Pharmacokinetic comparison of the buprenorphine sublingual liquid and tablet

Abstract

Buprenorphine is a μ opioid partial agonist being developed as a treatment for opioid dependence. Buprenorphine, usually administered as a sublingual liquid, is now being developed as a sublingual tablet for clinical use. The present study compared participants’ plasma concentrations after daily maintenance on three buprenorphine liquid doses (2, 4 and 8 mg) and one tablet dose (8 mg). Fourteen opioid-dependent individuals (11 males, three females) participated. Plasma samples were collected over a 24-h period after at least 7 days of maintenance on each dose. Results showed that the liquid doses produced dose-related increases in plasma concentrations. The 8-mg tablet produced mean plasma concentrations significantly lower than those of the 8-mg liquid, although there was substantial individual variability. Thus, the buprenorphine tablet dose might have to be adjusted to produce plasma concentrations equivalent to those of the liquid.

Introduction

Buprenorphine is a partial μ opioid agonist marketed as an analgesic and under development as a treatment for opioid dependence. Both as an analgesic and as an opioid maintenance treatment, buprenorphine appears to be safe and effective. Due to its partial agonist profile, buprenorphine produces limited respiratory depression even after administration of high doses (Lewis, 1985, Walsh et al., 1994, Walsh et al., 1995). A relatively mild withdrawal syndrome has been reported following discontinuation of chronic administration (Jasinski et al., 1978, Mello and Mendelson, 1980, Kosten et al., 1991), most likely due to its high affinity (Hambrook and Rance, 1976, Dum and Herz, 1981). Chronically administered buprenorphine attenuates the effects of subsequently administered opioid challenges (Jasinski et al., 1978, Bickel et al., 1988, Rosen et al., 1994, Schuh et al., 1995) and reduces heroin self-administration (Mello and Mendelson, 1980, Mello et al., 1982). In clinical trials, buprenorphine maintenance can be as effective as methadone in reducing illicit opioid use (Johnson et al., 1992, Strain et al., 1994). Because buprenorphine has a long duration of action (Hambrook and Rance, 1976), it has been shown to retain its efficacy using alternate-day dosing schedules when the daily dose or double the daily dose is alternated with placebo administrations (Fudala et al., 1990, Amass et al., 1994, Johnson et al., 1995).

Buprenorphine has generally been administered as a sublingual liquid which the patient holds under his/her tongue for 5 min. Mendelson et al. (1997) showed bioavailability for the buprenorphine liquid at approximately 30%, and equivalent results from sublingual exposure times of 3 or 5 min. Kuhlman et al. (1996) showed bioavailability of a 4-mg liquid by the sublingual and buccal routes to be 51.4 and 27.8%, respectively. Walsh et al. (1994) measured plasma concentrations up to 96 h after sublingual administration of 2, 4, 8, 16 and 32 mg buprenorphine. Results showed proportionate increases in plasma concentration as a function of dose indicating no apparent limit on the sublingual absorption. Plasma concentrations peaked 60 min after administration of 2 and 4 mg, and 30 min after 8, 16 and 32 mg.

When used clinically, it is expected that buprenorphine will be available as a sublingual tablet instead of a liquid. A tablet will be used because of the difficulties in packaging an alcoholic solution for commercial production, in addition to stability problems with the solution. Recent studies have compared the plasma concentrations produced by these two formulations. Mendelson et al. (1996) compared an 8-mg sublingual tablet with an 8-mg solution. Results indicate that area-under-the-curve (AUC) and peak concentration were less after the tablet than after the solution. The tablet yielded about 50–60% of the buprenorphine compared with the 8-mg solution. The present study was done to compare the plasma concentrations produced by three doses of the liquid buprenorphine (2, 4 and 8 mg) with the 8-mg tablet when stable plasma concentrations had been achieved after a minimum of seven daily administrations.