Deaths involving buprenorphine: a compendium of French cases

doi:10.1016/S0379-0738(01)00454-6

Forensic Science International

Volume 121, Issues 1–2, 15 September 2001, Pages 65-69

https://doi.org/10.1016/S0379-0738(01)00454-6 Get rights and content

Abstract

Buprenorphine at high dosage became available in France in 1996, as a substitution treatment for heroin addicts. Since this date, numerous deaths were attributed to this drug. This paper reports two original series of 39 and 78 fatalities involving buprenorphine observed at the Institute of Legal Medicine of Strasbourg and at 13 other French forensic centers, respectively. The files were recorded from January 1996–May 2000. The first 20 fatalities that were previously published were excluded from this epidemiological study. From these 117 subjects, 96 were male (82%). Buprenorphine and its primary metabolite norbuprenophine were assayed in post-mortem blood by HPLC/MS (n=11 labs) or by GC/MS (n=3 labs). Blood levels for buprenorphine ranged from 0.5 to 51.0 ng/ml (mean 10.2 ng/ml) and 0.1 to 76 ng/ml (mean 12.6 ng/ml) in Strasbourg and the other centers, respectively. Blood levels for norbuprenorphine ranged from 0.2 to 47.1 ng/ml (mean 8.2 ng/ml) and <0.1 to 65 ng/ml (mean 10.6 ng/ml) in Strasbourg and the other centers, respectively. The mean values appear to be within the therapeutic range. Buprenorphine was identified in 24 of the 26 hair samples assayed in Strasbourg, at concentrations ranging from 10 to 1080 pg/mg. Intravenous injection of crushed tablets, a concomitant intake of psychotropics (especially benzodiazepines and neuroleptics) and the high dosage of the buprenorphine formulation available in France appear as the major risk factors for such fatalities. In addition, two suicide-related deaths were also observed, with blood buprenorphine concentrations at 144 and 3276 ng/ml.

Introduction

Buprenorphine is a semisynthetic opioid derivative, closely related to morphine which is obtained from thebaine after a seven-step chemical procedure. At low doses (typically 0.3–0.6 mg intravenous or intramuscular), buprenorphine is a powerful analgesic, 25–40 times more potent than morphine, with mixed agonist/antagonist activity on central receptors. The drug is a partial mu receptor agonist and a kappa receptor antagonist. It shows a very slow dissociation from opiate receptors and consequently has a duration of action of at least 24 h. Buprenorphine is weakly antagonized by naloxone [1], [2].

Buprenorphine is characterized by a weak oral bioavailability and low therapeutic concentrations, owing to its high lipid solubility. Its main metabolite is desalkyl-buprenorphine or norbuprenorphine and both drugs are glucuro-conjugated.

Following a single 0.4 mg sublingual dose, Bullingham et al. reported plasma concentrations of buprenorphine in the range 0.45 to 0.84 ng/ml [3]. According to Kuhlman et al. [4], average peak plasma concentrations of 3.31 ng/ml (range 1.93–7.19 ng/ml) and 1.98 ng/ml (range 0.25–3.90 ng/ml) were observed for buprenorphine in six subjects given 4.0 mg sublingual and buccal, respectively.

Under the tradename Temgesic^® at dosages of 0.2 mg, buprenorphine has been widely prescribed for about 20 years for the treatment of moderate to severe pain as well as in anaesthesiology for the premedication and/or anaesthetic induction.

More recently it has been also recognized as a medication of interest for the substitutive management of opiate-dependent individuals. Under the tradename Subutex^®, a high-dosage formulation (0.4, 2, and 8 mg tablets for sublingual use) is available in France since February 1996 in this specific indication. Contrary to methadone, delivered on a daily basis in specific centers and continuous survey of the patient by urine analysis achieved each week, Subutex^® may be ordered by any physician up to 28 days, and is supplied by any pharmacist. Patients are not entailed to take the drug in presence of the physician or pharmacist. Urine controls are not mandatory, and in practice are almost never realized.

Today, this drug is largely used in France for the treatment of about 60 000 heroin addicts, but can also be easily found on the black market.

From a general point of view, this substitution program can be considered as successful. The number of fatal heroin overdoses has dramatically dropped during the last years, from about 500 cases per year to less than 100 in 1999.

However, since the first buprenorphine fatality observed by Tracqui et al. [5] in August 1996, several cases were recorded by the French toxicologists. In 1998, Tracqui et al. [6] published a series of 20 fatalities collected from five centers. In all cases, a concomitant intake of psychotropics (mostly benzodiazepines) was observed.

Besides other sources of information (drug enforcement services, customs, intensive care units, etc.), the epidemiological data collected from forensic toxicologists may be of value to follow the evolutions of narcotic deaths in the course of time.

This paper presents the results of a new retrospective survey on buprenorphine-related deaths in the region of Strasbourg from March 1998–July 2000 and from 13 different forensic centers of France from mid 1996–March 2000.

Section snippets

Subjects

Thirty nine from about 1200 postmortem examinations at the laboratory of toxicology from the Institute of Legal Medicine of Strasbourg were positive for buprenorphine in blood during the mentioned period. Hair specimens were available in 26 cases. In all cases, autopsies revealed signs of asphyxia (cyanosis, multivisceral congestion, pulmonary oedema, etc.) but showed no signs of violence. No other cause of death could be established by experienced pathologists.

Data from other centers were

Results

Generally, when interpreting a blood concentration from a postmortem case, the toxicologist can find helpful informations in databases presenting therapeutic, toxic and lethal concentrations. Unfortunately, there is quite no suitable references in the literature, that is very poor for buprenorphine. At best, therapeutic concentrations can be evaluated from clinical studies in the range 2–20 ng/ml [10]. No toxic nor lethal concentrations are available, as this drug seems to be a typical French

Discussion

Fatalities involving buprenorphine alone seem very unusual: in these series, all cases but one involved a concomitant intake of psychotropics. In this unique case, the cause of death was listed as tracheobronchial inhalation (Mendelsson’ syndrome). The blood buprenorphine concentration was 0.8 ng/ml. Benzodiazepines ranked first in association, since they were present in 91 observations (from which 64 with nordiazepam). The role of associated benzodiazepines had been previously emphasized in

Conclusion

This paper has presented an original compendium of 117 fatalities attributed to buprenorphine overdosage that completes the 20 first cases previously observed and recorded in France since the introduction of a high-dosage formulation devoted to the substitution of opiate addicts. This seems to be a specific French problem, as no other deaths were reported anywhere else.

The risks incurred by the misuse of buprenorphine seem to arise through a combination of two practices: (1) association of

Acknowledgements

The author would like to thank the following scientists for sharing their data: Cathala Philippe, Cirimele Vincent, Deveaux Marc, Dumestre Véronique, Eysseric Hélène, Ghysel Marie-Hélène, Goullé Jean-Pierre, Lachatre Gérard, Lacroix Christian, Lebouil Anne, Ludes Bertrand, Marquet Pierre, Mathieu-Daudé Jean-Claude, Mura Patrick, Pépin Gilbert, Ricordel Ivan, Tracqui Antoine and Wennig Robert.

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Deaths involving buprenorphine: a compendium of French cases

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Conclusion

Acknowledgements

Buprenorphine: a review of its pharmacological properties and therapeutic efficacy

Drugs

Agonist and antagonist properties of buprenorphine: a new anti-nociceptive agent

Br. J. Pharm.

Sublingual buprenorphine used postoperatively: 10 h plasma drug concentration analysis

Br. J. Clin. Pharmacol.

Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine

J. Anal. Toxicol.

Intoxications mortelles par buprénorphine (Subutex®) et benzodiazépines: 4 cas

J. Med. Leg. Droit Méd.

Buprenorphine-related deaths among drug addicts in France: a report on 20 fatalities

J. Anal. Toxicol.

HPLC/MS determination of buprenorphine and norbuprenorphine in biological fluids and hair samples

J. Foren. Sci.

Intoxications mortelles par buprénorphine (Subutex^®) et benzodiazépines: 4 cas