The effect of buprenorphine and benzodiazepines on respiration in the rat

Abstract

Methadone and buprenorphine are the two main opioid substitution treatments for heroin dependence currently offered in Australia. A number of publications have implicated buprenorphine as being potentially dangerous in combination with benzodiazepines but no comparison has been made to the relative dangers of benzodiazepines combined with buprenorphine or methadone. The effect of i.v. methadone and buprenorphine on respiration was investigated by evaluating arterial blood pCO_2, pO₂ and pH, and measuring respiratory rate in rats. Measurements were taken at 0, 15, 30, 60, 120, 180 and 240 min after i.v. administration of methadone or buprenorphine. Effects on respiration were greatest 15 min after i.v. drug administration. The effect of methadone and buprenorphine on respiration was compared with and without diazepam pretreatment (20 mg/kg). Buprenorphine alone exhibited a bell shaped dose response inhibition of respiration; however the plateau of the dose response inhibition on respiration was lost when administered in combination with diazepam. Methadone showed a dose-dependent inhibitory effect on respiration, which was potentiated with diazepam pretreatment. While the effect of diazepam pretreatment was the abolishment of the protective bell shaped dose response effect on respiration, the effect of buprenorphine and diazepam was not greater than methadone and diazepam.

Introduction

Since the introduction of buprenorphine as a substitution therapy in the treatment of opioid dependence its benefits and effectiveness have been widely documented (Johnson et al., 1992, Kosten et al., 1993, Strain et al., 1994, Ling et al., 1996, Ling et al., 1998, Schottenfeld et al., 1997, West et al., 2000, Barnett et al., 2001). The advantages of buprenorphine are both in its unique pharmacology as well as becoming another treatment option alongside methadone. Buprenorphine, being a partial agonist at the μ opioid receptor, has been demonstrated to have a low ability to produce respiratory depression (Walsh et al., 1994). For this reason it is considered safer than a full opioid agonist such as methadone. Unfortunately, there have been a series of buprenorphine-related deaths in France (Reynaud et al., 1998, Tracqui et al., 1998b, Gaulier et al., 2000, Kintz, 2001, Kintz, 2002). Benzodiazepines, a highly abused class of prescription medication have also been implicated in the majority of these deaths, with benzodiazepine use frequently being reported in this population (Thirion et al., 2001, Darke et al., 2003). Prior to this, the interaction between buprenorphine and benzodiazepines causing respiratory depression in a peri-operative setting had also been well documented (Faroqui et al., 1983, Forrest, 1983, Sekar and Mimpriss, 1987, Thorn et al., 1988, Jain and Shah, 1993). While there is anecdotal evidence suggesting an interaction exists between buprenorphine and benzodiazepines, whether the interaction is potentially more dangerous than the effect of methadone and benzodiazepines has not been evaluated.

Opioid receptors have a high density within the brain stem, the region of the brain involved in control of respiration (Wamsley, 1983). The ability of opioids to cause severe respiratory depression is attributed to this. Only a small number of benzodiazepines receptors are located in the medulla hence benzodiazepines on their own have a limited effect on respiration (Study and Barker, 1982). The exact mechanism of the interaction between opioids and benzodiazepines is not known.

Research with methadone and diazepam in rats, using methadone 5 mg/kg and diazepam 20 mg/kg in both acute and chronic dosing paradigms has established that the most severe respiratory depression occurs when a subject is naïve to both opiates and benzodiazepines. Tolerance develops to the respiratory depression induced by both methadone and diazepam (McCormick et al., 1984). In contrast to the reduction in respiration seen with methadone, high doses of buprenorphine have been reported to have no significant effect on arterial blood gases in the rat (Gueye et al., 2001), however when combined with midazolam the combination depressed ventilation (Gueye et al., 2002b). In opioid naïve rats flunitrazepam was found to cause a six-fold reduction in the median lethal dose (MLD) of buprenorphine while combined with methadone, flunitrazepam only caused a two-fold reduction in the methadone MLD (Borron et al., 2002).

The aim of this study is to evaluate the respiratory depressant effect of methadone and buprenorphine alone and in combination with diazepam in order to characterise and compare the interaction to gain an understanding of whether buprenorphine or methadone appears to be more toxic in combination with benzodiazepines.