does high-dose buprenorphine cause respiratory depression?

Toxicol Rev 2006; 25 (2): 79-85REVIEW ARTICLE 1176-2551/06/0002-0079/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

Does High-Dose Buprenorphine CauseRespiratory Depression?Possible Mechanisms and Therapeutic Consequences

Bruno Megarbane,1,2 Raymond Hreiche,1 Stephane Pirnay,1,3 Nicolas Marie1 and Frederic J. Baud1,2

1 INSERM U705, CNRS, UMR 7157, Universite Paris 7, Universite Paris 5, Hopital Fernand Widal, Paris, France2 Assistance Publique – Hopitaux de Paris, Hopital Lariboisiere, Reanimation Medicale et Toxicologique, Universite Paris 7,

Paris, France3 Laboratoire de Toxicologie de la Prefecture de Police, Paris, France

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791. Pharmacological Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802. Buprenorphine-Associated Toxic Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 813. Respiratory Effects of Buprenorphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 824. Mechanisms of Interaction with Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Buprenorphine is an opioid agonist-antagonist with a ‘ceiling effect’ for respiratory depression. ComparedAbstractwith methadone, its unique pharmacology offers practical advantages and enhanced safety when prescribed asrecommended and supervised by a physician. Buprenorphine has been approved in several countries as anefficient and safe maintenance therapy for heroin addiction. Its use resulted in a salutary effect with a reductionin heroin overdose-related deaths in countries that implemented office-based buprenorphine maintenance. InFrance, however, where high-dose buprenorphine has been marketed since 1996, several cases of asphyxicdeaths were reported among addicts treated with buprenorphine. Death resulted from buprenorphine intravenousmisuse or concomitant sedative drug ingestion, such as benzodiazepines. In these situations of abuse, misuse, orin association with elevated doses of psychotropic drugs, buprenorphine may cause severe respiratory depres-sion. 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 norbupre-norphine, the main N-dealkylated buprenorphine metabolite with potent respiratory depressor activity, alsoremains unclear. Experimental studies investigating the respiratory effects of combinations of high doses ofbuprenorphine and benzodiazepines suggested that this drug-drug interaction may result from a pharmacody-namic 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 withbuprenorphine use, we aimed to present a comprehensive critical review of the published clinical andexperimental studies on buprenorphine respiratory effects.

Heroin addiction remains a major concern worldwide and involvement in the illicit drug scene, by shifting the context ofcauses numerous fatalities.[1,2] Treatment of heroin addicts under- heroin use into a medically supervised framework that offers morewent a profound evolution with the development of maintenance support and greater possibilities of health promotion and socialtherapies including methadone and buprenorphine. The objective integration. Countries have chosen different strategies for mainte-of the substitution programmes is to decrease intravenous drug nance and detoxification treatment of opioid dependence. Numer-abuse-related mortality and morbidities. Treatments aim to reduce ous opioid molecules have been approved, different facilities for

80 Megarbane et al.

prescription and delivery established, and various treatment moni- respiratory depression induced by anaesthetic doses of fentanyl,toring systems organised. without preventing opioid pain relief.[11] Like all opioids, side

effects include sedation, nausea, vomiting, dizziness, sweating andIn October 2002, the US FDA approved buprenorphine for theheadaches. Similarly, when discontinued, a typical morphine-liketreatment of opioid dependence. Treatment of heroin addicts waswithdrawal syndrome develops with a delayed onset of 2–15 days.limited to physicians with specialised training or experience and

limited to a maximum of 30 patients per physician.[3] Bupre- Buprenorphine pharmacokinetic properties help explain its re-norphine has been used in some European countries for a longer markable effects. High-dosage buprenorphine undergoes exten-period of time. In France, a high-dosage buprenorphine formula- sive first-pass hepatic metabolism, thus it is administered sub-tion has been marketed since 1996. While methadone was still lingually with a 60–70% bioavailability. Tissue distribution isprescribed in specialised health centres, buprenorphine was wide, with a peak plasma concentration at 90 minutes. Kineticsauthorised for all registered practitioners and pharmacies.[4] In this follow a three-compartment model with a terminal eliminationcountry, about 90 000 addicts are treated today with high-dosage half-life of 27 hours (values ranging from 3 to 44 hours), abuprenorphine versus 25 000 with methadone.[5] The success of distribution volume of 48 L/kg, and a total clearance of 100 mL/the French heroin substitution programme was demonstrated by kg/min.[12] Cerebral distribution is important due to its lipophilicthe decrease of deaths due to heroin overdoses (from 465 in 1996 properties (octanol/water partition coefficient: 1943 ± 50 and pKa:to 89 in 2003) and the decline of the arrests due to heroin use (from 8.42 ± 0.03). Buprenorphine is highly (96%) bound to plasma17 328 to 4025 in the same period).[6,7] The public health benefits proteins, mainly globulins. Buprenorphine is transformed in theexperienced in France bring to question the value of the more liver to inactive conjugated metabolites. However, its extensive N-stringent regulations on prescribing buprenorphine imposed in dealkylation, catalysed by cytochrome P450 (CYP) 3A4, producesmany other countries throughout the world. an active metabolite called norbuprenorphine (figure 1).[13] Human

Buprenorphine exhibits unique pharmacological properties and pharmacokinetic studies showed low plasma concentrations ofhas shown to be lacking of significant respiratory effects at thera- norbuprenorphine following buprenorphine administration, butpeutic doses, both in experimental and clinical studies. However, with peaks and elimination half-lives that markedly varied accord-since its availability as a substitution therapy in humans, several ing to the routes of administration and among individuals.[12] Mostcases of severe respiratory depression and death have been report- of buprenorphine (70–90%) is excreted in the faeces. Both N-ed in drug addicts. Our objective was to review the recent hypothe- dealkylated and conjugated metabolites are detected in the urine.sis on the mechanisms of the respiratory effects of buprenorphine Various drugs that induce (antiepileptic drugs) or inhibitin the light of its pharmacology. (macrolides, azole-based antimycotic drugs and HIV protease

inhibitors) the CYP 3A4, may interfere with buprenorphine me-1. Pharmacological Properties tabolism. However, their clinical implications remain unknown.

The relationship between buprenorphine plasma concentration andBuprenorphine is a semi-synthetic, highly lipophilic opioidresponse in the opioid-dependence treatment has not been stud-derived from thebaine. It is used as an analgesic (usual dosesied.[12] Buprenorphine dosage does not need to be significantly[Temgesic®]:1 0.3mg every 6 hours by intravenous or intramuscu-adjusted in patients with renal impairment; however, it is possiblelar routes or 0.4–0.8 mg/day sublingually) and as maintenancethat the metabolism of buprenorphine will be altered in patientstherapy (high-dosage [Subutex®]: 8–32 mg/day). Regarding itswith severe chronic liver disease including decreased CYP3Aanalgesic properties, buprenorphine is 25–50 times more potentactivity.than morphine.[8] It is considered a partial mu-opioid receptor

Finally, it is well known that buprenorphine is frequentlyagonist and a weak kappa-receptor antagonist. It possesses a highinjected by users (around 33%), despite the labelling for sublin-affinity for both receptors (1000 times higher than morphine),gual use.[14,15] Thus, routine monitoring of buprenorphine misuseresulting in a slow dissociation (K(i) in the subnanomolar range:may be warranted, needing the development of effective counter-6.10–12 and 4.10–12 mol/L, respectively) and a long duration ofmeasures to address diversion and injection in this setting.[16]action.[9] Buprenorphine affinity for the delta receptors is lowerConsequently, a sublingual preparation (Suboxone®) associating(K(i): 4.8.10–10 mol/L). The half-life for dissociation from the mu-buprenorphine and the poorly gastrointestinal-absorbed naloxonereceptor is 166 minutes, compared with 7 minutes for fentanyl.[10]

(4 : 1 combination) has been marketed, aiming to limit diversionThese properties explain the slower onset and longer duration thanby precipitating withdrawal symptoms, if parenterally self-inject-morphine. For example, intramuscular administration results ined by addicts.[17] The presence of naloxone does not appear topeak respiratory effects at 3 hours and maximal miosis at 6 hoursinfluence the pharmacokinetics of buprenorphine.in humans. Like naloxone, buprenorphine is able to antagonise the

1 The use of trade names is for product identification purposes only and does not imply endorsement.

© 2006 Adis Data Information BV. All rights reserved. Toxicol Rev 2006; 25 (2)

Does High-Dose Buprenorphine Cause Respiratory Depression? 81

HO

O

N

H3CO

CHO CH3

CH3 CH2OHCH3

M1

HO

O

N

H3CO

CHO CH3

CH3 CH3CH3

Buprenorphine

HO

O

N

H3CO

OH

CHO CH3

CH3 CH3CH3

M2

HO

O

NH

H3CO

OH

CHO CH3

CH3 CH3CH3

M4 (or M5)

HO

O

NH

H3CO

CHO CH3

CH3 CH2OHCH3

M3

HO

O

N

H3CO

CHO CH3

CH3 CH3

CH3

Norbuprenorphine

N-dealkylation

CYP3A5, 3A4, 3A7, 2C8

Hydroxylation

CYP3A4, 3A5

Hydroxylation

CYP3A5, 3A4, 3A7, 2C8

N-dealkylation

N-dealkylation

Hydroxylation

Fig. 1. Molecular structure of buprenorphine and its different metabolic pathways in the liver (reproduced from Chang et al.,[13] with permission). M1–M5 =different metabolites.

2. Buprenorphine-Associated Toxic Deaths ingestion.[18] Poisonings are characterised by a high frequency ofmultiple opiate/opioid association, as well as psychoactive drugco-ingestion. In fatalities, as neither toxic nor lethal concentrationsDespite limited side effects, >100 cases of buprenorphine-of buprenorphine were available, forensic studies reported eitherrelated fatalities have been reported in France.[18-23] Several otherelevated or therapeutic blood concentrations (evaluated fromcases were also reported in the Nordic countries (Denmark, Fin-clinical studies in the range of 2–20 ng/mL).[21-23] However, sys-land, Iceland, Norway and Sweden).[24] Similarly, an increase intematic analysis of death causes revealed the difficulties in deter-buprenorphine-related deaths has been identified since 1999 in themining the role of substitution drugs in the death process, as manyUK.[25] Forensic reports consistently concluded that death resultedother factors might be involved, including circumstances sur-from asphyxiation.[18-23] Fatality was usually associated withrounding death, past history, differential selection of subjects intobuprenorphine intravenous misuse (intravenous injection ofeither substitution modality and concomitant intake of othercrushed tablets) or concomitant sedative drug ingestion, such as

benzodiazepines. In one case, death was due to a massive oral drugs.[23] Moreover, as death caused by benzodiazepines in the


82 Megarbane et al.

absence of underlying disease is uncommon,[26] fatalities were prolonged and biphasic manner at various times up to 20 hoursattributed in some cases to the association of buprenorphine and after administration of epidural buprenorphine 0.15mg.[36]

benzodiazepines. However, as many addicts regularly use benzo- This ‘ceiling effect’ was thought to confer in humans a highdiazepines in association with their maintenance therapies, the safety profile, mild mental status changes, mild to minimal respir-mechanism of the deleterious interaction between buprenorphine atory depression, small but not pinpoint pupils and relativelyand benzodiazepines is questionable. The potential for synergistic normal vital signs.[3] In fact, since its availability as a maintenanceor additive actions by other psychoactive molecules, including therapy, respiratory side-effects have been rarely reported, espe-opioids, alcohol and neuroleptics should also be considered. cially in office-based treatment of opioid dependence.[37] In con-

trast, in situations of abuse, typical features of severe opioid3. Respiratory Effects of Buprenorphine poisoning (coma + miosis + respiratory depression) were de-

scribed.[6,38,39] However, because of the retrospective data collec-The exact mechanism of buprenorphine acute toxicity remainstion in these studies and the lack of systematic laboratory-con-misunderstood. Respiratory depression is the suspected aetiologyfirmed poisonings, significant limitations make conclusions cau-of buprenorphine-related deaths. The majority of opioids induce atious, warranting further prospective observational studies.dose-dependent respiratory depression in experimental models.[27]

Particularly in regard to the management of buprenorphine over-In rats, morphine and methadone elicit the rapid onset of dose-doses, where contradictory results appeared. Indeed, in one casedependent respiratory acidosis and hypoxia.[28,29] In contrast, dose-series, a rapid improvement of the patients using 0.4–0.8mg nalox-effect relationships of buprenorphine suggest either limited effectsone was reported,[38] whereas in a placebo-controlled study inover a 0.008–3 mg/kg intravenous dose range[30] or a plateau ofvolunteers, no effects of 1mg naloxone on mild respiratory depres-respiratory effects due to its antagonist effects at highersion and non-immediate reversal despite higher doses were ob-doses.[27,31,32] These results were confirmed by the absence ofserved, once the effects have been produced.[40]

significant effects on arterial blood gases after a single 3, 30, or 90The exact mechanism of buprenorphine-induced respiratorymg/kg buprenorphine infusion, compared with the solvent.[33] A

effects is unclear. In several fatal cases related to buprenorphinemore recent study in volunteers showed that while the analgesicoverdoses, high plasma or tissue concentrations of norbupre-effect of buprenorphine increased significantly when administer-norphine were reported, suggesting its role in the onset ofing a dose from 0.2 to 0.4mg per 70kg, respiratory depression wasdeath.[18-23] Norbuprenorphine, the main N-dealkylated bupre-similar in magnitude and timing for the tested doses.[34] Bupre-norphine metabolite, is a very potent respiratory depressor. Signif-norphine caused depression of the minute ventilation, which lev-icant respiratory depression has been demonstrated following theelled off at doses ≥3 μg/kg to about 50% of baseline. Irrespectiveadministration of a single intravenous dose of 3 mg/kg norbupre-of the time at which measurements were obtained, buprenorphinenorphine in rats.[41-43] However, it is unclear whether norbupre-showed a modest non-linear effect on arterial carbon dioxidenorphine alone can fully explain buprenorphine-related deaths.tension (maximum value measured, 5.5 kPa), with a ceiling effectRecent experimental data in rats have shown that significantat doses >1.4 μg/kg.[35] In another volunteer study, the carbonquantities of norbuprenorphine can be detected in the plasma,dioxide response curves were depressed in a time-dependent,

Mechanism ofreversion

Mechanism ofprevention

Respiratorydepression

NN

N N N N

B B B B

μ δ


μ δ


μ δ

Fig. 2. Schematic representation based on binding experiments, of the buprenorphine (B)-related protection and reversion of the norbuprenorphine (N)-induced respiratory depression in rats.[42]



immediately after buprenorphine administration.[44] Differentmechanisms for the norbuprenorphine role were proposed, includ-ing a transient decrease in respiratory frequency, an early onset ofseizures, as well as a sustained muscle rigidity. However, in rats,when buprenorphine and norbuprenorphine were co-administered,buprenorphine completely prevented, as well as reversednorbuprenorphine-induced respiratory effects.[43] Binding experi-ments suggested a role for mu- and to a lesser extent for delta-opioid receptors in buprenorphine protective effect againstnorbuprenorphine-induced respiratory depression (figure 2). Inanimals, significant protective effect was observed even whennorbuprenorphine exceeded buprenorphine concentrations in plas-ma,[43] whereas in the majority of reported human fatalities, bupre-norphine exceeded norbuprenorphine concentrations.[18-23] Thus,discrepancy between human and experimental data calls intoquestion the role of norbuprenorphine alone as the mechanism ofbuprenorphine-associated death in humans.

Alteration of opioid receptor expression in the CNS may alsoinfluence the respiratory effects of buprenorphine. A recent studyin rats using a β-imager clearly established that an acute bupre-

Table I. The different possible levels of a pharmacodynamic interactionbetween opioids (including buprenorphine) and benzodiazepines

Interaction at the level of breathing control

GABA and opioid receptors are co-expressed in the CNS including thebrain stem[54]

GABA and opioid receptors are implicated in the phasic and/or tonicactivity of the neurons controlling the ventilation[55]

There are common intracellular transduction pathways (Gi/o protein)regarding the GABAB and opioid receptors[56]

Some benzodiazepines are antagonists of the delta and kappa receptorsat high concentrations[57,58]

Addition of various central and peripheral physiological effects(A + B)

A. Benzodiazepines: command of the respiratory muscles and control ofthe pharyngeal dilatation, resulting in: (i) upper-airway obstruction inrelation to relaxation of pharyngeal muscles; and (ii) diaphragmaticdysfunction[59]

B. Opioids: reduction in the response to ventilation in different situations,including: (i) resistance during inspiration; (ii) hypoxia; and (iii)hypercapnia[60]

norphine administration induced a down-regulation of mu-opioidreceptors throughout the brain.[45] Whereas a single buprenorphine netic or from a pharmacodynamic process. The majority of theadministration induced no changes in kappa- or delta-opioid re- studies analysing opioid/benzodiazepine interactions reported syn-ceptor binding, repeated administration up-regulated kappa-recep- ergistic or at least additive hypnotic, analgesic and ventilatory-tor density and decreased delta-receptor affinity.[46] depressant effects based on pharmacodynamic interactions.

Regarding the respiratory effects of the buprenorphine/4. Mechanisms of Interaction with Benzodiazepines benzodiazepine combination, a pharmacokinetic mechanism can-

not be excluded. Interestingly, in rodents, diazepam was demon-Given the forensic data collected in addicts who died in relationstrated to inhibit the metabolism of methadone, even though such ato buprenorphine use, a deleterious interaction between bupre-kinetic interaction is lacking in humans.[49,50] Recent unpublishednorphine and benzodiazepines was hypothesised to explain acutedata obtained in our laboratory showed that buprenorphine signifi-toxicity. The interaction between benzodiazepines and opioidscantly altered the kinetics of desmethylflunitrazepam, the metabo-including buprenorphine and methadone has resulted in respirato-lite of flunitrazepam, suggesting the likelihood of interaction ofry depression in both animal models and humans.[29,47,48] McCor-buprenorphine with the distribution of flunitrazepam (unpublishedmick et al.[29] reported severe and long-lasting respiratory acidosisdata). However in vitro studies failed to demonstrate any signifi-in rats following the administration of diazepam 20 mg/kg subcu-cant P450 cytochrome-mediated metabolic interactions betweentaneously, in association with methadone 5 mg/kg intraperitoneal-buprenorphine and flunitrazepam.[51,52] Moreover, in a study usingly, corresponding to one-tenth of the median lethal dose (LD50) ofcerebral microdialysis in rats, flunitrazepam pre-administrationeach drug. Gueye et al.[33,48] showed that a single intravenous dosedid not alter the distribution kinetics of buprenorphine in theof buprenorphine 30 mg/kg in rats did not result in any significantstriatum.[53] Thus, the main hypothesis regarding the respiratoryeffect on blood gases, while, in combination with an intraper-effects of the buprenorphine/benzodiazepine combination reliesitoneal dose of midazolam 140 mg/kg, it induced a rapid onset ofon a pharmacodynamic basis.severe and sustained respiratory acidosis. Borron et al.[47] demon-

Different mechanisms of interaction regarding respiratory ef-strated, in a blinded randomised study, that flunitrazepam altersfects may be hypothesised due to common pathways and sites ofbuprenorphine lethality in rats, with a 6-fold decrease of its

intravenous LD50. However, the deleterious effect of the same action (table I). Opioids and benzodiazepines act in combinationdose of flunitrazepam was opioid-specific, as flunitrazepam with different classes of the opioid and the GABA receptors. Allcaused only a 2-fold decrease in methadone LD50, with no signifi- these receptors are co-expressed in the CNS, including in the areascant effect on morphine LD50. of ventilation control.[54] Both GABA and opioid systems play an

important role in both phasic and tonic activity of the neurons thatThe exact mechanism of buprenorphine/benzodiazepine inter-action remains to be clarified, resulting either from a pharmacoki- control the ventilation.[55] Interestingly, these receptors use com-


84 Megarbane et al.

norphine treatment: prescribers’ practices [in French]. Presse Med 2005; 34:mon intracellular transduction pathways such as the Gi/o prote-1213-9

in.[56] Regarding opioid receptors, however, only limited interac- 6. Gueye PN, Megarbane B, Borron SW, et al. Trends in opiate and opioid poisoningsin addicts in north-east Paris and suburbs, 1995-99. Addiction 2000; 97:tions of benzodiazepines have been reported, especially at very1295-304high concentrations such as those observed after intrathecal ad-

7. Emmanuelli J, Desenclos JC. Harm reduction interventions, behaviors and associ-ministration.[57,58] Drug-induced coma involving benzodiazepines ated health outcomes in France, 1996-2003. Addiction 2005; 100: 1690-700

8. Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman J, Limbirdis characterised by snoring with flow limitation and obstructiveL, Molinoff P, et al., editors. Goodman & Gilman’s the pharmacological basis

apnoea.[59] The mechanism of respiratory insufficiency in non- of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 521-559. Huang P, Kehner GB, Cowan A, et al. Comparison of pharmacological activities ofintubated patients with drug-induced coma involving benzodi-

buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioidazepines is an increase in upper airway resistance and work ofagonist. J Pharmacol Exp Ther 2001; 297: 688-95

breathing. The interaction of sleep and opioid administration pro- 10. Boas RA, Villiger JW. Clinical actions of fentanyl and buprenorphine: the signifi-cance of receptor binding. Br J Anaesth 1985; 57: 192-6duces well known disturbances in the ventilatory pattern, causing

11. Boysen K, Hertel S, Chraemmer-Jorgensen B, et al. Buprenorphine antagonism ofprofound oxygen destruction.[60] Regarding the buprenorphine/ ventilatory depression following fentanyl anaesthesia. Acta Anaesthesiol Scandbenzodiazepine interaction, we suggest that buprenorphine may 1988; 32: 490-2

12. Elkader A, Sproule B. Buprenorphine: clinical pharmacokinetics in the treatmentalter the response of the brain-stem respiratory centres to theof opioid dependence. Clin Pharmacokinet 2005; 44: 661-80

benzodiazepine-induced increase in the upper-airway resistance. 13. Chang Y, Moody DE, McCance-Katz EF. Novel metabolites of buprenorphinedetected in human liver microsomes and human urine. Drug Metab DisposThis hypothetic mechanism of interaction has yet to be elucidated2006; 34: 440-8and appropriate animal models and techniques, such as plethys-

14. Obadia Y, Perrin V, Feroni I, et al. Injecting misuse of buprenorphine amongmography, should be utilised to further our current understanding. french drug users. Addiction 2001; 96: 267-72

15. Comer SD, Collins ED, Fischman MW. Intravenous buprenorphine self-adminis-tration by detoxified heroin abusers. J Pharmacol Exp Ther 2001; 301: 266-765. Conclusion

16. Jenkinson RA, Clark NC, Fry CL, et al. Buprenorphine diversion and injection inMelbourne, Australia: an emerging issue? Addiction 2005; 100: 197-205

Buprenorphine is an efficient and safe maintenance therapy. Its 17. Robinson GM, Dukes PD, Robinson BJ, et al. The misuse of buprenorphine and abuprenorphine-naloxone combination in Wellington, New Zealand. Drug Alco-marketing in several European countries was responsible for ahol Depend 1993; 33: 81-6significant decrease in heroin-associated deaths. However, due to

18. Reynaud M, Tracqui A, Petit G, et al. Six deaths linked to misuse of bupre-diversion, misuse and co-ingestions of various other psychotropic norphine-benzodiazepine combinations. Am J Psychiatry 1998; 155: 448-9

19. Tracqui A, Kintz P, Ludes B. Buprenorphine-related deaths among drug addicts indrugs in addicts, the specific ceiling effect observed in clinicalFrance: a report on 20 fatalities. J Anal Toxicol 1998; 22: 430-4studies may be altered, resulting in severe respiratory depression

20. Gaulier JM, Marquet P, Lacassie E, et al. Fatal intoxication following self-and even death. To date, >100 deaths have been attributed to administration of a massive dose of buprenorphine. J Forensic Sci 2000; 45:

226-8buprenorphine use in France, the UK and the Nordic European21. Kintz P. Deaths involving buprenorphine: a compendium of French cases. Forensic

countries. A deleterious interaction between buprenorphine and Sci Int 2001; 121: 65-922. Kintz P. A new series of 13 buprenorphine-related deaths. Clin Biochem 2002; 35:benzodiazepines was hypothesised, based on experimental studies.

513-6It appears that this interaction is more likely to be a pharmacody-23. Pirnay S, Borron SW, Giudicelli CP, et al. A critical review of the causes of death

namic (additive or synergistic) than a pharmacokinetic interaction. among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths. Addiction 2004; 99: 978-88However, the exact mechanism of buprenorphine respiratory tox-

24. Steentoft A, Teige B, Holmgren P, et al. Fatal poisoning in Nordic drug addicts inicity remains to be determined. 2002. Forensic Sci Int 2006; 160 (2-3): 148-5625. Schifano F, Corkery J, Gilvarry E, et al. Buprenorphine mortality, seizures and

prescription data in the UK, 1980-2002. Hum Psychopharmacol 2005; 20:Acknowledgements343-8

26. Serfaty M, Masterton G. Fatal poisonings attributed to benzodiazepines in BritainThe authors would like to acknowledge Dr Rebeca Gracia, PharmD,during the 1980s. Br J Psychiatry 1993; 163: 386-93DABAT, from the North Texas Poison Center, Dallas, USA for her helpful

27. Cowan A, Doxey J, Harry E. The animal pharmacology of buprenorphine, anreview of this manuscript.oripavine analgesic agent. Br J Pharmacol 1977; 60: 547-54

No source of funds was used to assist in the preparation of this manuscript. 28. Verborgh C, De Coster R, D’Haese J, et al. Effects of chlordiazepoxide on opioid-The authors are not aware of any potential conflicts of interest directly relevant induced antinociception and respiratory depression in restrained rats.

Pharmacol Biochem Behav 1998; 59: 663-70to the content of this review.29. McCormick GY, White WJ, Zagon IS, et al. Effects of diazepam on arterial blood

gas concentrations and pH of adult rats acutely and chronically exposed toReferences methadone. J Pharmacol Exp Ther 1984; 230: 353-9

1. Darke S, Zador D. Fatal heroin ’overdose’: a review. Addiction 1996; 91: 1765-72 30. Ohtani M, Kotaki H, Nishitateno K, et al. Kinetics of respiratory depression in rats2. Warner-Smith M, Darke S, Lynskey M, et al. Heroin overdose: causes and induced by buprenorphine and its metabolite, norbuprenorphine. J Pharmacol

consequences. Addiction 2001; 96: 1113-25 Exp Ther 1997; 281: 428-333. Sporer KA. Buprenorphine: a primer for emergency physicians. Ann Emerg Med 31. Walsh SL, Preston KL, Stitzer ML, et al. Clinical pharmacology of buprenorphine:

2004; 43: 580-4 ceiling effects at high doses. Clin Pharmacol Ther 1994; 55: 569-804. Auriacombe M, Fatseas M, Dubernet J, et al. French field experience with 32. Nielsen S, Taylor DA. The effect of buprenorphine and benzodiazepines on

buprenorphine. Am J Addict 2004; 13 Suppl. 1: S17-28 respiration in the rat. Drug Alcohol Depend 2005; 79: 95-1015. Feroni I, Aubisson S, Bouhnik AD, et al. Collaboration between general practition- 33. Gueye PN, Borron SW, Risede P, et al. Lack of effect of single high doses of

ers and pharmacists in the management of patients on high-dosage bupre- buprenorphine on arterial blood gases in the rat. Toxicol Sci 2001; 62: 148-54



34. Dahan A, Yassen A, Romberg R, et al. Buprenorphine induces ceiling in respirato- 49. Shah N, Patel V, Donald A. Effect of diazepam, desmethylimipramine, and SKFry depression but not in analgesia. Br J Anaesth 2006; 96: 627-32 525-A on the disposition of levo-methadone in mice after single or double

injection. Drug Metab Dispos 1979; 7: 241-235. Dahan A, Yassen A, Bijl H, et al. Comparison of the respiratory effects ofintravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth 2005; 50. Pond SM, Tong TG, Benovitz NL, et al. Lack of effect of diazepam on methadone94: 825-34 metabolism in methadone-maintained addicts. Clin Pharmacol Ther 1982; 31:

139-4336. Molke Jensen F, Jensen NH, Holk IK, et al. Prolonged and biphasic respiratorydepression following epidural buprenorphine. Anaesthesia 1987; 42: 470-5 51. Ibrahim RB, Wilson JG, Thorsby ME, et al. Effect of buprenorphine on CYP3A

37. Cicero TJ, Inciardi JA. Potential for abuse of buprenorphine in office-based activity in rat and human liver microsomes. Life Sci 2000; 66: 1293-8treatment of opioid dependence. N Engl J Med 2005; 353: 1863-4

52. Kilicarslan T, Sellers EM. Lack of interaction of buprenorphine with flunitrazepam38. Rainey HB. Abuse of buprenorphine. N Z Med J 1986; 99: 72 metabolism. Am J Psychiatry 2000; 157: 1164-639. Boyd J, Randell T, Luurila H, et al. Serious overdoses involving buprenorphine in

53. Megarbane B, Pirnay S, Borron SW, et al. Flunitrazepam does not alter cerebralHelsinki. Acta Anaesthesiol Scand 2003; 47: 1031-3

distribution of buprenorphine in the rat. Toxicol Lett 2005; 157: 211-940. Gal TJ. Naloxone reversal of buprenorphine-induced respiratory depression. Clin

54. Kalyuzhny AE, Dooyema J, Wessendorf MW. Opioid- and GABA(A)-receptorsPharmacol Ther 1989; 45: 66-71are co-expressed by neurons in rat brain. Neuroreport 2000; 11: 2625-8

41. Ohtani M, Kotaki H, Uchino K, et al. Pharmacokinetic analysis of enterohepatic55. Yamada KA, Norman WP, Hamosh P, et al. Medullary ventral surface GABAcirculation of buprenorphine and its active metabolite, norbuprenorphine, in

receptors affect respiratory and cardiovascular function. Brain Res 1982; 248:rats. Drug Metab Dispos 1994; 22: 2-771-842. Ohtani M, Kotaki H, Sawada Y, et al. Comparative analysis of buprenorphine- and

norbuprenorphine-induced analgesic effects based on pharmacokinetic-phar- 56. Dan’ura T, Kurokawa T, Yamashita A, et al. Inhibition of rat brain adenylatemacodynamic modeling. J Pharmacol Exp Ther 1995; 272: 505-10 cyclase activity by benzodiazepine through the effects on Gi and catalytic

proteins. Life Sci 1988; 42: 469-7543. Megarbane B, Marie N, Pirnay S, et al. Buprenorphine is protective against thedepressive effects of norbuprenorphine on ventilation. Toxicol Appl Pharmacol 57. Yanez A, Sabbe MB, Stevens CW, et al. Interaction of midazolam and morphine in2006; 212: 256-67 the spinal cord of the rat. Neuropharmacology 1990; 29: 359-64

44. Gopal S, Tzeng TB, Cowan A. Characterization of the pharmacokinetics of 58. Cox RF, Collins MA. The effects of benzodiazepines on human opioid receptorbuprenorphine and norbuprenorphine in rats after intravenous bolus administra- binding and function. Anesth Analg 2001; 93: 354-8tion of buprenorphine. Eur J Pharm Sci 2002; 15: 287-9

59. Gueye PN, Lofaso F, Borron SW, et al. Mechanism of respiratory insufficiency in45. Debruyne D, Quentin T, Poisnel G, et al. Acute and chronic administration ofpure or mixed drug-induced coma involving benzodiazepines. J Toxicol Clinclorazepate modifies the cell surface regulation of mu opioid receptors inducedToxicol 2002; 40: 35-47by buprenorphine in specific regions of the rat brain. Brain Res 2005; 1052:

222-31 60. Catley DM, Thornton C, Jordan C, et al. Pronounced, episodic oxygen desaturationin the postoperative period: its association with ventilatory pattern and analge-46. Quentin T, Debruyne D, Lelong-Boulouard V, et al. Clorazepate affects cellsic regimen. Anesthesiology 1985; 63: 20-8surface regulation of delta and kappa opioid receptors, thereby altering bupre-

norphine-induced adaptation in the rat brain. Brain Res 2005; 1063: 84-95

47. Borron SW, Monier C, Risede P, et al. Flunitrazepam variably alters morphine,Correspondence and offprints: Bruno Megarbane, Reanimation Medicale etbuprenorphine, and methadone lethality in the rat. Hum Exp Toxicol 2002; 21:Toxicologique, Hopital Lariboisiere, 2 Rue Ambroise Pare, 75010 Paris,599-605France.48. Gueye PN, Borron SW, Risede P, et al. Buprenorphine and midazolam act in

combination to depress respiration in rats. Toxicol Sci 2002; 65: 107-14 E-mail: [email protected]


does high-dose buprenorphine cause respiratory depression?

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