients in the naloxone group, of whom 50% had moderate to severe pain (P less than 0.05). It seems as if buprenorphine is as effective as naloxone in antagonizing respiratory rate depression following fentanyl anaesthesia.

Topics: Adult; Aged; Anesthesia, General; Buprenorphine; Double-Blind Method; Female; Fentanyl; Humans; Middle Aged; Naloxone; Prospective Studies; Respiratory Insufficiency

The degree of respiratory depression caused by buprenorphine and tramadol were studied in two groups of 25 patients each by means of Read's re-breathing technique. The estimations were made during the immediate postoperative stage in order to include potential residual effects of the general anaesthesia. The slope of the CO2 curve as a measure of respiratory depression decreased by 27 per cent after administration of 0.3 mg of buprenorphine, a reduction which equals that produced by potent morphine-type analgesics. The response to 50 mg of tramadol was a non-significant decrease by 3 per cent. At doses mentioned buprenorphine produced reliable pain relief, whereas with tramadol the failure rate was 28 per cent. There was no difference between the two drugs in respect of circulatory reactions and side-effects. Despite its depressing effect on the respiration (an action it shares with all potent analgesics) buprenorphine is a very useful analgesic because it provides excellent pain relief, has no or only minimal addictive properties and is not subject to the Dangerous Drugs Act.

Topics: Analgesia; Anesthesia, General; Buprenorphine; Carbon Dioxide; Cyclohexanols; Female; Humans; Male; Morphinans; Postoperative Period; Respiration; Respiratory Insufficiency; Tramadol

The objective of this study was to understand the effect buprenorphine rotations have on respiratory risk and other safety outcomes. This was a retrospective observational study evaluating Veterans who underwent an opioid rotation from full-agonist opioids to buprenorphine products or to alternative opioids. The primary endpoint was change in the Risk Index for Overdose or Serious Opioid-induced Respiratory Depression (RIOSORD) score from baseline to six months post-rotation. Median baseline RIOSORD scores were 26.0 and 18.0 in the Buprenorphine Group and the Alternative Opioid Group, respectively. There was no statistically significant difference between groups in baseline RIOSORD score. At six months post-rotation, median RIOSORD scores were 23.5 and 23.0 in the Buprenorphine Group and Alternative Opioid Group, respectively. The difference in change in RIOSORD scores between groups was not statistically significant (

Topics: Analgesics, Opioid; Buprenorphine; Humans; Opioid-Related Disorders; Pain Management; Respiratory Insufficiency; Retrospective Studies

Buprenorphine is a partial agonist at the mu opioid receptor. Due to its relatively low maximum effect on respiratory depression it is considered by some to be a safe opioid. But it can produce serious respiratory depression, particularly when combined with sedatives such as benzodiazepines.

Topics: Analgesics, Opioid; Benzodiazepines; Buprenorphine; Humans; Receptors, Opioid, mu; Respiratory Insufficiency

Topics: Anesthesia, Conduction; Anesthetics, Local; Buprenorphine; Extremities; Humans; Peripheral Nerves; Respiratory Insufficiency

Opioid-related deaths are increasing globally. Respiratory complications of opioid use and underlying respiratory disease in people with Opioid Use Disorder (OUD) are potential contributory factors. Individual variation in susceptibility to overdose is, however, incompletely understood. This study investigated the prevalence of respiratory depression (RD) in OUD treatment and compared this to patients with chronic obstructive pulmonary disease (COPD) of equivalent severity. We also explored the contribution of opioid agonist treatment (OAT) dosage, and type, to the prevalence of RD.. Undetected RD is common in OUD cohorts receiving OAT and is significantly more severe than in opioid-naïve controls. RD can be assessed using simple objective measures. Further studies are required to determine the association between RD and overdose risk.

Topics: Analgesics, Opioid; Buprenorphine; Carbon Dioxide; Drug Overdose; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pulmonary Disease, Chronic Obstructive; Respiratory Insufficiency

Medications for opioid use disorder (MOUD) including buprenorphine is recommended for patients with opioid use disorders. We sought to evaluate the frequencies of respiratory depression, intubation, and naloxone administration, and clinical outcomes among patients reported to the National Poison Database System (NPDS) following single-substance and multiple-substance buprenorphine oral exposures.. NPDS was queried for all MOUD-approved buprenorphine product exposures between 1 January 2003 and 31 December 2019. Data abstracted included year, route, gender, age, site of exposure, management site, medical outcome, recorded "related" respiratory depression ("respiratory rate <10 breaths/min and/or a SpO2 (pulse oximetry)≤90%), reported administration of naloxone and intubation in oral exposure cases followed to known outcome. Concomitant products were also recorded in multiple-substance buprenorphine cases.. 27,275 (11,010 multiple and 16,265 single) buprenorphine oral exposures were identified and followed to known outcome. A 65-fold increase in reported cases was reported over the study interval. A steady increase in the frequency of more serious outcomes by year was also observed. Respiratory depression occurred at a frequency of 11.8% (pediatric single-substance), 11.2% (pediatric multiple-substance), 11.3% (adult single-substance), and 11.9% (adult multiple-substance). Among oral exposures of buprenorphine and only one other product, benzodiazepines, opioids, ethanol, and amphetamines were most common.. Oral exposures have increased substantially between 2003 and 2019. More serious outcomes including deaths following oral exposures to buprenorphine have also increased over the same interval for both adult and pediatric patients. Clinically significant rates of respiratory depression in both adult and pediatric patients when taken alone and with additional substances were observed.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Buprenorphine; Child; Humans; Middle Aged; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Poison Control Centers; Respiratory Insufficiency; United States; Young Adult

Topics: Blood-Brain Barrier; Buprenorphine; Humans; Naloxone; Respiratory Insufficiency

We describe the sudden death of a middle-aged man while having a sauna under the influence of α-pyrrolidinovalerophenone (α-PVP) (PM blood concentration: 0.8 mg/L), amphetamine (0.34 mg/L), and other drugs (buprenorphine, benzodiazepines), and engaging in solitary sexual activities. The drugs' effects on the cardio-circulatory system and on body thermoregulation combined with the high temperatures are likely to have been central mechanisms leading to death. The high levels of adrenaline triggered by sexual arousal and the respiratory depression caused by buprenorphine, in association with benzodiazepines, may have also contributed to his death. This previously unreported type of accidental autoerotic death illustrates the risk of using amphetamine-like sympathomimetic drugs (e.g. cathinone derivates) in hot environments such as a sauna, and during sexual activities therein.

Topics: Amphetamine; Benzodiazepines; Buprenorphine; Designer Drugs; Humans; Male; Masturbation; Middle Aged; Pyrrolidines; Respiratory Insufficiency; Steam Bath; Substance-Related Disorders

Topics: Analgesics, Opioid; Antidotes; Buprenorphine; Drug Overdose; Humans; Methadone; Naloxone; Prospective Studies; Respiratory Insufficiency

Opiate-induced respiratory depression is sexually dimorphic and associated with increased risk among the obese. The mechanisms underlying these associations are unknown. The present study evaluated the two-tailed hypothesis that sex, leptin status, and obesity modulate buprenorphine-induced changes in breathing.. Mice (n = 40 male and 40 female) comprising four congenic lines that differ in leptin signaling and body weight were injected with saline and buprenorphine (0.3 mg/kg). Whole-body plethysmography was used to quantify the effects on minute ventilation. The data were evaluated using three-way analysis of variance, regression, and Poincaré analyses.. Relative to B6 mice with normal leptin, buprenorphine decreased minute ventilation in mice with diet-induced obesity (37.2%; P < 0.0001), ob/ob mice that lack leptin (62.6%; P < 0.0001), and db/db mice with dysfunctional leptin receptors (65.9%; P < 0.0001). Poincaré analyses showed that buprenorphine caused a significant (P < 0.0001) collapse in minute ventilation variability that was greatest in mice with leptin dysfunction. There was no significant effect of sex or body weight on minute ventilation.. The results support the interpretation that leptin status but not body weight or sex contributed to the buprenorphine-induced decrease in minute ventilation. Poincaré plots illustrate that the buprenorphine-induced decrease in minute ventilation variability was greatest in mice with impaired leptin signaling. This is relevant because normal respiratory variability is essential for martialing a compensatory response to ventilatory challenges imposed by disease, obesity, and surgical stress.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Disease Models, Animal; Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Respiratory Insufficiency; Sex Factors; Signal Transduction

Exploratory buprenorphine ingestions in young children have been associated with clinically significant toxicity. However, detailed data on the clinical presentation and management of these patients are lacking. In an attempt to obtain more comprehensive data, we sought to examine a single center cohort of patients with report of buprenorphine exposure and provide descriptive analysis of rates of respiratory depression, time to respiratory depression, interventions, disposition, and outcomes.. We performed a retrospective cohort study at a single pediatric tertiary care center of children between the age of 6 months and 7 years of age hospitalized between 1 January 2006 and 1 September 2014 with report of buprenorphine or buprenorphine/naloxone exposure. Patients with possible exposure to more than one agent were excluded. We extracted clinical findings, including time to respiratory depression, interventions, and disposition from the medical record.. Pediatric patients exposed to buprenorphine are likely to exhibit signs and symptoms of opioid toxicity, including respiratory depression, altered mental status and miosis. Although the majority of patients developed signs of clinical toxicity within 8 h of reported exposure, the optimum duration of monitoring remains unclear.

Topics: Analgesics, Opioid; Antidotes; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Charcoal; Child; Child, Preschool; Cohort Studies; Female; Hospitalization; Humans; Infant; Length of Stay; Male; Narcotic Antagonists; Oximetry; Oxygen; Respiratory Insufficiency; Retrospective Studies; Time Factors

Respiratory depression and fatalities have been attributed to ethanol/buprenorphine (BUP) combination in drug addicts maintained with BUP/naloxone or BUP alone. The exact mechanisms of the ethanol/BUP interaction and the contribution to the toxicity of norbuprenorphine (NBUP), the main BUP metabolite with respiratory depressant properties are unknown. We investigated the sedative and plethsymographic effects resulting from the co-administration of intragastric ethanol (3 g/kg) and intravenous BUP (30 mg/kg) in Sprague-Dawley rats. We determined the whole blood pharmacokinetics of ethanol (using gas chromatography coupled to mass spectrometry), BUP and its metabolites (using liquid chromatography coupled to tandem mass spectrometry) and investigated the mechanisms of drug-drug interactions in the presence or absence of naloxone (7.5 mg/kg). Ethanol/BUP and ethanol/BUP/naloxone combinations significantly deepened sedation in comparison to BUP alone (P < .01) and BUP/naloxone (P < .05), respectively. Ethanol/BUP combination significantly increased the inspiratory time and decreased the minute volume in comparison to BUP alone (P < .01 and P < .01, respectively) and ethanol/BUP/naloxone (P < .05 and P < .01, respectively). Neither naloxone nor flumazenil reversed ethanol/BUP-induced sedation and respiratory depression. In the presence of ethanol, the area under the BUP concentration-time curve was significantly decreased (P < .05), BUP volume of distribution increased (P < .05) and the metabolic ratios of NBUP and norbuprenorphine-3-glucuronide increased (P < .01). In conclusion, the ethanol/BUP combination results in marked sedation and respiratory depression in the rat, prevented but not reversed by naloxone. Ethanol/BUP interactions are mainly pharmacokinetic resulting in increased NBUP production. Despite the non-reversal by naloxone and flumazenil of the effects attributed to the ethanol/BUP combination, protection provided by naloxone suggests an additional pharmacodynamic interaction.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Drug Interactions; Ethanol; Gas Chromatography-Mass Spectrometry; Male; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Respiration; Respiratory Insufficiency

Administration of naloxone is a common treatment for opioid-dependent patients who present with respiratory depression. Although safe in opioid-naive patients, naloxone may cause severe and even life-threatening complications in opioid-dependent patients, including acute respiratory distress syndrome and myocardial infarction. It has been suggested that administration of buprenorphine, a partial μ-opioid receptor agonist, to an opioid-intoxicated patient may result in reversal of respiratory depression with less severe withdrawal signs and symptoms. In addition, the longer half-life of buprenorphine compared with naloxone may reduce the need for repetitive administration of antidote. We present a 20-year-old morphine-addicted man who presented with methadone-induced respiratory depression and responded safely and effectively to intravenous administration of buprenorphine. Buprenorphine may be a useful alternative opioid reversal agent for opioid-dependent patients.

Topics: Administration, Intravenous; Buprenorphine; Drug Overdose; Humans; Male; Methadone; Naloxone; Narcotic Antagonists; Respiratory Insufficiency; Treatment Outcome; Young Adult

We report a case series of buprenorphine-related respiratory and neurological depression in opioid-naïve elderly hospitalised patients who received buprenorphine for acute pain management at our institution over a 24-month period. All six patients had risk factors for respiratory depression such as advanced age, concurrent comorbidities, or the ingestion of other potential central nervous system depressants. All patients required escalation of management with additional monitoring, with some transferred to a high dependency or intensive care unit. Five patients had attempted naloxone reversal with varying results. Our cases highlight the fact that while buprenorphine has been demonstrated to have a ceiling effect in relation to respiratory depression in healthy volunteers, it remains an important side-effect and may result in significant respiratory depression in patients with reduced respiratory or neurological reserve. Difficulties with buprenorphine's reversal using naloxone are described. We recommend additional caution when considering buprenorphine for acute pain management in elderly opioid-naïve patients, especially if they have comorbidities or are taking other central nervous system depressants. When buprenorphine is used in patients with risk factors, we recommend additional monitoring and education about potential adverse respiratory effects and their management.

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Female; Hospitalization; Humans; Male; Naloxone; Respiratory Insufficiency

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

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

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

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

Buprenorphine is largely prescribed for maintenance treatment in opioid dependence due to its safety profile. Nevertheless, fatalities at therapeutic dose have been described when associated with other central nervous system depressants, such as ethanol or benzodiazepines. Here, we report a case of death due to association of buprenorphine at therapeutic dose with benzodiazepines and ethanol. Although toxicity has been often attributed to its metabolite norbuprenorphine rather than to buprenorphine itself, in our case, norbuprenorphine was not detected in urine and bile and only in traces in blood. Moreover, the presence in blood of free buprenorphine but not of glucuronide metabolites argues for an unusual early death, at the beginning of buprenorphine metabolism. We propose that in the context of prior toxic impregnation, buprenorphine directly (and not via its metabolite norbuprenorphine) acted as a triggering factor by blocking the ventilatory response, rapidly leading to fatal respiratory depression.

Topics: Adult; Analgesics, Opioid; Benzodiazepines; Bile; Buprenorphine; Central Nervous System Depressants; Chromatography, High Pressure Liquid; Ethanol; Fatal Outcome; Forensic Toxicology; Gastrointestinal Contents; Humans; Male; Respiratory Insufficiency; Tandem Mass Spectrometry

Topics: Accidents, Home; Analgesics, Opioid; Biological Availability; Buprenorphine; Disorders of Excessive Somnolence; Humans; Infant; Male; Naloxone; Narcotic Antagonists; Neurotoxicity Syndromes; Respiratory Insufficiency; Treatment Outcome

Respiratory depression has been attributed to buprenorphine (BUP) misuse or combination with benzodiazepines. BUP/naloxone (NLX) has been marketed as maintenance treatment, aiming at preventing opiate addicts from self-injecting crushed pills. However, to date, BUP/NLX benefits in comparison to BUP alone remain debated. We investigated the plethysmography effects of BUP/NLX in comparison to BUP/solvent administered by intravenous route in naive and BUP-tolerant Sprague-Dawley rats, and in combination with diazepam (DZP) or its solvent. In naive rats, BUP/NLX in comparison to BUP significantly increased respiratory frequency (f, P<0.05) without altering minute volume (VE). In combination to DZP, BUP/NLX significantly increased expiratory time (P<0.01) and decreased f (P<0.01), tidal volume (VT, P<0.001), and VE (P<0.001) while BUP only decreased VT (P<0.5). In BUP-tolerant rats, no significant differences in respiratory effects were observed between BUP/NLX and BUP. In contrast, in combination to DZP, BUP/NLX did not significantly alter the plethysmography parameters, while BUP increased inspiratory time (P<0.001) and decreased f (P<0.01) and VE (P<0.001). In conclusion, differences in respiratory effects between BUP/NLX and BUP are only significant in combination with DZP, with increased depression in naive rats but reduced depression in BUP-tolerant rats. However, BUP/NLX benefits in humans remain to be determined.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Buprenorphine; Diazepam; Drug Interactions; Drug Tolerance; Hypnotics and Sedatives; Male; Naloxone; Narcotic Antagonists; Plethysmography, Whole Body; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency

While most deaths from asphyxia related to buprenorphine (BUP) overdose have been reported in males, higher plasma concentrations of BUP and its toxic metabolite norbuprenorphine (NBUP) have been observed in females. We previously demonstrated that P-glycoprotein (P-gp) modulation at the blood-brain barrier (BBB) contributes highly to BUP-related respiratory toxicity, by limiting NBUP entrance into the brain. In this work, we sought to investigate the role of P-gp-mediated transport at the BBB in gender and strain-related variability of BUP and NBUP-induced respiratory effects in mice. Ventilation was studied using plethysmography, P-gp expression using western blot, and transport at the BBB using in situ cerebral perfusion. In male Fvb and Swiss mice, BUP was responsible for ceiling respiratory effects. NBUP-related reduction in minute volume was dose-dependent but more marked in Fvb (p<0.01 at 1mg/kg NBUP and p<0.001 at 3 and 9mg/kg NBUP) than in Swiss mice (p<0.001 at 9mg/kg NBUP). Female Fvb mice were more susceptible to BUP than males with significantly increased inspiratory time (p<0.05) and to NBUP with significantly increased expiratory time (p<0.01). Following BUP administration, plasma BUP concentrations were significantly higher (p<0.01) and plasma NBUP concentrations significantly lower (p<0.001) in Fvb mice compared to Swiss mice. Plasma BUP concentrations were significantly higher (p<0.05) and plasma NBUP concentrations significantly lower (p<0.01) in male compared to female Fvb mice. In contrast, following NBUP administration, comparable plasma NBUP concentrations were observed in both genders and strains. No differences in P-gp expression or BUP and NBUP transport across the BBB were observed between male and female Fvb mice as well as between Swiss and Fvb mice. Our results suggest that P-gp-mediated transport across the BBB does not play a key-role in gender and strain-related variability in BUP and NBUP-induced respiratory toxicity in mice. Both gender- and strain-related differences in respiratory effects of BUP could be attributed to BUP itself rather than to its metabolite, NBUP.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blood-Brain Barrier; Blotting, Western; Buprenorphine; Capillaries; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Female; Male; Mice; Narcotics; Plethysmography, Whole Body; Respiratory Insufficiency; Sex Characteristics; Species Specificity

Topics: Anti-Anxiety Agents; Buprenorphine; Female; Humans; Lorazepam; Naloxone; Narcotic Antagonists; Respiratory Insufficiency

Deaths due to asphyxia as well as following acute poisoning with severe respiratory depression have been attributed to buprenorphine in opioid abusers. However, in human and animal studies, buprenorphine exhibited ceiling respiratory effects, whereas its metabolite, norbuprenorphine, was assessed as being a potent respiratory depressor in rodents. Recently, norbuprenorphine, in contrast to buprenorphine, was shown in vitro to be a substrate of human P-glycoprotein, a drug-transporter involved in all steps of pharmacokinetics including transport at the blood-brain barrier. Our objectives were to assess P-glycoprotein involvement in norbuprenorphine transport in vivo and study its role in the modulation of buprenorphine-related respiratory effects in mice.. University-affiliated research laboratory, INSERM U705, Paris, France.. Wild-type and P-glycoprotein knockout female Friend virus B-type mice.. Respiratory effects were studied using plethysmography and the P-glycoprotein role at the blood-brain barrier using in situ brain perfusion.. Norbuprenorphine(≥ 1 mg/kg) and to a lesser extent buprenorphine (≥ 10 mg/kg) were responsible for dose-dependent respiratory depression combining increased inspiratory (TI) and expiratory times (TE). PSC833, a powerful P-glycoprotein inhibitor, significantly enhanced buprenorphine-related effects on TI (p < .01) and TE (p < .05) and norbuprenorphine-related effects on minute volume (VE, p < .05), TI, and TE (p < .001). In P-glycoprotein-knockout mice, buprenorphine-related effects on VE (p < .01), TE (p < .001), and TI (p < .05) and norbuprenorphine-related effects on VE (p < .05) and TI (p < .001) were significantly enhanced. Plasma norbuprenorphine concentrations were significantly increased in PSC833-treated mice (p < .001), supporting a P-glycoprotein role in norbuprenorphine pharmacokinetics. Brain norbuprenorphine efflux was significantly reduced in PSC833-treated and P-glycoprotein-knockout mice (p < .001), supporting P-glycoprotein-mediated norbuprenorphine transport at the blood-brain barrier.. P-glycoprotein plays a key-protective role in buprenorphine-related respiratory effects, by allowing norbuprenorphine efflux at the blood-brain barrier. Our findings suggest a major role for drug-drug interactions that lead to P-glycoprotein inhibition in buprenorphine-associated fatalities and respiratory depression.

Topics: Analgesics, Opioid; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport, Active; Blood-Brain Barrier; Buprenorphine; Drug Interactions; Female; France; Mice; Mice, Knockout; Plethysmography; Respiratory Insufficiency

Topics: Administration, Intranasal; Alcohol Drinking; Animals; Buprenorphine; Forensic Toxicology; Humans; Narcotics; Respiratory Insufficiency

Topics: Adult; Anti-Anxiety Agents; Buprenorphine; Drug Interactions; Female; Humans; Intubation, Intratracheal; Lorazepam; Naloxone; Narcotic Antagonists; Respiratory Insufficiency

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

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

Opioids are known to induce respiratory depression. We aimed to characterize in rats the effects of four opioids on arterial blood gases and plethysmography after intraperitoneal administration at 80% of their LD(50) in order to identify opioid molecule-specific patterns and classify response severity. Opioid-receptor (OR) antagonists, including intravenous 10 mg kg(-1)-naloxonazine at 5 min [mu-OR antagonist], subcutaneous 30 mg kg(-1)-naloxonazine at 24 h [mu1-OR antagonist], subcutaneous 3 mg kg(-1)-naltrindole at 45 min [delta-OR antagonist], and subcutaneous 5 mg kg(-1)-Nor-binaltorphimine at 6 h [kappa-OR antagonist] were pre-administered to test the role of each OR. Methadone, morphine, and fentanyl significantly decreased PaO(2) (P<0.001) and increased PaCO(2) (P<0.05), while buprenorphine only decreased PaO(2) (P<0.05). While all opioids significantly increased inspiratory time (T(I), P<0.001), methadone and fentanyl also increased expiratory time (T(E), P<0.05). Intravenous 10 mg kg(-1)-naloxonazine at 5 min completely reversed opioid-related effects on PaO(2) (P<0.05), PaCO(2) (P<0.001), T(I) (P<0.05), and T(E) (P<0.01) except in buprenorphine. Subcutaneous 30 mg kg(-1)-naloxonazine at 24 h completely reversed effects on PaCO(2) (P<0.01) and T(E) (P<0.001), partially reversed effects on T(I) (P<0.001), and did not reverse effects on PaO(2). Naltrindole reversed methadone-induced T(E) increases (P<0.01) but worsened fentanyl's effect on PaCO(2) (P<0.05) and T(I) (P<0.05). Nor-binaltorphimine reversed morphine- and buprenorphine-induced T(I) increases (P<0.001) but worsened methadone's effect on PaO(2) (P<0.05) and morphine (P<0.001) and buprenorphine's (P<0.01) effects on pH. In conclusion, opioid-related respiratory patterns are not uniform. Opioid-induced hypoxemia as well as increases in T(I) and T(E) are caused by mu-OR, while delta and kappa-OR roles appear limited, depending on the specific opioid. Regarding severity of opioid-induced respiratory effects at 80% of their LD(50), all drugs increased T(I). Methadone and fentanyl induced hypoxemia, hypercapnia, and T(E) increases, morphine caused both hypoxemia and hypercapnia while buprenorphine caused only hypoxemia.

Topics: Animals; Blood Gas Analysis; Buprenorphine; Catheterization; Fentanyl; Lactic Acid; Male; Methadone; Morphine; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Narcotics; Plethysmography, Whole Body; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Respiratory Insufficiency; Respiratory Mechanics

Buprenorphine is a mixed opioid receptor agonist-antagonist used in acute and chronic pain management. Although this agent's analgesic effect increases in a dose-dependent manner, buprenorphine-induced respiratory depression shows a marked ceiling effect at higher doses, which is considered to be an indicator of safety. Nevertheless, cases of overdose mortality or severe respiratory depression associated with buprenorphine use have been reported. Naloxone can reverse buprenorphine-induced respiratory depression, but is slow-acting and unstable, meaning that new drug candidates able to specifically antagonize buprenorphine-induced respiratory depression are needed in order to enable maximal analgesic effect without respiratory depression. Acetylcholine is an excitatory neurotransmitter in central respiratory control. We previously showed that a long-acting acetylcholinesterase inhibitor, donepezil, antagonizes morphine-induced respiratory depression. We have now investigated how donepezil affects buprenorphine-induced respiratory depression in anesthetized, paralyzed, and artificially ventilated rabbits. We measured phrenic nerve discharge as an Index of respiratory rate and amplitude, and compared discharges following the injection of buprenorphine with discharges following the injection of donepezil. Buprenorphine-induced suppression of the respiratory rate and respiratory amplitude was antagonized by donepezil (78.4 +/- 4.8 %, 92.3% +/- 22.8 % of control, respectively). These findings indicate that systemically administered donepezil restores buprenorphine-induced respiratory depression in anesthetized rabbits.

Topics: Animals; Buprenorphine; Cholinesterase Inhibitors; Donepezil; Indans; Male; Narcotic Antagonists; Phrenic Nerve; Piperidines; Rabbits; Respiratory Insufficiency

High-dosage buprenorphine (BUP) consumed concomitantly with benzodiazepines (BZDs) including flunitrazepam (FZ) may cause life-threatening respiratory depression despite a BUP ceiling effect and BZDs' limited effects on ventilation. However, the mechanism of BUP/FZ interaction remains unknown. We hypothesized that BUP may alter the disposition of FZ active metabolites in vivo, contributing to respiratory toxicity. Plasma FZ, desmethylflunitrazepam (DMFZ), and 7-aminoflunitrazepam (7-AFZ) concentrations were measured using gas chromatography-mass spectrometry. Intravenous BUP 30 mg/kg pretreatment did not alter plasma FZ and 7-AFZ kinetics in Sprague-Dawley rats infused with 40 mg/kg FZ over 30 min, whereas resulting in a three-fold increase in the area under the curve (AUC) of DMFZ concentrations compared with control (p < 0.01). In contrast, BUP did not significantly modify plasma DMFZ concentrations after intravenous infusion of 7 mg/kg DMFZ, whereas resulting in a similar peak concentration to that generated from 40 mg/kg FZ administration. Regarding the effects on ventilation, BUP (30 mg/kg) as well as its combination with FZ (0.3 mg/kg) significantly increased PaCO(2), whereas only BUP/FZ combination decreased PaO(2) (p < 0.001). Interestingly, FZ (40 mg/kg) but not DMFZ (40 mg/kg) significantly increased PaCO(2) (p < 0.05), whereas DMFZ but not FZ decreased PaO(2) (p < 0.05). Thus, decrease in PaO(2) appears related to BUP-mediated effects on DMFZ disposition, although increases in PaCO(2) relate to direct BUP/FZ additive or synergistic dynamic interactions. We conclude that combined high-dosage BUP and FZ is responsible for increased respiratory toxicity in which BUP-mediated alteration in DMFZ disposition may play a significant role.

Topics: Analgesics, Opioid; Animals; Biotransformation; Buprenorphine; Carbon Dioxide; Drug Interactions; Flunitrazepam; GABA Modulators; Hydrogen-Ion Concentration; Infusions, Intravenous; Male; Oxygen; Pulmonary Ventilation; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency

There are few reports in children of overdoses of buprenorphine, a partial opioid agonist used in the treatment of opioid dependence and pain. The purpose of this study was to analyze buprenorphine overdoses in young children reported by US poison centers to the Researched Abuse, Diversion, and Addiction-Related Surveillance System.. A retrospective review of buprenorphine overdoses in children < 6 years of age reported to the Researched Abuse, Diversion, and Addiction-Related Surveillance System from November 2002 through December 2005 was performed. Patients lost to follow-up and those ingesting multiple substances were excluded.. Eighty-six cases met inclusion criteria. In the 54 children who developed toxicity, the clinical effects included drowsiness or lethargy (55%), vomiting (21%), miosis (21%), respiratory depression (7%), agitation or irritability (5%), pallor (3%), and coma (2%). There were no fatalities. The mean time to onset of effects was 64.2 minutes, with a range of 20 minutes to 3 hours. Duration of clinical effects was under 2 hours in 11%, 2 to 8 hours in 59%, 8 to 24 hours in 26%, and > 24 hours in 4%. Children who ingested > or = 2 mg of buprenorphine were more likely to experience clinical effects, and all of the children who ingested > 4 mg experienced some effect. No child ingesting < 4 mg experienced a severe effect. Of the 22 children administered naloxone, 67% had at least a partial response.. Buprenorphine overdoses are generally well tolerated in children, with significant central nervous system and respiratory depression occurring in only 7%. Any child ingesting > 2 mg and children < 2 years of age ingesting more than a lick or taste should be referred to the emergency department for a minimum of 6 hours of observation. Naloxone can be used to reverse respiratory depression.

Topics: Analgesics, Opioid; Buprenorphine; Child; Child, Preschool; Cohort Studies; Dose-Response Relationship, Drug; Drug Overdose; Female; Follow-Up Studies; Humans; Incidence; Infant; Male; Poisoning; Respiratory Insufficiency; Retrospective Studies; Risk Assessment

This investigation describes the interspecies scaling of the pharmacokinetics and pharmacodynamics of buprenorphine.. Data on the time course of the antinociceptive and respiratory depressant effects of buprenorphine in rats and in humans were simultaneously analysed on the basis of a mechanism-based pharmacokinetic-pharmacodynamic model.. An allometric three-compartment pharmacokinetic model described the time course of the concentration in plasma. The value of the allometric coefficient for clearance was 35.2 mL/min (relative standard error [RSE] = 5.6%) and the value of the allometric exponent was 0.76 (RSE 5.61%). A combined biophase distribution-receptor association/dissociation model with a linear transduction function described hysteresis between plasma concentration and effect. The values of the drug-specific pharmacodynamic parameters were identical in rats and in humans. For the respiratory depressant effect, the values of the second-order rate constant of receptor association (k(on)) and the first-order rate constant of receptor dissociation (k(off)) were 0.23 mL/ng/min (RSE = 15.8%) and 0.014 min(-1) (RSE = 27.7%), respectively, and the value of the equilibrium dissociation constant (K(diss)) was 0.13 nmol/L. The value of the intrinsic activity alpha was 0.52 (RSE = 3.4%). For the antinociceptive effect, the values of the k(on) and k(off) were 0.015 mL/ng/min (RSE = 18.3%) and 0.053 min(-1) (RSE = 23.1%), respectively. The value of the K(diss) was 7.5 nmol/L. An allometric equation described the scaling of the system-specific parameter, the first-order distribution rate constant (k(e0)). The value of the allometric coefficient for the k(e0) was 0.0303 min(-1) (RSE = 11.3%) and the value of the exponent was -0.28 (RSE = 9.6%).. The different values of the drug-specific pharmacodynamic parameters are consistent with the different opioid mu receptor subtypes involved in the antinociceptive and respiratory depressant effects.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Humans; Models, Biological; Rats; Reproducibility of Results; Respiratory Insufficiency

High dose buprenorphine is used as substitution treatment in heroin addiction. However, deaths have been reported in addicts using buprenorphine. The role of norbuprenorphine, an N-dealkyl metabolite of buprenorphine, was hypothesized to explain these fatal cases. We determined the median intravenous lethal dose (LD(50)) of norbuprenorphine in male Sprague-Dawley rats. The effects of a single intravenous dose of 3 or 9 mg/kg norbuprenorphine alone on arterial blood gases were studied. Finally, the effect of pre- and post-administrations of buprenorphine on norbuprenorphine-induced changes on arterial blood gases were analyzed. Norbuprenorphine's LD(50) was 10 mg kg(-1). Norbuprenorphine 3 mg kg(-1) produces the rapid onset of sustained respiratory depression, as demonstrated at 20 min by a maximal significant increase in PaCO(2) (8.4+/-0.9 versus 5.7+/-0.1 kPa), decrease in arterial pH (7.25+/-0.06 versus 7.44+/-0.01), and hypoxia (8.3+/-0.6 versus 11.1+/-0.2 kPa). Buprenorphine not only protected against the effects of 3 mg kg(-1) norbuprenorphine in a dose-dependent manner but also reversed the effects when given afterward. Binding experiments suggest a role for micro- and to a lesser extent for delta-opioid receptors in buprenorphine protective effect against norbuprenorphine-induced respiratory depression. In conclusion, our data clearly show that norbuprenorphine alone causes important deleterious effects on ventilation in rats. However, buprenorphine protective effect calls into question the role for norbuprenorphine in respiratory toxicity associated with buprenorphine use.

Topics: Animals; Arteries; Blood Gas Analysis; Buprenorphine; Dose-Response Relationship, Drug; Drug Antagonism; Lethal Dose 50; Lung; Male; Narcotic Antagonists; Pulmonary Ventilation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu; Respiratory Insufficiency

We measured the effect of two weight adjusted i.v. doses (0.2 mg per 70 kg and 0.4 mg per 70 kg) of the potent opioid buprenorphine on analgesia and respiratory depression in healthy volunteers. The aim of the study was to compare buprenorphine's behaviour with respect to the occurrence of ceiling (or apparent maximum) in these typical micro-opioid protein-(MOP) receptor effects.. Ten subjects (5 males) received 0.2 mg per 70 kg, 10 others (5 males) 0.4 mg per 70 kg i.v. buprenorphine. Steady-state inspired minute ventilation at a fixed end-tidal Pco(2) of 7 kPa was measured before drug infusion and at regular intervals after drug infusion. Experimental pain was induced using transcutaneous electrical stimulation and a gradually increasing current. Pain tolerance was measured at regular intervals before and after drug infusion. The studies lasted 8 h.. After infusion of the drug ventilation showed a rapid decline and reached peak depression between 150 and 180 min after drug administration. This effect was dose-independent with respect to timing and magnitude. At peak respiratory depression minute ventilation was 13.1 (sd 1.8) litre min(-1) in the 0.2 mg group vs 12.0 (sd 1.3) litre min(-1) in the 0.4 mg group (n.s.). At buprenorphine 0.2 mg a small short-lived analgesic effect was observed with a maximum increase in pain tolerance current of 6.7 (sd 2.8) mA occurring at 75 min after drug administration. Peak analgesic effect was 29% above baseline current. In contrast, buprenorphine 0.4 mg caused a large and long-lived analgesic effect with a maximum increase in pain tolerance current of 23.8 (sd 7.4) mA occurring at 130 min after drug administration. Peak analgesic effect was 160% above baseline current (0.4 vs 0.2 mg, P<0.01).. While buprenorphine's analgesic effect increased significantly, respiratory depression was similar in magnitude and timing for the two doses tested. We conclude that over the dose range tested buprenorphine displays ceiling in respiratory effect but none in analgesic effect.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Electric Stimulation; Female; Humans; Male; Pain Threshold; Respiratory Insufficiency

A 2-year-old Japanese girl had transient left ventricular apical ballooning on echocardiography and ST-segment elevation and T-wave inversion on electrocardiogram after withdrawal of bupirenorphine and midazolam. The findings improved within 2 weeks. There are many case reports of adults with takotsubo cardiomyopathy but none in children. Takotsubo cardiomyopathy is not well known by pediatric cardiologists, so pediatric cases may have been overlooked. Awareness of a phenomenon similar to takotsubo cardiomyopathy, even in young children, may be important.

Topics: Age Factors; Analgesics, Opioid; Buprenorphine; Cardiomyopathies; Child, Preschool; Echocardiography; Electrocardiography; Female; Humans; Hypertrophy, Left Ventricular; Midazolam; Respiratory Insufficiency; Substance Withdrawal Syndrome; Ventricular Function, Left

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

Buprenorphine in sublingual formulation was recently introduced to the American market for treatment of opioid dependence. We report a series of 5 toddlers with respiratory and mental-status depression after unintentional buprenorphine exposure. Despite buprenorphine's partial agonist activity and ceiling effect on respiratory depression, all children required hospital admission and either opioid-antagonist therapy or mechanical ventilation. Results of routine urine toxicology screening for opioids were negative in all cases. Confirmatory testing was sent for 1 child and returned with a positive result. The increasing use of buprenorphine as a home-based therapy for opioid addiction in the United States raises public health concerns for the pediatric population.

Topics: Analgesics, Opioid; Buprenorphine; Consciousness Disorders; Female; Humans; Infant; Male; Naloxone; Narcotic Antagonists; Poisoning; Respiration, Artificial; Respiratory Insufficiency

In humans, asphyxic deaths and severe poisonings have been attributed to high-dosage buprenorphine, a maintenance therapy for heroin addiction. However, in rats, intravenous buprenorphine at doses up to 90 mg kg(-1) was not associated with significant effects on arterial blood gases. In contrast, norbuprenorphine, the buprenorphine major cytochrome P450 (CYP) 3A-derived metabolite, is a potent respiratory depressant. Thus, our aim was to study the consequences of CYP3A induction on buprenorphine-associated effects on resting ventilation in rats. We investigated the effects on ventilation of 30 mg kg(-1) buprenorphine alone or following cytochrome P450 (CYP) 3A induction with dexamethasone, using whole body plethysmography (N=24) and arterial blood gases (N=12). Randomized animals in 4 groups received sequential intraperitoneal dosing with: (dexamethasone [days 1-3]+buprenorphine [day 4]), (dexamethasone solvent [days 1-3]+buprenorphine [day 4]), (dexamethasone [days 1-3]+buprenorphine solvent [day 4]), or (dexamethasone solvent [days 1-3]+buprenorphine solvent [day 4]). Buprenorphine alone caused a significant rapid and sustained increase in the inspiratory time (P<0.001), without significant effects on the respiratory frequency, the tidal volume, the minute volume, or arterial blood gases. In dexamethasone-pretreated rats, there was no significant alteration in the respiratory parameters, despite CYP3A induction and significant increase of the ratio of plasma norbuprenorphine-to-buprenorphine concentrations. In conclusion, dexamethasone did not modify the effects of 30 mg kg(-1) buprenorphine on rat ventilation. Our results suggest a limited role of drug-mediated CYP3A induction in the occurrence of buprenorphine-attributed respiratory depression in addicts.

Topics: Animals; Buprenorphine; Cytochrome P-450 CYP3A; Dexamethasone; Enzyme Induction; Glucocorticoids; Injections, Intraperitoneal; Liver; Male; Narcotics; Pulmonary Ventilation; Rats; Rats, Sprague-Dawley; Respiratory Function Tests; Respiratory Insufficiency

The respiratory depression induced by buprenorphine and its active metabolite, norbuprenorphine (NBN), was evaluated in rats by measurement of changes in respiratory rate and arterial pCO2 levels. After i.v. bolus administration of buprenorphine no effects were noted over the dose range 0.008 to 3 mg/kg; by contrast, the respiratory rate after rapid i.v. administration of NBN decreased in a dose-dependent fashion within the dose range of 1 to 3 mg/kg, and the arterial pCO2 levels also varied in relation to the change in respiratory rate. The minimum respiratory rate was observed 15 min after NBN administration. Judging by the respiratory depressive effect after i.v. infusion, NBN was approximately 10 times more potent than the parent drug. In spite of the similarity of NBN concentrations in the brain after i.a. and after i.v. administration of NBN (3 mg/kg), neither the respiratory rate nor the arterial pCO2 levels after i.a. administration changed compared with the control levels. Moreover, the NBN concentration in the lungs after i.v. administration was approximately 4-fold higher than that after i.a. administration. NBN-induced depression was rapidly reduced after i.v. administration of naloxone and beta-funaltrexamine, but ICI 174864 was without effect. These results suggest that the respiratory depression induced by NBN may be mediated by opioid mu receptors in the lung rather than in the brain.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Carbon Dioxide; Infusions, Intravenous; Injections, Intravenous; Male; Naloxone; Rats; Rats, Wistar; Receptors, Opioid; Respiration; Respiratory Insufficiency

Opioids are among the most ancient and widely used drugs in anaesthesiology. The pharmacology of opioid analgesics and their receptors is a complex and not fully understood matter; even more complex are the interactions between different classes of opioids at both molecular and clinical levels. We want to report here a clinical observation to emphasize the importance of the theoretical basis of anaesthesiology. This paper contains a clinical observation of respiratory depression following the administration of buprenorphine as postoperative analgesic after balanced anaesthesia with fentanyl. The observed case is interpreted in the light of the pharmacokinetics and pharmacodynamics of the different classes of opioid drugs (agonists, agonists-antagonists, antagonists) and of the interactions with their respective receptors.

Topics: Analgesics, Opioid; Anesthesia; Buprenorphine; Child; Depression, Chemical; Female; Fentanyl; Humans; Pain, Postoperative; Respiration; Respiratory Insufficiency

A 48-year-old man who had undergone thoracotomy for carcinoma of the middle third of his oesophagus developed severe postoperative respiratory depression following intramuscular ketorolac 30 mg 2 h after 150 micrograms epidural buprenorphine. Summation of analgesia by drugs used in combination can have deleterious respiratory effects.

Topics: Analgesia, Epidural; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Depression, Chemical; Drug Interactions; Esophageal Neoplasms; Esophagectomy; Humans; Injections, Intramuscular; Ketorolac; Male; Middle Aged; Pain, Postoperative; Respiratory Insufficiency; Tolmetin

Topics: Acute Disease; Buprenorphine; Humans; Male; Middle Aged; Naloxone; Respiratory Insufficiency

The influence of different lung resection methods on pulmonary function was studied in 34 patients suffering from bronchial carcinoma. Daily measurements from the 1st to 10th postoperative day reveal the greatest losses of function after right upper lobectomy. Lower lobectomies or left upper lobectomy resulted in a less extensive loss of function. Recovery of function mainly occurs in the first 4 days after operation. Centrally acting analgetics are followed by a loss in pulmonary function whereas locally applied analgetics improve early postoperative function.

Topics: Adult; Aged; Airway Resistance; Analgesics; Buprenorphine; Carcinoma, Bronchogenic; Female; Humans; Lung Neoplasms; Lung Volume Measurements; Male; Meperidine; Middle Aged; Nerve Block; Pain, Postoperative; Pneumonectomy; Postoperative Complications; Respiratory Insufficiency

Topics: Almitrine; Buprenorphine; Central Nervous System Stimulants; Humans; Piperazines; Respiratory Insufficiency

Topics: Buprenorphine; Humans; Intraoperative Complications; Male; Middle Aged; Postoperative Complications; Respiratory Insufficiency; Temazepam

Topics: Adult; Anesthesia, Epidural; Buprenorphine; Hemorrhoids; Humans; Male; Respiratory Insufficiency

Topics: Anti-Anxiety Agents; Benzodiazepines; Buprenorphine; Humans; Morphinans; Postoperative Complications; Respiratory Insufficiency

Buprenorphine was given intravenously to produce analgesia in the immediate postoperative period, the dose being titrated against the response of each patient in order to obtain complete freedom from pain. In 50 patients following lower segment Caesarean section under general anaesthesia, buprenorphine in the dose range 0.4-7.0 mg was found to be a potent, long lasting and safe analgesic. Serial blood gas estimations performed on ten of the patients confirmed the clinically observed lack of respiratory depression.

Topics: Adult; Buprenorphine; Cesarean Section; Dose-Response Relationship, Drug; Female; Humans; Morphinans; Pain, Postoperative; Pregnancy; Respiratory Insufficiency; Time Factors

Topics: Age Factors; Aged; Buprenorphine; Female; Hemodynamics; Humans; Male; Morphinans; Respiratory Insufficiency

Buprenorphine, a partial opiate-receptor agonist with potent analgesic properties, was given to 7548 patients in the immediate postoperative period. Ninety per cent of patients had good or adequate pain relief for at least 4 hours; there were few adverse effects and the incidence of drug-associated respiratory depression was estimated at less than 1%. There were no other side-effects of clinical note.

Topics: Adolescent; Adult; Aged; Buprenorphine; Child; Child, Preschool; Drug Evaluation; Female; Humans; Male; Middle Aged; Morphinans; Nausea; Pain, Postoperative; Respiratory Insufficiency; Time Factors; Vomiting

Topics: Buprenorphine; Heroin; Humans; Morphinans; Myocardial Infarction; Respiratory Insufficiency

Topics: Acidosis; Blood Proteins; Buprenorphine; Female; Humans; Middle Aged; Morphinans; Postoperative Complications; Protein Binding; Respiratory Insufficiency; Time Factors