Intravenous buprenorphine and norbuprenorphine pharmacokinetics in humans

Abstract

Background

Prescribed sublingual (SL) buprenorphine is sometimes diverted for intravenous (IV) abuse, but no human pharmacokinetic data are available following high-dose IV buprenorphine.

Methods

Plasma was collected for 72 h after administration of placebo or 2, 4, 8, 12, or 16 mg IV buprenorphine in escalating order (single-blind, double-dummy) in 5 healthy male non-dependent opioid users. Buprenorphine and its primary active metabolite, norbuprenorphine, were quantified by liquid chromatography–tandem mass spectrometry with limits of quantitation of 0.1 μg/L.

Results

Maximum buprenorphine concentrations (mean ± SE) were detected 10 min after 2, 4, 8, 12, 16 mg IV: 19.3 ± 1.0, 44.5 ± 4.8, 85.2 ± 7.7, 124.6 ± 16.6, and 137.7 ± 18.8 μg/L, respectively. Maximum norbuprenorphine concentrations occurred 10–15 min (3.7 ± 0.7 μg/L) after 16 mg IV administration.

Conclusions

Buprenorphine concentrations increased in a significantly linear dose-dependent manner up to 12 mg IV buprenorphine. Thus, previously demonstrated pharmacodynamic ceiling effects (over 2–16 mg) are not due to pharmacokinetic adaptations within this range, although they may play a role at doses higher than 12 mg.

Introduction

High-dose SL buprenorphine, a partial mu-opioid receptor agonist, has been employed as substitution therapy for opioid addiction in France since 1996 (Gueye et al., 2002, Thirion et al., 2002) and in the US since 2002 (Sporer, 2004). Many early clinical studies utilized an ethanolic buprenorphine solution, while current formulations for buprenorphine opioid agonist maintenance are two types of SL tablets, one containing buprenorphine alone and a second combining buprenorphine with naloxone at a fixed dose ratio of 4:1 (2 mg buprenorphine:0.5 mg naloxone or 8 mg buprenorphine:2 mg naloxone). Oral administration is not employed clinically because of substantial hepatic first pass metabolism (Cone et al., 1984).

Prescribed SL buprenorphine is sometimes diverted for IV misuse, a world-wide problem (Alho et al., 2007, Bazazi et al., 2011, Comer et al., 2010, Moratti et al., 2010, Nordmann et al., 2012, Otiashvili et al., 2010, Vicknasingam et al., 2010). Human laboratory studies suggest that both SL and IV buprenorphine have a high safety margin for respiratory depression and cardiovascular effects because of a ceiling at higher doses (Umbricht et al., 2004, Walsh et al., 1994). One study of ascending SL buprenorphine doses (4–32 mg 30% ethanolic solution or 4–16 mg tablet) found a less than proportional relationship between increasing dose and plasma buprenorphine or norbuprenorphine (its major active metabolite) concentrations, suggesting that the observed plateau for such pharmacodynamic effects might be due to pharmacokinetic factors (Harris et al., 2004). We are unaware of any comparable study with IV buprenorphine.

We evaluated high-dose buprenorphine pharmacokinetics after IV administration to determine if the ceiling phenomenon for cardiorespiratory effects was due to changes in pharmacokinetic parameters rather than to pharmacodynamic adaptations (such as changes in receptor function).