Download Does High-Dose Buprenorphine Cause Respiratory Depression

Toxicol Rev 2006; 25 (2): 79-85
1176-2551/06/0002-0079/$39.95/0
REVIEW ARTICLE
 2006 Adis Data Information BV. All rights reserved.
Does High-Dose Buprenorphine Cause
Respiratory Depression?
Possible Mechanisms and Therapeutic Consequences
Bruno Mégarbane,1,2 Raymond Hreiche,1 Stéphane Pirnay,1,3 Nicolas Marie1 and Frédéric J. Baud1,2
1 INSERM U705, CNRS, UMR 7157, Université Paris 7, Université Paris 5, Hôpital Fernand Widal, Paris, France
2 Assistance Publique – Hôpitaux de Paris, Hôpital Lariboisière, Réanimation Médicale et Toxicologique, Université Paris 7,
Paris, France
3 Laboratoire de Toxicologie de la Préfecture de Police, Paris, France
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
1. Pharmacological Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
2. Buprenorphine-Associated Toxic Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
3. Respiratory Effects of Buprenorphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
4. Mechanisms of Interaction with Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Abstract
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.
Heroin addiction remains a major concern worldwide and
causes numerous fatalities.[1,2] Treatment of heroin addicts underwent a profound evolution with the development of maintenance
therapies including methadone and buprenorphine. The objective
of the substitution programmes is to decrease intravenous drug
abuse-related mortality and morbidities. Treatments aim to reduce
involvement in the illicit drug scene, by shifting the context of
heroin use into a medically supervised framework that offers more
support and greater possibilities of health promotion and social
integration. Countries have chosen different strategies for maintenance and detoxification treatment of opioid dependence. Numerous opioid molecules have been approved, different facilities for
80
Mégarbane et al.
prescription and delivery established, and various treatment monitoring systems organised.
In October 2002, the US FDA approved buprenorphine for the
treatment of opioid dependence. Treatment of heroin addicts was
limited to physicians with specialised training or experience and
limited to a maximum of 30 patients per physician.[3] Buprenorphine has been used in some European countries for a longer
period of time. In France, a high-dosage buprenorphine formulation has been marketed since 1996. While methadone was still
prescribed in specialised health centres, buprenorphine was
authorised for all registered practitioners and pharmacies.[4] In this
country, about 90 000 addicts are treated today with high-dosage
buprenorphine versus 25 000 with methadone.[5] The success of
the French heroin substitution programme was demonstrated by
the decrease of deaths due to heroin overdoses (from 465 in 1996
to 89 in 2003) and the decline of the arrests due to heroin use (from
17 328 to 4025 in the same period).[6,7] The public health benefits
experienced in France bring to question the value of the more
stringent regulations on prescribing buprenorphine imposed in
many other countries throughout the world.
Buprenorphine exhibits unique pharmacological properties and
has shown to be lacking of significant respiratory effects at therapeutic doses, both in experimental and clinical studies. However,
since its availability as a substitution therapy in humans, several
cases of severe respiratory depression and death have been reported in drug addicts. Our objective was to review the recent hypothesis on the mechanisms of the respiratory effects of buprenorphine
in the light of its pharmacology.
1. Pharmacological Properties
Buprenorphine is a semi-synthetic, highly lipophilic opioid
derived from thebaine. It is used as an analgesic (usual doses
[Temgesic]:1 0.3mg every 6 hours by intravenous or intramuscular routes or 0.4–0.8 mg/day sublingually) and as maintenance
therapy (high-dosage [Subutex]: 8–32 mg/day). Regarding its
analgesic properties, buprenorphine is 25–50 times more potent
than morphine.[8] It is considered a partial mu-opioid receptor
agonist and a weak kappa-receptor antagonist. It possesses a high
affinity for both receptors (1000 times higher than morphine),
resulting in a slow dissociation (K(i) in the subnanomolar range:
6.10–12 and 4.10–12 mol/L, respectively) and a long duration of
action.[9] Buprenorphine affinity for the delta receptors is lower
(K(i): 4.8.10–10 mol/L). The half-life for dissociation from the mureceptor is 166 minutes, compared with 7 minutes for fentanyl.[10]
These properties explain the slower onset and longer duration than
morphine. For example, intramuscular administration results in
peak respiratory effects at 3 hours and maximal miosis at 6 hours
in humans. Like naloxone, buprenorphine is able to antagonise the
1
respiratory depression induced by anaesthetic doses of fentanyl,
without preventing opioid pain relief.[11] Like all opioids, side
effects include sedation, nausea, vomiting, dizziness, sweating and
headaches. Similarly, when discontinued, a typical morphine-like
withdrawal syndrome develops with a delayed onset of 2–15 days.
Buprenorphine pharmacokinetic properties help explain its remarkable effects. High-dosage buprenorphine undergoes extensive first-pass hepatic metabolism, thus it is administered sublingually with a 60–70% bioavailability. Tissue distribution is
wide, with a peak plasma concentration at 90 minutes. Kinetics
follow a three-compartment model with a terminal elimination
half-life of 27 hours (values ranging from 3 to 44 hours), a
distribution volume of 48 L/kg, and a total clearance of 100 mL/
kg/min.[12] Cerebral distribution is important due to its lipophilic
properties (octanol/water partition coefficient: 1943 ± 50 and pKa:
8.42 ± 0.03). Buprenorphine is highly (96%) bound to plasma
proteins, mainly globulins. Buprenorphine is transformed in the
liver to inactive conjugated metabolites. However, its extensive Ndealkylation, catalysed by cytochrome P450 (CYP) 3A4, produces
an active metabolite called norbuprenorphine (figure 1).[13] Human
pharmacokinetic studies showed low plasma concentrations of
norbuprenorphine following buprenorphine administration, but
with peaks and elimination half-lives that markedly varied according to the routes of administration and among individuals.[12] Most
of buprenorphine (70–90%) is excreted in the faeces. Both Ndealkylated and conjugated metabolites are detected in the urine.
Various drugs that induce (antiepileptic drugs) or inhibit
(macrolides, azole-based antimycotic drugs and HIV protease
inhibitors) the CYP 3A4, may interfere with buprenorphine metabolism. However, their clinical implications remain unknown.
The relationship between buprenorphine plasma concentration and
response in the opioid-dependence treatment has not been studied.[12] Buprenorphine dosage does not need to be significantly
adjusted in patients with renal impairment; however, it is possible
that the metabolism of buprenorphine will be altered in patients
with severe chronic liver disease including decreased CYP3A
activity.
Finally, it is well known that buprenorphine is frequently
injected by users (around 33%), despite the labelling for sublingual use.[14,15] Thus, routine monitoring of buprenorphine misuse
may be warranted, needing the development of effective countermeasures to address diversion and injection in this setting.[16]
Consequently, a sublingual preparation (Suboxone) associating
buprenorphine and the poorly gastrointestinal-absorbed naloxone
(4 : 1 combination) has been marketed, aiming to limit diversion
by precipitating withdrawal symptoms, if parenterally self-injected by addicts.[17] The presence of naloxone does not appear to
influence the pharmacokinetics of buprenorphine.
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
n
atio
xyl
o
ydr
H
A7
,3
,
5
3A
4
3A
CH3
HO
8
C
,2
C
CH3
N-d
e
CH2OH
alk
CH3
YP
yla
tio
n
M1
C
HO
HO
HO
O
N-dealkylation
N
N
CYP3A5, 3A4, 3A7, 2C8
H3CO
O
Hydroxylation
O
NH
CYP3A4, 3A5
H3CO
H3CO
CH3
HO
CH3
C
HO
CH3
CH3
CH3
Buprenorphine
C
CH3
HO
CH3
CH3
M3
Norbuprenorphine
dro
xyl
atio
n
CH2OH
CH3
CH3
Hy
CH3
C
HO
HO
OH
OH
N-dealkylation
O
O
NH
N
H3CO
H3CO
CH3
HO
CH3
C
CH3
CH3
M2
CH3
HO
CH3
C
CH3
CH3
M4 (or M5)
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
Despite limited side effects, >100 cases of buprenorphinerelated fatalities have been reported in France.[18-23] Several other
cases were also reported in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden).[24] Similarly, an increase in
buprenorphine-related deaths has been identified since 1999 in the
UK.[25] Forensic reports consistently concluded that death resulted
from asphyxiation.[18-23] Fatality was usually associated with
buprenorphine intravenous misuse (intravenous injection of
crushed tablets) or concomitant sedative drug ingestion, such as
benzodiazepines. In one case, death was due to a massive oral
 2006 Adis Data Information BV. All rights reserved.
ingestion.[18] Poisonings are characterised by a high frequency of
multiple opiate/opioid association, as well as psychoactive drug
co-ingestion. In fatalities, as neither toxic nor lethal concentrations
of buprenorphine were available, forensic studies reported either
elevated or therapeutic blood concentrations (evaluated from
clinical studies in the range of 2–20 ng/mL).[21-23] However, systematic analysis of death causes revealed the difficulties in determining the role of substitution drugs in the death process, as many
other factors might be involved, including circumstances surrounding death, past history, differential selection of subjects into
either substitution modality and concomitant intake of other
drugs.[23] Moreover, as death caused by benzodiazepines in the
Toxicol Rev 2006; 25 (2)
82
Mégarbane et al.
absence of underlying disease is uncommon,[26] fatalities were
attributed in some cases to the association of buprenorphine and
benzodiazepines. However, as many addicts regularly use benzodiazepines in association with their maintenance therapies, the
mechanism of the deleterious interaction between buprenorphine
and benzodiazepines is questionable. The potential for synergistic
or additive actions by other psychoactive molecules, including
opioids, alcohol and neuroleptics should also be considered.
3. Respiratory Effects of Buprenorphine
The exact mechanism of buprenorphine acute toxicity remains
misunderstood. Respiratory depression is the suspected aetiology
of buprenorphine-related deaths. The majority of opioids induce a
dose-dependent respiratory depression in experimental models.[27]
In rats, morphine and methadone elicit the rapid onset of dosedependent respiratory acidosis and hypoxia.[28,29] In contrast, doseeffect relationships of buprenorphine suggest either limited effects
over a 0.008–3 mg/kg intravenous dose range[30] or a plateau of
respiratory effects due to its antagonist effects at higher
doses.[27,31,32] These results were confirmed by the absence of
significant effects on arterial blood gases after a single 3, 30, or 90
mg/kg buprenorphine infusion, compared with the solvent.[33] A
more recent study in volunteers showed that while the analgesic
effect of buprenorphine increased significantly when administering a dose from 0.2 to 0.4mg per 70kg, respiratory depression was
similar in magnitude and timing for the tested doses.[34] Buprenorphine caused depression of the minute ventilation, which levelled off at doses ≥3 µg/kg to about 50% of baseline. Irrespective
of the time at which measurements were obtained, buprenorphine
showed a modest non-linear effect on arterial carbon dioxide
tension (maximum value measured, 5.5 kPa), with a ceiling effect
at doses >1.4 µg/kg.[35] In another volunteer study, the carbon
dioxide response curves were depressed in a time-dependent,
prolonged and biphasic manner at various times up to 20 hours
after administration of epidural buprenorphine 0.15mg.[36]
This ‘ceiling effect’ was thought to confer in humans a high
safety profile, mild mental status changes, mild to minimal respiratory depression, small but not pinpoint pupils and relatively
normal vital signs.[3] In fact, since its availability as a maintenance
therapy, respiratory side-effects have been rarely reported, especially in office-based treatment of opioid dependence.[37] In contrast, in situations of abuse, typical features of severe opioid
poisoning (coma + miosis + respiratory depression) were described.[6,38,39] However, because of the retrospective data collection in these studies and the lack of systematic laboratory-confirmed poisonings, significant limitations make conclusions cautious, warranting further prospective observational studies.
Particularly in regard to the management of buprenorphine overdoses, where contradictory results appeared. Indeed, in one case
series, a rapid improvement of the patients using 0.4–0.8mg naloxone was reported,[38] whereas in a placebo-controlled study in
volunteers, no effects of 1mg naloxone on mild respiratory depression and non-immediate reversal despite higher doses were observed, once the effects have been produced.[40]
The exact mechanism of buprenorphine-induced respiratory
effects is unclear. In several fatal cases related to buprenorphine
overdoses, high plasma or tissue concentrations of norbuprenorphine were reported, suggesting its role in the onset of
death.[18-23] Norbuprenorphine, the main N-dealkylated buprenorphine metabolite, is a very potent respiratory depressor. Significant respiratory depression has been demonstrated following the
administration of a single intravenous dose of 3 mg/kg norbuprenorphine in rats.[41-43] However, it is unclear whether norbuprenorphine alone can fully explain buprenorphine-related deaths.
Recent experimental data in rats have shown that significant
quantities of norbuprenorphine can be detected in the plasma,
Mechanism of
reversion
Mechanism of
prevention
N
N
N
B
N
µ
δ
Respiratory
depression
N
N
B
µ
δ
Respiratory
depression
B
B
µ
δ
Respiratory
depression
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]
 2006 Adis Data Information BV. All rights reserved.
Toxicol Rev 2006; 25 (2)
Does High-Dose Buprenorphine Cause Respiratory Depression?
immediately after buprenorphine administration.[44] Different
mechanisms for the norbuprenorphine role were proposed, including a transient decrease in respiratory frequency, an early onset of
seizures, as well as a sustained muscle rigidity. However, in rats,
when buprenorphine and norbuprenorphine were co-administered,
buprenorphine completely prevented, as well as reversed
norbuprenorphine-induced respiratory effects.[43] Binding experiments suggested a role for mu- and to a lesser extent for deltaopioid receptors in buprenorphine protective effect against
norbuprenorphine-induced respiratory depression (figure 2). In
animals, significant protective effect was observed even when
norbuprenorphine exceeded buprenorphine concentrations in plasma,[43] whereas in the majority of reported human fatalities, buprenorphine exceeded norbuprenorphine concentrations.[18-23] Thus,
discrepancy between human and experimental data calls into
question the role of norbuprenorphine alone as the mechanism of
buprenorphine-associated death in humans.
Alteration of opioid receptor expression in the CNS may also
influence the respiratory effects of buprenorphine. A recent study
in rats using a β-imager clearly established that an acute buprenorphine administration induced a down-regulation of mu-opioid
receptors throughout the brain.[45] Whereas a single buprenorphine
administration induced no changes in kappa- or delta-opioid receptor binding, repeated administration up-regulated kappa-receptor density and decreased delta-receptor affinity.[46]
4. Mechanisms of Interaction with Benzodiazepines
Given the forensic data collected in addicts who died in relation
to buprenorphine use, a deleterious interaction between buprenorphine and benzodiazepines was hypothesised to explain acute
toxicity. The interaction between benzodiazepines and opioids
including buprenorphine and methadone has resulted in respiratory depression in both animal models and humans.[29,47,48] McCormick et al.[29] reported severe and long-lasting respiratory acidosis
in rats following the administration of diazepam 20 mg/kg subcutaneously, in association with methadone 5 mg/kg intraperitoneally, corresponding to one-tenth of the median lethal dose (LD50) of
each drug. Gueye et al.[33,48] showed that a single intravenous dose
of buprenorphine 30 mg/kg in rats did not result in any significant
effect on blood gases, while, in combination with an intraperitoneal dose of midazolam 140 mg/kg, it induced a rapid onset of
severe and sustained respiratory acidosis. Borron et al.[47] demonstrated, in a blinded randomised study, that flunitrazepam alters
buprenorphine lethality in rats, with a 6-fold decrease of its
intravenous LD50. However, the deleterious effect of the same
dose of flunitrazepam was opioid-specific, as flunitrazepam
caused only a 2-fold decrease in methadone LD50, with no significant effect on morphine LD50.
The exact mechanism of buprenorphine/benzodiazepine interaction remains to be clarified, resulting either from a pharmacoki 2006 Adis Data Information BV. All rights reserved.
83
Table I. The different possible levels of a pharmacodynamic interaction
between opioids (including buprenorphine) and benzodiazepines
Interaction at the level of breathing control
GABA and opioid receptors are co-expressed in the CNS including the
brain stem[54]
GABA and opioid receptors are implicated in the phasic and/or tonic
activity 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 receptors
at high concentrations[57,58]
Addition of various central and peripheral physiological effects
(A + B)
A. Benzodiazepines: command of the respiratory muscles and control of
the pharyngeal dilatation, resulting in: (i) upper-airway obstruction in
relation to relaxation of pharyngeal muscles; and (ii) diaphragmatic
dysfunction[59]
B. Opioids: reduction in the response to ventilation in different situations,
including: (i) resistance during inspiration; (ii) hypoxia; and (iii)
hypercapnia[60]
netic or from a pharmacodynamic process. The majority of the
studies analysing opioid/benzodiazepine interactions reported synergistic or at least additive hypnotic, analgesic and ventilatorydepressant effects based on pharmacodynamic interactions.
Regarding the respiratory effects of the buprenorphine/
benzodiazepine combination, a pharmacokinetic mechanism cannot be excluded. Interestingly, in rodents, diazepam was demonstrated to inhibit the metabolism of methadone, even though such a
kinetic interaction is lacking in humans.[49,50] Recent unpublished
data obtained in our laboratory showed that buprenorphine significantly altered the kinetics of desmethylflunitrazepam, the metabolite of flunitrazepam, suggesting the likelihood of interaction of
buprenorphine with the distribution of flunitrazepam (unpublished
data). However in vitro studies failed to demonstrate any significant P450 cytochrome-mediated metabolic interactions between
buprenorphine and flunitrazepam.[51,52] Moreover, in a study using
cerebral microdialysis in rats, flunitrazepam pre-administration
did not alter the distribution kinetics of buprenorphine in the
striatum.[53] Thus, the main hypothesis regarding the respiratory
effects of the buprenorphine/benzodiazepine combination relies
on a pharmacodynamic basis.
Different mechanisms of interaction regarding respiratory effects may be hypothesised due to common pathways and sites of
action (table I). Opioids and benzodiazepines act in combination
with different classes of the opioid and the GABA receptors. All
these receptors are co-expressed in the CNS, including in the areas
of ventilation control.[54] Both GABA and opioid systems play an
important role in both phasic and tonic activity of the neurons that
control the ventilation.[55] Interestingly, these receptors use comToxicol Rev 2006; 25 (2)
84
Mégarbane et al.
mon intracellular transduction pathways such as the Gi/o protein.[56] Regarding opioid receptors, however, only limited interactions of benzodiazepines have been reported, especially at very
high concentrations such as those observed after intrathecal administration.[57,58] Drug-induced coma involving benzodiazepines
is characterised by snoring with flow limitation and obstructive
apnoea.[59] The mechanism of respiratory insufficiency in nonintubated patients with drug-induced coma involving benzodiazepines is an increase in upper airway resistance and work of
breathing. The interaction of sleep and opioid administration produces well known disturbances in the ventilatory pattern, causing
profound oxygen destruction.[60] Regarding the buprenorphine/
benzodiazepine interaction, we suggest that buprenorphine may
alter the response of the brain-stem respiratory centres to the
benzodiazepine-induced increase in the upper-airway resistance.
This hypothetic mechanism of interaction has yet to be elucidated
and appropriate animal models and techniques, such as plethysmography, should be utilised to further our current understanding.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
5. Conclusion
Buprenorphine is an efficient and safe maintenance therapy. Its
marketing in several European countries was responsible for a
significant decrease in heroin-associated deaths. However, due to
diversion, misuse and co-ingestions of various other psychotropic
drugs in addicts, the specific ceiling effect observed in clinical
studies may be altered, resulting in severe respiratory depression
and even death. To date, >100 deaths have been attributed to
buprenorphine use in France, the UK and the Nordic European
countries. A deleterious interaction between buprenorphine and
benzodiazepines was hypothesised, based on experimental studies.
It appears that this interaction is more likely to be a pharmacodynamic (additive or synergistic) than a pharmacokinetic interaction.
However, the exact mechanism of buprenorphine respiratory toxicity remains to be determined.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Acknowledgements
The authors would like to acknowledge Dr Rebeca Gracia, PharmD,
DABAT, from the North Texas Poison Center, Dallas, USA for her helpful
review of this manuscript.
No source of funds was used to assist in the preparation of this manuscript.
The authors are not aware of any potential conflicts of interest directly relevant
to the content of this review.
26.
27.
28.
29.
References
1. Darke S, Zador D. Fatal heroin ’overdose’: a review. Addiction 1996; 91: 1765-72
2. Warner-Smith M, Darke S, Lynskey M, et al. Heroin overdose: causes and
consequences. Addiction 2001; 96: 1113-25
3. Sporer KA. Buprenorphine: a primer for emergency physicians. Ann Emerg Med
2004; 43: 580-4
4. Auriacombe M, Fatseas M, Dubernet J, et al. French field experience with
buprenorphine. Am J Addict 2004; 13 Suppl. 1: S17-28
5. Feroni I, Aubisson S, Bouhnik AD, et al. Collaboration between general practitioners and pharmacists in the management of patients on high-dosage bupre 2006 Adis Data Information BV. All rights reserved.
30.
31.
32.
33.
norphine treatment: prescribers’ practices [in French]. Presse Med 2005; 34:
1213-9
Gueye PN, Mégarbane B, Borron SW, et al. Trends in opiate and opioid poisonings
in addicts in north-east Paris and suburbs, 1995-99. Addiction 2000; 97:
1295-304
Emmanuelli J, Desenclos JC. Harm reduction interventions, behaviors and associated health outcomes in France, 1996-2003. Addiction 2005; 100: 1690-700
Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman J, Limbird
L, Molinoff P, et al., editors. Goodman & Gilman’s the pharmacological basis
of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 521-55
Huang P, Kehner GB, Cowan A, et al. Comparison of pharmacological activities of
buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid
agonist. J Pharmacol Exp Ther 2001; 297: 688-95
Boas RA, Villiger JW. Clinical actions of fentanyl and buprenorphine: the significance of receptor binding. Br J Anaesth 1985; 57: 192-6
Boysen K, Hertel S, Chraemmer-Jorgensen B, et al. Buprenorphine antagonism of
ventilatory depression following fentanyl anaesthesia. Acta Anaesthesiol Scand
1988; 32: 490-2
Elkader A, Sproule B. Buprenorphine: clinical pharmacokinetics in the treatment
of opioid dependence. Clin Pharmacokinet 2005; 44: 661-80
Chang Y, Moody DE, McCance-Katz EF. Novel metabolites of buprenorphine
detected in human liver microsomes and human urine. Drug Metab Dispos
2006; 34: 440-8
Obadia Y, Perrin V, Feroni I, et al. Injecting misuse of buprenorphine among
french drug users. Addiction 2001; 96: 267-72
Comer SD, Collins ED, Fischman MW. Intravenous buprenorphine self-administration by detoxified heroin abusers. J Pharmacol Exp Ther 2001; 301: 266-76
Jenkinson RA, Clark NC, Fry CL, et al. Buprenorphine diversion and injection in
Melbourne, Australia: an emerging issue? Addiction 2005; 100: 197-205
Robinson GM, Dukes PD, Robinson BJ, et al. The misuse of buprenorphine and a
buprenorphine-naloxone combination in Wellington, New Zealand. Drug Alcohol Depend 1993; 33: 81-6
Reynaud M, Tracqui A, Petit G, et al. Six deaths linked to misuse of buprenorphine-benzodiazepine combinations. Am J Psychiatry 1998; 155: 448-9
Tracqui A, Kintz P, Ludes B. Buprenorphine-related deaths among drug addicts in
France: a report on 20 fatalities. J Anal Toxicol 1998; 22: 430-4
Gaulier JM, Marquet P, Lacassie E, et al. Fatal intoxication following selfadministration of a massive dose of buprenorphine. J Forensic Sci 2000; 45:
226-8
Kintz P. Deaths involving buprenorphine: a compendium of French cases. Forensic
Sci Int 2001; 121: 65-9
Kintz P. A new series of 13 buprenorphine-related deaths. Clin Biochem 2002; 35:
513-6
Pirnay S, Borron SW, Giudicelli CP, et al. A critical review of the causes of death
among post-mortem toxicological investigations: analysis of 34 buprenorphineassociated and 35 methadone-associated deaths. Addiction 2004; 99: 978-88
Steentoft A, Teige B, Holmgren P, et al. Fatal poisoning in Nordic drug addicts in
2002. Forensic Sci Int 2006; 160 (2-3): 148-56
Schifano F, Corkery J, Gilvarry E, et al. Buprenorphine mortality, seizures and
prescription data in the UK, 1980-2002. Hum Psychopharmacol 2005; 20:
343-8
Serfaty M, Masterton G. Fatal poisonings attributed to benzodiazepines in Britain
during the 1980s. Br J Psychiatry 1993; 163: 386-93
Cowan A, Doxey J, Harry E. The animal pharmacology of buprenorphine, an
oripavine analgesic agent. Br J Pharmacol 1977; 60: 547-54
Verborgh C, De Coster R, D’Haese J, et al. Effects of chlordiazepoxide on opioidinduced antinociception and respiratory depression in restrained rats.
Pharmacol Biochem Behav 1998; 59: 663-70
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 to
methadone. J Pharmacol Exp Ther 1984; 230: 353-9
Ohtani M, Kotaki H, Nishitateno K, et al. Kinetics of respiratory depression in rats
induced by buprenorphine and its metabolite, norbuprenorphine. J Pharmacol
Exp Ther 1997; 281: 428-33
Walsh SL, Preston KL, Stitzer ML, et al. Clinical pharmacology of buprenorphine:
ceiling effects at high doses. Clin Pharmacol Ther 1994; 55: 569-80
Nielsen S, Taylor DA. The effect of buprenorphine and benzodiazepines on
respiration in the rat. Drug Alcohol Depend 2005; 79: 95-101
Gueye PN, Borron SW, Risède P, et al. Lack of effect of single high doses of
buprenorphine on arterial blood gases in the rat. Toxicol Sci 2001; 62: 148-54
Toxicol Rev 2006; 25 (2)
Does High-Dose Buprenorphine Cause Respiratory Depression?
34. Dahan A, Yassen A, Romberg R, et al. Buprenorphine induces ceiling in respiratory depression but not in analgesia. Br J Anaesth 2006; 96: 627-32
35. Dahan A, Yassen A, Bijl H, et al. Comparison of the respiratory effects of
intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth 2005;
94: 825-34
36. Molke Jensen F, Jensen NH, Holk IK, et al. Prolonged and biphasic respiratory
depression following epidural buprenorphine. Anaesthesia 1987; 42: 470-5
37. Cicero TJ, Inciardi JA. Potential for abuse of buprenorphine in office-based
treatment of opioid dependence. N Engl J Med 2005; 353: 1863-4
38. Rainey HB. Abuse of buprenorphine. N Z Med J 1986; 99: 72
39. Boyd J, Randell T, Luurila H, et al. Serious overdoses involving buprenorphine in
Helsinki. Acta Anaesthesiol Scand 2003; 47: 1031-3
40. Gal TJ. Naloxone reversal of buprenorphine-induced respiratory depression. Clin
Pharmacol Ther 1989; 45: 66-71
41. Ohtani M, Kotaki H, Uchino K, et al. Pharmacokinetic analysis of enterohepatic
circulation of buprenorphine and its active metabolite, norbuprenorphine, in
rats. Drug Metab Dispos 1994; 22: 2-7
42. Ohtani M, Kotaki H, Sawada Y, et al. Comparative analysis of buprenorphine- and
norbuprenorphine-induced analgesic effects based on pharmacokinetic-pharmacodynamic modeling. J Pharmacol Exp Ther 1995; 272: 505-10
43. Mégarbane B, Marie N, Pirnay S, et al. Buprenorphine is protective against the
depressive effects of norbuprenorphine on ventilation. Toxicol Appl Pharmacol
2006; 212: 256-67
85
49. Shah N, Patel V, Donald A. Effect of diazepam, desmethylimipramine, and SKF
525-A on the disposition of levo-methadone in mice after single or double
injection. Drug Metab Dispos 1979; 7: 241-2
50. Pond SM, Tong TG, Benovitz NL, et al. Lack of effect of diazepam on methadone
metabolism in methadone-maintained addicts. Clin Pharmacol Ther 1982; 31:
139-43
51. Ibrahim RB, Wilson JG, Thorsby ME, et al. Effect of buprenorphine on CYP3A
activity in rat and human liver microsomes. Life Sci 2000; 66: 1293-8
52. Kilicarslan T, Sellers EM. Lack of interaction of buprenorphine with flunitrazepam
metabolism. Am J Psychiatry 2000; 157: 1164-6
53. Mégarbane B, Pirnay S, Borron SW, et al. Flunitrazepam does not alter cerebral
distribution of buprenorphine in the rat. Toxicol Lett 2005; 157: 211-9
54. Kalyuzhny AE, Dooyema J, Wessendorf MW. Opioid- and GABA(A)-receptors
are co-expressed by neurons in rat brain. Neuroreport 2000; 11: 2625-8
55. Yamada KA, Norman WP, Hamosh P, et al. Medullary ventral surface GABA
receptors affect respiratory and cardiovascular function. Brain Res 1982; 248:
71-8
56. Dan’ura T, Kurokawa T, Yamashita A, et al. Inhibition of rat brain adenylate
cyclase activity by benzodiazepine through the effects on Gi and catalytic
proteins. Life Sci 1988; 42: 469-75
57. Yanez A, Sabbe MB, Stevens CW, et al. Interaction of midazolam and morphine in
the spinal cord of the rat. Neuropharmacology 1990; 29: 359-64
44. Gopal S, Tzeng TB, Cowan A. Characterization of the pharmacokinetics of
buprenorphine and norbuprenorphine in rats after intravenous bolus administration of buprenorphine. Eur J Pharm Sci 2002; 15: 287-9
58. Cox RF, Collins MA. The effects of benzodiazepines on human opioid receptor
binding and function. Anesth Analg 2001; 93: 354-8
45. Debruyne D, Quentin T, Poisnel G, et al. Acute and chronic administration of
clorazepate modifies the cell surface regulation of mu opioid receptors induced
by buprenorphine in specific regions of the rat brain. Brain Res 2005; 1052:
222-31
59. Gueye PN, Lofaso F, Borron SW, et al. Mechanism of respiratory insufficiency in
pure or mixed drug-induced coma involving benzodiazepines. J Toxicol Clin
Toxicol 2002; 40: 35-47
46. Quentin T, Debruyne D, Lelong-Boulouard V, et al. Clorazepate affects cell
surface regulation of delta and kappa opioid receptors, thereby altering buprenorphine-induced adaptation in the rat brain. Brain Res 2005; 1063: 84-95
47. Borron SW, Monier C, Risède P, et al. Flunitrazepam variably alters morphine,
buprenorphine, and methadone lethality in the rat. Hum Exp Toxicol 2002; 21:
599-605
48. Gueye PN, Borron SW, Risède P, et al. Buprenorphine and midazolam act in
combination to depress respiration in rats. Toxicol Sci 2002; 65: 107-14
 2006 Adis Data Information BV. All rights reserved.
60. Catley DM, Thornton C, Jordan C, et al. Pronounced, episodic oxygen desaturation
in the postoperative period: its association with ventilatory pattern and analgesic regimen. Anesthesiology 1985; 63: 20-8
Correspondence and offprints: Bruno Mégarbane, Réanimation Médicale et
Toxicologique, Hôpital Lariboisière, 2 Rue Ambroise Paré, 75010 Paris,
France.
E-mail: [email protected]
Toxicol Rev 2006; 25 (2)