Lack of Effect of Single High Doses of Buprenorphine on Arterial Blood Gases in the Rat

Abstract

High dose buprenorphine, a potent semisynthetic agonist-antagonist for opiate receptors, is now used in substitution treatment of human heroin addiction. Deaths have been reported in addicts misusing buprenorphine. We determined the median lethal dose (LD(50)) and studied the effects of high doses of intravenous buprenorphine on arterial blood gases in rats. Male Sprague-Dawley rats were administered buprenorphine intravenously to determine the LD(50) using the up-and-down method. Subsequently, catheterized groups of 10 restrained rats received no drug, saline, acid-alcohol aqueous solvent (required to dissolve buprenorphine at a high concentration), or 3, 30, or 90 mg/kg of buprenorphine intravenously. Serial arterial blood gases were obtained over 3 h. The LD(50) determined in triplicate was 146.5 mg/kg (median of 3 series, range: 142.6-176.5). The mean dose received by surviving animals was 96.9 +/- 46.7 mg/kg. There was a significant effect of the acid-alcohol aqueous solvent on arterial blood gases. Excluding the solvent effect, 3, 30, and 90-mg/kg buprenorphine doses had no significant effects on arterial blood gases. The toxicity of intravenous buprenorphine in adult rats, assessed by the LD(50), is low. These data are consistent with a wide margin of safety of buprenorphine. The mechanism of death after the intravenous administration of a lethal dose of buprenorphine remains to be determined.

Effects of buprenorphine on body temperature, locomotor activity and cardiovascular function when assessed by telemetric monitoring in rats

“…However, no signs of arrhythmia or changes in the ECG complex were observed. The administered doses of buprenorphine in this study were well tolerated and toxic/ pharmacological effects were minor in comparison with those effects reported to be associated with a high intake of buprenorphine in which severe adverse effects and Figure 9 Effects on body temperature and heart rate -1 -6 h after a single subcutaneous administration of buprenorphine at 0.03 mg/kg body weight in conscious rats Figure 8 Effects on body temperature and heart rate 0 -7 h after a single subcutaneous administration of saline (NaCl) in conscious rats response patterns develop, including respiratory depression and death (Gueye et al 2001). It was intriguing to note how well spontaneous locomotor activity, body temperature, heart rate and blood pressure changes followed each other in the saline-treated rats.…”

Toxicological and pathological findings in a series of buprenorphine related deaths. Possible risk factors for fatal outcome

“…The ceiling effect of the negative responses to buprenorphine has been extensively studied [36][37][38][39]. It has been shown in animal studies that buprenorphine itself does not cause respiratory depression at elevated doses [2] and even that it has a protective role against the effects of its metabolite, norbuprenorphine [40]. Norbuprenorphine formation is catalyzed by CYP3A4 and to some extent CYP2C8/9 [41,42] and variations in enzyme activity might be important in the overall pharmacology of buprenorphine.…”

“…produce a ''ceiling effect'' for respiratory depression even at higher doses. This has been shown in animal studies [2]. Still, there are several reports on buprenorphine related deaths that points in another direction and many of these cases present with buprenorphine concentrations in the therapeutic range [3][4][5][6][7][8][9][10][11].…”

Development and validation of a gas chromatography–mass spectrometry method for the simultaneous determination of buprenorphine, flunitrazepam and their metabolites in rat plasma: application to the pharmacokinetic study

“…; Dow Corning, Midland, MI, USA). The catheters were then tunneled subcutaneously and fixed at the back of the neck [35]. The rats were given at least a 24 h recovery period to allow for washout of anaesthesia.…”

“…Immediately after, the rats were given a dose of 40 mg/kg FNZ (Hoffmann-LaRoche, Neuilly-sur-Seine, France), also in a volume of 1.3 ml, by intravenous perfusion over 30 min and at a rate of 43.3 l/min. Drug solutions were freshly prepared: BUP, 18.2 mg/ml, was prepared in a mixture of sterile water and ethanol (8.5% (v/v)) adjusted to pH 5.2 with HCl 0.1 M [35]; FNZ, 10.0 mg/ml, was prepared in a mixture of sterile water and Tween-80 (20% (v/v)) [14]. Prior to injection, the solutions were diluted with sterile water to adjust the doses of BUP and FNZ to the weight of each rat.…”