Efficacy of daily and alternate-day dosing regimens with the combination buprenorphine–naloxone tablet
Introduction
Buprenorphine is a high affinity, partial μ-opioid agonist pending FDA approval as a pharmacotherapy for opioid dependence (see Bickel and Amass, 1995). Buprenorphine’s utility as a pharmacotherapy results from a unique profile of effects related to its partial agonist character and slow dissociation from μ-opioid receptors. Buprenorphine’s ceiling on agonist activity decreases the danger of overdose, may limit its abuse liability (Walsh et al., 1994, Walsh et al., 1995) and confers low toxicity even at high intravenous doses (Lange et al., 1990, Huestis et al., 1999), increasing the dose range over which it may be safely administered. Buprenorphine can also produce sufficient tolerance to block the effects of exogenously administered opioids (Bickel et al., 1988a, Rosen et al., 1994, Walsh et al., 1995), suggesting that it may help reduce illicit opioid use. Finally, buprenorphine’s slow dissociation from μ-opioid receptors (Rance and Dickens, 1978) not only results in a long duration of action but also diminishes withdrawal signs and symptoms upon its discontinuation (Jasinski et al., 1978, Seow et al., 1986, Fudala et al., 1990, Amass et al., 1994b, Bickel et al., 1995, Bickel et al., 1997, Cheskin et al., 1994), making it particularly useful for opioid detoxification.
Controlled clinical evaluations confirm buprenorphine’s utility for opioid dependence treatment. Studies comparing the relative efficacy of a sublingual buprenorphine solution to oral methadone have reported comparable retention and abstinence rates for up to 25 weeks of maintenance and detoxification treatment (Bickel et al., 1988b, Johnson et al., 1992, Strain et al., 1994). Additionally, buprenorphine is a safe, effective candidate for long term maintenance (Ling et al., 1996), compares favorably to other full-agonist alternatives such as levomethadyl acetate hydrochloride (LAAM; Chutuape et al., 1999), and produces significant and substantial improvements over time in psychosocial functioning (Strain et al., 1996).
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. Although alternate-day dosing regimens have been examined in several placebo-controlled studies with buprenorphine solution formulations, the most effective doses to use when administering buprenorphine on a less than daily basis have not yet been resolved (Fudala et al., 1990, Amass et al., 1994a, Amass et al., 1998, Johnson et al., 1995, Bickel et al., 1999). Some studies have given an 8-mg dose of buprenorphine every 48 h (Fudala et al., 1990, Johnson et al., 1995) while others have increased the dose to 16 mg when dosing every other day (Amass et al., 1994a, Amass et al., 1998, Bickel et al., 1999). Subjects receiving 8 mg of buprenorphine every other day have reported increased withdrawal scores relative to subjects receiving 8 mg every day (Fudala et al., 1990) and their treatment outcomes have tended to be slightly worse, even though these latter effects were not statistically significant (Johnson et al., 1995). Using multiples of the daily dose when administering buprenorphine every other day has resulted in minimal reports of withdrawal relative to daily dosing, an improved therapeutic profile (Amass et al., 1994a, Amass et al., 1998) and is preferred by subjects to daily dosing even when evaluated under open-label conditions (Amass et al., 1998). Multiplying the daily dose when dosing less than daily is feasible because the ceiling on buprenorphine's agonist activity renders high dose therapy safe and does not interfere with patient management (Amass et al., 1993, Walsh et al., 1994, Walsh et al., 1995). Moreover, since plasma concentrations of buprenorphine and its metabolites increase proportionately as a function of dose following single dose administration (Walsh et al., 1994), multiplying the daily dose can also maintain buprenorphine blood levels that are comparable to those seen with daily dosing using a lower dose. Thus, while increasing the daily dose of buprenorphine appears to improve the clinical response to alternate-day dosing, finding optimal doses for alternate-day dosing awaits more research.
Treatment with buprenorphine in the USA 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). Combination tablet dosages will be 8 mg of buprenorphine and 2 mg of naloxone, and 2 mg of buprenorphine and 0.5 mg of naloxone, respectively. The combination tablet was developed to help mitigate potential diversion and abuse of buprenorphine once it becomes available for widespread clinical use and is expected to be particularly useful sublingually because of the different parenteral to sublingual potencies of buprenorphine and naloxone. While buprenorphine has an approximately 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, in essence, permitting the combination tablet to behave like buprenorphine alone, while precipitating withdrawal if administered parenterally by opioid-dependent individuals.
Less than daily dosing strategies have not been evaluated using the buprenorphine–naloxone combination tablet and no studies have been published in which the two different alternate-day dosing strategies noted above have been directly compared to each other and to daily dosing. The purpose of the present study was to establish the clinical efficacy of alternate-day buprenorphine treatment using the combination buprenorphine–naloxone tablet and determine whether using multiples of the daily dose during alternate-day dosing was essential for providing an efficacious alternate-day treatment. Daily dosing with the combination tablet was compared to alternate-day combination tablet dosing during which either the daily dose or a multiple of the daily dose was dispensed every other day.
Section snippets
Subjects
Forty-seven opioid-dependent subjects (33 male, 14 female) participated in an 11-week outpatient study. Subjects were recruited through newspaper and poster advertisements and referred from local treatment programs. To be included in the study, subjects had to be at least 18 years old, in good health, and meet DSM-IV criteria for opioid dependence and FDA criteria for methadone treatment [i.e. a history of opioid dependence and either significant current opioid use (i.e. opioid-positive urines)
Buprenorphine induction
Seven (24%) of the 29 subjects inducted with combination products complained of withdrawal symptoms sufficient to warrant notation by medical staff on the second day of participation. The symptoms consisted of prototypic signs of opioid withdrawal including sweating, runny nose, chills and vomiting. By comparison, only two (11%) of the 18 subjects inducted with buprenorphine alone products complained of withdrawal symptoms on the second day of treatment.
Of the 29 subjects inducted with
Discussion
The combination buprenorphine–naloxone tablet was as acceptable and effective when administered on alternate days as when administered every day. There were no reports of any significant opioid agonist or withdrawal effects by subjects or staff during the study, and rates of medication compliance and drug abstinence were roughly equivalent across daily and alternate-day conditions. These results compliment other placebo-controlled studies comparing daily versus alternate-day dosing using the 8
Acknowledgements
We thank the staff of the Vine Street Center, especially Dr Robert Willard, Margery Johnson and Janet Robinson, for medical services, Jason Thrun for excellent technical assistance, David Yeats and Butch Rodgers for counseling services, and Connie Miles, for medications preparation. Special thanks to Reckitt and Colman, Drs Richard Hawks and Nora Chiang of the Medications Development Division at the National Institute on Drug Abuse, and Dr George Bigelow for their helpful comments and support
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