Thrice-weekly supervised dosing with the combination buprenorphine-naloxone tablet is preferred to daily supervised dosing by opioid-dependent humans

Abstract

A sublingual tablet formulation of buprenorphine combining 8 mg of buprenorphine with 2 mg of naloxone is being targeted for use in settings where less than daily dosing strategies and/or prescription-based dispensing will likely be employed. This study determined patient preferences for, and clinical outcomes during, daily and 3-day per week supervised dosing schedules using the combination tablet. Twenty-four opioid-dependent subjects completing a 16-day baseline entered an outpatient triple crossover trial. Twenty-one days of daily dosing were compared to two different 21-day periods of 3-day per week supervised dosing: a 3-day per week clinic schedule and a 3-day per week take-home schedule in which tablets were provided to subjects to take at home on days between clinic visits. Thirteen patients completed the study. Significantly more doses were ingested under the 3-day per week schedules. Illicit drug use did not differ across conditions and 45% of urine samples tested positive for illicit opioids. Subjects ‘liked’ both 3-day per week schedules more than the daily schedule, and ratings of feeling ‘good’ were higher for the 3-day take-home as opposed to 3-day clinic condition. Almost all subjects (91%) rated 3-day take-home as the most preferred schedule. Overall, reducing clinic attendance improved medication compliance and increased client satisfaction without impacting illicit drug use.

Introduction

Buprenorphine is a high affinity, partial μ-opioid agonist pending FDA approval as a pharmacotherapy for opioid dependence treatment (cf., Bickel and Amass, 1995). Buprenorphine is a safe and effective alternative to methadone (Bickel et al., 1988, Johnson et al., 1992, Strain et al., 1994, Ling et al., 1996) and levomethadyl acetate hydrochloride (LAAM; Chutuape et al., 1999) that produces significant and substantial improvements over time in psychosocial functioning (Strain et al., 1996). Buprenorphine also has unique features that permit novel uses which may alter current strategies for maintenance and detoxification treatment (cf. Bickel and Amass, 1995, Amass et al., 2000).

An important feature of buprenorphine is that, unlike methadone and like LAAM, it can be used safely on an alternate-day or thrice-weekly basis without the use of take-home medication. However, like methadone and unlike LAAM, buprenorphine can also be administered safely on a daily basis. This feature may promote the use of buprenorphine in diverse settings, including primary care facilities and office-based practices. Alternate-day buprenorphine dosing regimens have been examined in several placebo-controlled studies with liquid (Fudala et al., 1990, Amass et al., 1994, Amass et al., 1998, Johnson et al., 1995, Bickel et al., 1999) and tablet (Amass et al., 2000) formulations and consistently have been found to be as effective as daily dosing. Importantly, using multiples of the daily dose when dosing every other day yields slightly better treatment outcomes and is intrinsically safe (Amass et al., 1994, Amass et al., 1998, Amass et al., 2000). Buprenorphine's partial agonist nature results in a ceiling on agonist activity such that high dose buprenorphine treatment does not interfere with patient management (Amass et al., 1993, Walsh et al., 1994, Walsh et al., 1995). Despite this ceiling effect, higher doses continue to produce extended action since plasma buprenorphine concentrations increase proportionately as a function of dose (Walsh et al., 1994). Finally, alternate-day dosing regimens are preferred to daily dosing by buprenorphine-maintained outpatients (Amass et al., 1998), suggesting this regimen could be used to reinforce behavior change such as opioid abstinence.

Laboratory-based evaluations have shown that the liquid formulation of buprenorphine is well tolerated at 72-hour dose intervals (Eissenberg et al., 1997, Bickel et al., 1999), leading to the development of successful 3-day per week dosing regimens using the liquid formulation in multiple treatment settings, including primary care clinics (O'Connor et al., 1996, O'Connor et al., 1998, Schottenfeld et al., 1999). These 3-day per week regimens do not require the use of take-home doses and seem to have comparable efficacy to daily maintenance when an equivalent weekly dose is used (Schottenfeld et al., 1999).

Treatment with buprenorphine in the United States will employ a sublingual combination tablet containing buprenorphine and naloxone in a 4:1 ratio (Chiang and Hawks, 1994, Chiang et al., 1996a, Chiang et al., 1996b). This combination tablet was developed to help mitigate potential diversion and abuse of buprenorphine once it becomes available for widespread clinical use. The combination tablet is expected to be particularly useful sublingually because of the different parenteral to sublingual potencies of buprenorphine and naloxone. While buprenorphine has an ≈2:1 parenteral to sublingual potency ratio (McQuay et al., 1986), studies with opioid-dependent subjects indicate a parenteral to sublingual potency ratio up to 20:1 for naloxone (Preston et al., 1990). A sublingual naloxone dose up to five times greater than the intravenous dose that reverses toxic opioid overdose can be administered safely to opioid abusers without precipitating withdrawal (Preston et al., 1990). Thus, this combination tablet may permit buprenorphine's agonist effects to be expressed when administered sublingually and allow the combination tablet to behave like buprenorphine alone, while precipitating withdrawal if administered parenterally by opioid-dependent individuals. This combination tablet can be administered safely and effectively on an alternate-day basis (Amass et al., 2000).

Three-day dosing strategies have not been evaluated using the buprenorphine-naloxone combination tablet and at least three issues are unclear: (a) whether 3-day per week buprenorphine dosing at the clinic offers any therapeutic advantages over a schedule in which take-home medication is provided on intervening dose days, (b) whether a reduced attendance schedule compromises early treatment outcome, or (c) whether a 24 mg combination tablet dose would be well tolerated during a 72 h inter-dose-interval given that this represents use of increasing doses of sublingual naloxone. The purpose of the present study was to establish the preference for daily and 3-day per week supervised dosing schedules using the combination tablet and investigate clinical outcomes using these schedules. Daily combination tablet administration was compared to two different 3-day per week dosing schedules. Under one 3-day per week schedule (3-day clinic), subjects ingested all of their medication at each clinic visit. On the other 3-day per week schedule (3-day take-home), subjects received one dose at each clinic visit and doses to take at home on days between clinic visits.