Buprenorphine is protective against the depressive effects of norbuprenorphine on ventilation
Introduction
Heroin addiction is still responsible for large numbers of deaths (Henry, 1999). Substitution therapies, including methadone, levomethadyl acetate, and buprenorphine, provide successful maintenance therapy, with a substantial reduction in consumption of illicit opiate and psychoactive substances (Johnson et al., 2000). Since 1996, high dose (8–16 mg/day) of buprenorphine has been available in France as a substitution product for heroin addiction (Obadia et al., 2001, Gueye et al., 2002a). More recently, the US Food and Drug Administration approved buprenorphine as a maintenance therapy, suggesting a future large expansion of prescriptions on the American continent (Sporer, 2004). In spite of an estimated 90,000 patients treated actively with buprenorphine in France, the number of significant reported side effects has been limited. However, fatal cases have been reported in relation to buprenorphine “overdoses.” Forensic studies concluded that these deaths were due to asphyxia, with the underlying cause attributed to misuse and/or co-administration of psychotropic substances (Tracqui et al., 1998, Gaulier et al., 2000, Kintz, 2001, Kintz, 2002, Pirnay et al., 2004). It is well known that buprenorphine is injected by some users, in spite of the labeling for sublingual use (Obadia et al., 2001, Comer et al., 2001, Kintz, 2002).
The exact mechanism of buprenorphine respiratory toxicity is still misunderstood. Experimental and clinical studies clearly demonstrate a dose–effect relationship for respiratory depression with a definite plateau (Cowan et al., 1977, Walsh et al., 1994, Ohtani et al., 1997). In a recent study, we showed that a single intravenous high dose of buprenorphine (up to 90 mg/kg), administered alone to naive rats, did not result in significant respiratory depression, whereas co-administration of a non-respiratory-depressant dose of midazolam (160 mg/kg, i.p.) significantly altered arterial blood gases (Gueye et al., 2002b).
Norbuprenorphine is an active metabolite derived from the N-dealkylation of buprenorphine, catalyzed in humans by cytochrome P450 (CYP) 3A4, mainly in the liver (Iribarne et al., 1997, Kobayashi et al., 1998). Human pharmacokinetic studies showed low plasma concentrations of norbuprenorphine following buprenorphine administration, but with peaks and elimination half-lives which varied markedly according to the routes of administration and among individuals (Kuhlman et al., 1996). 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 (Tracqui et al., 1998, Gaulier et al., 2000, Kintz, 2001, Kintz, 2002, Pirnay et al., 2004). It is unclear whether norbuprenorphine alone can fully explain buprenorphine-related deaths. Indeed, buprenorphine CYP-mediated transformation into norbuprenorphine may be influenced in drug users by interactions with co-ingested psychoactive substances or otherwise altered by the modalities of abuse. Drugs that induce CYP3A, such as phenobarbital, carbamazepine, and phenytoin, could increase norbuprenorphine levels (Sporer, 2004). However, the clinical effects of these interactions are unknown. Recent experimental data in rats have shown that significant quantities of norbuprenorphine can be detected in the plasma, immediately after buprenorphine administration (Gopal et al., 2002), in contradiction to previous studies (Ohtani et al., 1994, Ohtani et al., 1995). Furthermore, significant respiratory depression has been demonstrated following the administration of a single intravenous dose of 3 mg kg−1 norbuprenorphine in rats (Ohtani et al., 1997).
To date, the acute toxicity and respiratory effects of norbuprenorphine are poorly understood. To address this issue, we undertook a series of studies, looking at the median lethal dose (LD50) of intravenous norbuprenorphine and the effects of high dose of norbuprenorphine alone or in combination with buprenorphine on arterial blood gases in adult rats.
Section snippets
Materials and methods
All experiments were carried out within the ethical guidelines established by the National Institutes of Health and the French Minister of Agriculture.
Study 1: determination of norbuprenorphine median lethal dose
The median lethal doses were 10, 12, and 7 mg kg−1 in the three series. The median value of the LD50 was 10 mg kg−1. The mean delay to death was 8 ± 4 h (extremes: 0.7–48 h). Deep coma and apnea were the apparent cause of death.
Clinical signs
Control animals receiving aqueous solvent remained alert during the whole study period. Animals receiving 3 mg kg−1 norbuprenorphine were all sedated and exhibited muscle rigidity. Among them, one died 20 min after norbuprenorphine administration. Animals receiving 9 mg
Discussion
The majority of opioids induce a dose-dependent respiratory depression (Cowan et al., 1977). In rats, morphine and methadone elicit the rapid onset of dose-dependent respiratory acidosis and hypoxia (Verborgh et al., 1998, McCormick et al., 1984). In contrast, buprenorphine has limited effects over a 0.008–3 mg kg−1 intravenous dose range (Ohtani et al., 1997). Furthermore, we showed the absence of significant effects on blood gases after a single 3, 30, or 90 mg kg−1 buprenorphine infusion, in
Acknowledgment
B. Mégarbane received grant support from the Fondation pour la Recherche Médicale and from the Mission Interministerielle de Lutte contre les Drogues et la Toxicomanie (MILDT).
This study was presented in part at the 22nd Congress of the European Association of Poisons Centers and Clinical Toxicologists, Rome, Italy, May 2002.
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Contributed equally to this work.