Buprenorphine Treatment of Opioid Dependence: A Revie · of these effects (Lange, Fudala, Dax, & Johnson, 1990). Moreover, researchers obtained similar profiles of self- ... REVIEW

Experimental and Clinical Psychopharmacology1995, Vol. 3, No. 4,477-489

Copyright 1995 by the American Psychological Association, Inc.m * ' " 1064-1297/95/S3.00

Buprenorphine Treatment of Opioid Dependence: A Review

Warren K. Bickel and Leslie AmassUniversity of Vermont

Buprenorphine, a partial mu-agonist opioid, is a promising pharmacotherapy for the treatment ofopioid dependence. One hundred and eight papers are organized according to 3 componentsessential to buprenorphine's use as a pharmacotherapy for opioid dependence: inducting patientsonto buprenorphine, maintaining patients on buprenorphine, and discontinuing patients frombuprenorphine treatment. The research suggests that inducting patients onto buprenorphineshould lead to limited discomfort if appropriate procedures are followed. As a maintenancetreatment, buprenorphine is as efficacious as methadone, blocks the effects of exogenouslyadministered opioids, promotes treatment compliance, and, importantly, can support an alternate-day dosing regimen by doubling the daily dose. Discontinuing buprenorphine treatment appears toresult in a mild-to-moderate opioid withdrawal syndrome that is less severe than that observed withfull-efficacy agonists.

Heroin and other opioid dependencies are an enduringpublic health problem and, unfortunately, the prevalence ofthat problem has been increasing. For example, between thesecond and third quarters of 1991, heroin- and morphine-related cases increased 10% across 500 hospital emergencyrooms in 21 U.S. cities (Swan, 1992). Decreased price andincreased purity of street heroin may have, in part, fueled thisresurgence. Given the association between intravenous heroinuse and AIDS, the drug abuse treatment and public healthcommunity would be wise not to underestimate the severity ofthis increased heroin problem.

Fortunately, the National Institute on Drug Abuse (NIDA)has been actively developing a new medication, buprenor-phine, for the treatment of opioid dependence. NIDA antici-pates Food and Drug Administration (FDA) approval ofbuprenorphine for this indication in the near future (D. Segal,personal communication, December 8, 1994). Buprenorphine,a low-efficacy, partial agonist of the morphine-type, exhibits aunique profile of effects, including (a) a ceiling on agonistactivity that decreases the possibility of overdose and may limitabuse liability (Walsh, Preston, Stitzer, Cone, & Bigelow,1994), (b) opioid-antagonist activity that blocks the effects ofexogenously administered opioids (Bickel et al., 1988b), (c) ahigh affinity for the u,-opioid receptor that decreases themagnitude of withdrawal signs and symptoms (Ranee &Dickens, 1978), and (d) opioid-agonist activity that promotestreatment compliance (Jasinski, Pevnick, & Griffith, 1978).

Although more work is necessary to identify and character-

Warren K. Bickel and Leslie Amass, Department of Psychiatry andDepartment of Psychology, University of Vermont. Leslie Amass isnow at the Addiction Research Foundation, Toronto, Ontario, Canada.

Preparation of this article was supported by Grants R18DA06969and 5T32DA07242 from the National Institute on Drug Abuse. Wethank Jonathan B. Kamien and Stephen T. Higgins for their thoughtfulcomments on an earlier version of this article.

Correspondence concerning this article should be addressed toWarren K. Bickel, Human Behavioral Pharmacology Laboratory,Department of Psychiatry, University of Vermont, 38 Fletcher Place,Ira Allen School, Burlington, Vermont 05401-1419. Electronic mailmay be sent via Internet to [email protected].

ize buprenorphine's unique clinical pharmacology, results todate suggest that it is a viable and useful pharmacotherapy foropioid dependence. Given that buprenorphine may soon beavailable for widespread clinical use, reviewing the literatureavailable to guide practitioners in the use of buprenorphine foropioid dependence treatment is both practical and timely.Thus, in this review we address three main topic areas: (a)transferring opioid-dependent patients onto buprenorphine;(b) maintaining patients on buprenorphine; and (c) discontinu-ing patients from buprenorphine treatment. We also reviewadditional research elucidating buprenorphine's therapeuticpotential and make recommendations for integrating buprenor-phine into existing treatment programs. Before doing this, webriefly review buprenorphine's pharmacology and side effectsprofile.

Buprenorphine's Pharmacology and Side Effects

Buprenorphine hydrochloride, a derivative of the morphinealkaloid thebaine, is a partial agonist opioid at the p. receptorand an opioid antagonist at the K receptor (Lewis, 1985).Buprenorphine's partial agonist effects at, and its unusuallyhigh affinity for, the u. receptor have been proposed as theprincipal determinants of its pharmacological profile (Lewis,1985).

Partial agonists can be defined as agents whose maximalresponse is below the maximum possible for that system(Kenakin, 1987). For example, the prototypical full agonistmorphine produced dose-related decreases in respiration rate,while buprenorphine produced effects less than that of mor-phine and reached a "ceiling" above which further increases indose had no further effect (Cowan, Doxey, & Harry, 1977).This ceiling on buprenorphine's agonist activity limits thepossibility of overdose and provides a wide margin of safety.

The other determinant of buprenorphine's pharmacologicalprofile is its unusually high affinity for the |j, receptor. Thisaffinity has been characterized as irreversible and is demon-strated by the inability of the prototypical opioid antagonistnaloxone to fully antagonize buprenorphine's effects (Woods,France, Bertalmio, Gmerek, & Winger, 1985). For example,

477

478 BICKEL AND AMASS

naloxone doses that are 10- to 30-fold those required to reversemorphine's effects are necessary to partially reverse the effectsof buprenorphine (Heel, Brogden, Speight, & Avery, 1979;Woods et a!., 1985). Buprenorphine's irreversibility will there-fore allow it to block other opioid agonists in a fashion notdissimilar from opioid antagonists. This irreversibility of bu-prenorphine once bound to the receptor is also the mechanismthat extends its duration of action beyond its plasma half-life of3 hr (Jaffe & Martin, 1990).

The medical side effects of acute buprenorphine administra-tion are similar to those of opioid agonists and includeconstipation, dizziness, drowsiness, headache, miosis, nausea,respiratory depression, sweating, and vomiting (Heel et al.,1979). Opioid-dependent individuals show tolerance to manyof these effects (Lange, Fudala, Dax, & Johnson, 1990).Moreover, researchers obtained similar profiles of self-reported adverse effects for opioid-dependent individualsreceiving either buprenorphine or methadone (Johnson, Jaffe,& Fudala, 1992). One study reported increased serum amino-transferase levels in opioid-dependent individuals receivingbuprenorphine (Lange et al., 1990). This finding suggests thatbuprenorphine induced hepatic dysfunction. Given the highprevalence of hepatic disease in parental drug abusers, theseresults should be considered seriously (Lange et al., 1990).However, the authors provided several plausable alternativehypotheses for these results and concluded that further re-search will be needed to discern buprenorphine's effect onhepatic function.

For more detailed reviews of buprenorphine's basic, behav-ioral, and clinical pharmacology, consult Heel et al. (1979),Lewis, Ranee, and Sanger (1983), and Mello and Mendelson(1985).

Transferring Patients Onto Buprenorphine

When the FDA approves buprenorphine for the treatmentof opioid dependence, opioid-dependent individuals usingillicit opioids or receiving treatment with methadone may betransferred to buprenorphine. The transfer of opioid-depen-dent individuals to buprenorphine raises the important clinicalissue of whether patients may initially experience withdrawaldiscomfort from buprenorphine. Because withdrawal discom-fort could adversely affect treatment retention and abstinencerates, understanding how withdrawal occurs and how to avoidit will be important when transferring patients onto buprenor-phine.

Withdrawal discomfort could result from three separateprocesses (Johnson, Cone, Henningfield, & Fudala, 1989).First, the buprenorphine dose may be too low and, therefore,possess insufficient agonist effects to substitute for anotheropioid agonist. In this case, a higher dose of buprenorphinewould suppress withdrawal. Second, buprenorphine, as apartial agonist, may not fully substitute for full opioid agonists.In this case, buprenorphine at any dose would fail to suppresswithdrawal completely (i.e., withdrawal would occur but to alesser degree than that obtained without buprenorphine admin-istration). Third, buprenorphine, as a partial agonist, maydirectly precipitate withdrawal. In this case, higher doses ofbuprenorphine would produce more withdrawal than lower

doses. The first and second sources of withdrawal would resultin greatest withdrawal discomfort during the typical time-course of withdrawal expected with the maintenance opioidused. The third source of withdrawal discomfort (directprecipitation of withdrawal) would result in peak withdrawaldiscomfort during buprenorphine's acute effects and couldpose the greatest difficulty in transferring opioid-dependentpatients to buprenorphine.

Both precipitation and suppression of opioid withdrawal bybuprenorphine have been demonstrated in preclinical studies.In those studies, withdrawal intensity was directly related tothe dose of the maintenance drug (e.g., morphine) and thedose of buprenorphine (Cowan, 1974; Martin, Gilbert, Eades,Thompson, & Huppler, 1975; Martin, Eades, Thompson,Huppler, & Gilbert, 1976). Importantly, whether buprenor-phine precipitates or suppresses withdrawal seems to bedetermined by the interval between agonist and buprenor-phine administration. Buprenorphine precipitated withdrawalin a dose-related fashion when it was administered to morphine-dependent monkeys 1 hr after the last morphine administra-tion, when morphine's effects were still evident (Aceto, 1984).In contrast, buprenorphine suppressed withdrawal in a dose-related fashion when it was administered 15 hr after the lastmorphine administration; that is, when morphine's agonisteffects had dissipated and withdrawal signs and symptomswere present (Aceto, 1984). These findings suggest thatbuprenorphine's withdrawal-precipitating or withdrawal-attenuating effects are critically determined by the activity atthe receptor at the time of buprenorphine administration.When receptor activity is high (i.e., when a u, agonist ispresent), buprenorphine will displace opioid agonists from thereceptor. This displacement will result in reduced receptoractivity because buprenorphine is less efficacious than full jxagonists. The reduced receptor activity will in turn result inopioid withdrawal. However, when receptor activity is low (i.e.,when there is no ^.-agonist activity for some time), buprenor-phine will occupy the receptor, increase receptor activity, andconsequently suppress opioid withdrawal.

Buprenorphine's withdrawal-producing effects have alsobeen observed in opioid-dependent patients and are related tothe level of opioid dependence (i.e., level of use of streetopioids, maintenance dose of methadone, or both), the bu-prenorphine substitution dose, and the temporal intervalbetween agonist administration and buprenorphine. For ex-ample, opioid withdrawal has been observed when methadonemaintenance patients were transferred abruptly to buprenor-phine. Three patients maintained on 25, 58, or 60 mg orally(PO) methadone per day were abruptly transferred to 2 mgsubcutaneously (SC) buprenorphine per day and experienceda mild transient opioid withdrawal (Lukas, Jasinski, & Johnson,1984). However, whether the withdrawal was precipitated bybuprenorphine or was due to buprenorphine failing to substi-tute fully for methadone is unclear. Similarly, withdrawalsymptoms emerged when heroin-dependent and methadone-maintained patients (25 mg PO) were transferred to 2, 4, or 8mg sublingually (SL) buprenorphine in an open trial (Kosten& Kleber, 1988). Although patients transferred to the 4-mgbuprenorphine dose experienced only transient increases inwithdrawal scores, withdrawal symptoms emerged in patients

REVIEW OF BUPRENORPHINE TREATMENT 479

transferred to the 2- or 8-mg dose. Whereas the 2-mg dose mayhave had insufficient agonist activity to suppress withdrawalsymptomology (i.e., the normally occurring withdrawal), the8-mg dose may have directly precipitated opioid withdrawal(Johnson et al., 1989). Finally, two laboratory studies supportthe role of level of opioid dependence (i.e., maintenance doseof methadone) in buprenorphine-precipitated withdrawal(June, Preston, Bigelow, & Stitzer, 1993; Strain, Preston,Liebson, & Bigelow, 1992). Acute buprenorphine (2, 4, and 8mg SL) precipitated withdrawal dose-dependently in patientsmaintained on high-dose (60 mg PO) methadone (June et al.,1993); however, acute buprenorphine (0.5-8.0 mg intramuscu-larly, IM) did not precipitate withdrawal in patients main-tained on low-dose (30 mg PO) methadone (Strain et al.,1992).

Clinical reports indicate that when equipotent doses ofbuprenorphine and methadone are used, buprenorphine ap-pears as effective as methadone in suppressing opioid with-drawal symptomology (Bickel et al., 1988a; Johnson et al.,1992). This information has helped determine adequate bu-prenorphine substitution doses for patients transferring frommethadone or street opioids to buprenorphine. Double-blindclinical observations indicate that opioid-dependent patientsrandomized to receive either outpatient methadone (30 mgPO) or buprenorphine (2 mg SL) treatment do not experiencesignificantly different withdrawal (Bickel et al., 1988a). Simi-larly, methadone (20 or 60 mg PO) and buprenorphine (8 mgSL) were equally effective at suppressing withdrawal in opioid-dependent patients in a double-blind, double-dummy outpa-tient comparison (Johnson et al., 1992). However, withdrawalscores of patients receiving 20 mg methadone were suspect dueto the increased illicit opioid use in that group (Johnson et al.,1992). The data to date suggest that 8 mg SL buprenorphineappears to suppress withdrawal symptomology as effectively as60 mg PO methadone.

On the basis of the aforementioned clinical reports, doseequivalencies between commonly used street opioids, metha-done, and buprenorphine can be constructed and used toguide clinicians in the determination of the appropriatebuprenorphine substitution dose (see Table 1). The guidepresented in Table 1 has been used successfully in outpatientstudies at the University of Vermont's Outpatient Buprenor-phine Treatment Program to determine the buprenorphinemaintenance dose (Amass, Bickel, Crean, & Higgins, 1995;Amass, Bickel, Higgins, & Badger, 1994; Amass, Bickel,Higgins, & Hughes, 1994; Amass, Bickel, Higgins, Hughes, &Peterson, 1993; Bickel, Amass, Crean, & Higgins, 1995). Onthe basis of the patients' treatment records, self-reports ofopioid use, or both, the patients' buprenorphine maintenancedose is determined during the first week of treatment. Forexample, if a patient reported being maintained on 60 mg oforal methadone or injecting more than three bags of heroin perday, the patient's sublingual buprenorphine maintenance dosewould be 8 mg. To decrease the likelihood of precipitatedwithdrawal by buprenorphine, we would recommend that thepatients report for induction in the beginning stages ofwithdrawal. We would ask them to accomplish this by eitherabstaining or reducing the amount of the maintenance drugthey use in the 24 to 72 hr before induction. We would then

Table 1Guidelines for Optimal Buprenorphine Dose Based onSelf-Reported Opioid Use

Opioid

Oxycodone(Percoset)

Hydrocodone(Vicodan)

Codeine

Meperidine(Demerol)

Hydro-morphone(Dilaudid)

Heroin

Morphine

Self-reported use

5-7 pills10-14 pills> 20 pills

7-10 pills14-20 pills•> 20 pills7-10 pills14-20 pills> 20 pills

4 pills (300 mg) per 150 IV8 pills per 600 mg IV> 8 pills per 600 mg IV

2-3 4-mg pills4-7 4-mg pills> 8 4-mg pillsIbag2-3 bags> 3 bags1-2 pills3-4 pills> 5 pills (60 mg IV)

Note. PO = orally; SL = sublingually; IV =

Bupren-Methadone orphineequivalent equivalent(mgPO) (mgSL)

20-3040

50-60

20-3040

50-6020-30

4050-60

20-3040

50-60

20-3040

50-6020-30

4050-6020-30

4050-60

intravenous.

248

248248

248

248248248

follow the procedures described by Johnson et al. (1989).Johnson et al. (1989) transferred 19 heroin-dependent menfrom heroin to buprenorphine by administering buprenor-phine in ascending daily doses of 2, 4, and 8 mg SL, withoutprecipitating withdrawal. In our treatment program, patientsare carefully monitored for signs and symptoms of opioidwithdrawal or intoxication during Week 1 of treatment, andadditional dose adjustments are made if necessary. Inductingpatients with these procedures seemed acceptable to patientsand did not result in early treatment termination, suggestingthat the procedures may be effective.

To date, the role of temporal interval between agonistadministration and buprenorphine in opioid-dependent hu-mans has not been explored. However, in the two studies thatexamined transferring patients from methadone to buprenor-phine, an interval of at least 20 hr occurred between the lastdose of methadone and the first dose of buprenorphine (Juneet al., 1993; Strain et al., 1992). In other studies, patients havebeen instructed to be opioid abstinent for at least 12 hr beforereceiving their initial buprenorphine dose to minimize bu-prenorphine-precipitated withdrawal during buprenorphineinduction (Amass et al., 1993, in press; Amass, Bickel, Higgins,& Badger, 1994; Amass, Bickel, Higgins, & Hughes, 1994;Bickel et al., 1988a; Fudala, Jaffe, Dax, & Johnson, 1990;Johnson et al., 1989, 1992). This approach places patients inthe initial stages of withdrawal (i.e., low activity at the receptorsite) and, therefore, enhances buprenorphine's withdrawal-suppressing effects. These studies, however, did not determine


whether these induction procedures were more effective ornecessary relative to any other procedure. Thus, research iswarranted to determine the efficacy of different inductionprocedures.

In conclusion, comfortably transferring patients from metha-done or other opioids to buprenorphine requires four steps:

1. Instruct patients to abstain or lower maintenance dose ofmethadone or other opioids for 24 to 72 hr before buprenor-phine induction.

2. Select the appropriate buprenorphine substitution dose(see Table 1).

3. Start the patient on a dose of buprenorphine lower thanthe recommended substitution dose and increment the bu-prenorphine dose to the final substitution dose over the firstseveral days of treatment.

4. Impose a temporal interval of at least 12 hr between prioragonist and buprenorphine administration. The presence ofmild withdrawal symptoms at the time of buprenorphineadministration is desirable.

Use of these procedures will permit patients to be placed ondoses of buprenorphine that will likely suppress withdrawalsigns and symptoms but not precipitate withdrawal.

Maintaining Patients on Buprenorphine

We will consider buprenorphine's utility as a maintenancetreatment by evaluating its similarity to other opioids, theopioid blockade it engenders, and its efficacy in clinicaloutcome trials. By doing so, buprenorphine's impact on theclinical status of opioid-dependent individuals is elucidatedand the outcome of treatment studies may be more easilyinterpreted.

Agonist Effects

Agonist activity as used here refers to the extent to whichbuprenorphine, a partial |j,-opioid agonist, exhibits actionssimilar to full ^.-opioid agonists such as morphine and metha-done. Such actions are relevant to the clinical issues ofsubstitution, abuse liability, compliance, and duration of ac-tion. Agents similar to full efficacy agonists are more likely tobe accepted by patients, to maintain medication compliance, andhence to be substitutable; however, the more similar an agent is tomorphine or methadone, the greater the liability for abuse. More-over, the duration of buprenorphine's agonist actions is essential indetermining optimal interdosing intervals.

Discriminative stimulus and self-reported effects. The extentto which discriminative stimulus and self-reported effects ofbuprenorphine are similar to full opioid agonists can elucidatehow well buprenorphine will substitute for other treatmentagents such as methadone. The drug discrimination procedureis one of the most rigorous laboratory procedures for assessingsubstitutability of psychoactive drugs (Schuster & Johanson,1988). The drug discrimination procedure trains a discrimina-tion based on the interoceptive drug effects between a drug(such as morphine) and placebo. The resulting discriminationis typically highly specific. Thus, if a discrimination weretrained between morphine and placebo, then generally onlymorphinelike drugs would substitute for morphine (i.e., pro-

duce morphine-appropriate responses) and all other drugs,such as secobarbital orrf-amphetamine, would produce placebo-appropriate responses. The utility of this procedure is derivedfrom the concordance of results between animal and humanopioid drug discrimination studies (Kamien, Bickel, Hughes,Higgins, & Smith, 1993) and measures of drug discriminationand self-reports in human opioid drug discrimination studies(Preston, Bigelow, Bickel, & Liebson, 1987, 1989; Bickel,Bigelow, Preston, & Liebson, 1989).

Buprenorphine generally substitutes for other morphinelikeopioids in drug discrimination studies across several species,including humans. For example, in nondependent rhesusmonkeys trained to discriminate codeine (5 mg/kg) fromsaline, buprenorphine produced codeine-appropriate respond-ing; that is, buprenorphine was identified as "codeine-like"(Hoffmeister, 1988). Humans show a similar profile of results.For example, when nondependent humans were trained todiscriminate hydromorphone from saline, buprenorphine pro-duced hydromorphone-appropriate responding and was ratedas being subjectively similar to hydromorphone (Preston,Liebson, & Bigelow, 1992). However, buprenorphine partiallygeneralized to both hydromorphone and pentazocine in post-addict volunteers trained to discriminate between saline,hydromorphone, and pentazocine, while producing effectsunlike either drug on measures of self-report (Preston et al.,1989). In other human studies, buprenorphine produced aprofile of subjective effects similar to those effects produced bymorphine in dependent and nondependent opiate abusers(Jasinski et al., 1978; Johnson et al., 1989; Mello & Mendelson,1980) as well as in healthy volunteers (Blom, Bondesson, &Gunne, 1987; Fullerton, Timm, Kolski, & Bertino, 1991; Gal,1989). Overall, these studies, with one exception, indicate thatbuprenorphine and full efficacy morphinelike agonists gener-ally share a common profile of discriminative stimulus andself-reported agonist effects, suggesting that buprenorphineshould substitute well for other treatment agents such asmethadone.

Reinforcing effects: Abuse liability and treatment compliance.The reinforcing effects of morphinelike drugs are importantclinically because they play a large role in the agent's potentialfor abuse and maintenance of treatment compliance. Gener-ally, reinforcing effects are inferred when a drug is self-administered at rates greater than placebo. However, reinforc-ing effects may also be inferred by examining an agents' abuseat the societal level, given that self-administered drugs are alsothose drugs abused by humans (Schuster & Thompson, 1969).Finally, treatment compliance can be considered to reflect, inpart, reinforcing effects of the agent and, thus, examiningcompliance can also reflect on buprenorphine's reinforcingeffects. Concordance across these three dimensions wouldprovide confirming evidence of buprenorphine's reinforcingeffects. Although no buprenorphine self-administration stud-ies on humans have been reported to date, nonhuman primateself-administration studies have demonstrated that buprenor-phine functions as a reinforcer and, therefore, has potential forabuse. Buprenorphine has been demonstrated to function as areinforcer in rhesus monkeys, maintaining responding above


that maintained by saline (Hoffmeister, 1988; Mello, Bree, &Mendelson, 1981; Winger, Skjoldager, & Woods, 1992; Woods,1977; Yanagita, Katoh, Wakasa, & Oinuma, 1982; Young,Stephens, Hein, & Woods, 1984), but it did so in only 1 of 4baboons in another study (Lukas, Brady, & Griffiths, 1986).Although buprenorphine has been reported to exhibit lowerreinforcing efficacy than morphine and other full efficacy M.agonists (Lukas et al., 1986; Mello, Lukas, Bree, & Mendelson,1988; Woods, 1977), these cross-drug comparisons of reinforc-ing efficacy must be interpreted with care (Katz, 1990).

A lower abuse liability for buprenorphine relative to a fullefficacy agonists is supported by the dose-related plateau onsubjective and physiological effects observed with buprenor-phine in humans (Amass et al., 1993; Bigelow, 1991; Walsh etal., 1994). Finally, buprenorphine, because of the risk ofprecipitated withdrawal, may have a lower abuse potentialthan other opioids in highly dependent individuals (Johnson etal., 1989), but it still may be abused by individuals with lowerlevels of dependence (e.g., Strang, 1985).

Clinical reports do indicate, however, that buprenorphineclearly has potential for abuse. Numerous reports exist ofbuprenorphine abuse in countries where its availability hasbeen largely unrestricted including Ireland (O'Connor,Moloney, Travers, & Campbell, 1988), England (Strang, 1985),Scotland (Gray, Ferry, & Jauhar, 1989; Hammerseley, Lavelle,& Forsyth, 1990; Robertson & Bucknall, 1986; Sakol, Stark, &Sykes, 1989), India (Chowdhury & Chowdhury, 1990; Singh,Mattoo, Malhotra, & Varma, 1992), Australia (Quigley, Brede-meyer, & Seow, 1984), New Zealand (Harper, 1983; Rainey,1986; Robinson, Dukes, Robinson, Cooke, & Mahoney, 1993),and Spain (San, Tremoleda, Olle, Serra, & de la Torre, 1989;Torrens, San, & Cami, 1993). Moreover, buprenorphine depen-dence has been reported in Germany by individuals notpreviously dependent on opiates (Richert, Strauss, Arnim,Vogel, & Zech, 1983) and was purportedly the drug of choicein Edinburgh, Scotland (Lavelle, Hammerseley, Forsyth, &Bain, 1991). Not surprisingly, restrictions on prescribing havebeen introduced in some of these countries (O'Connor et al.,1988; Strang, 1991). General practitioners and scientists fromabroad have noted that buprenorphine is purer, cheaper, andeasier to obtain than black market heroin. These qualitiesmake buprenorphine a popular and economic alternative toheroin, perhaps even more so when heroin supplies are low.

Buprenorphine is also active by several different routes ofadministration. For example, a large rise in intravenous use ofsublingual preparations has been reported (Sakol et al., 1989),consistent with a human laboratory investigation demonstrat-ing that intravenous buprenorphine has substantial potentialfor abuse (Pickworth, Johnson, Holicky, & Cone, 1993). Theintravenous use of the crushed tablet formulation is promptingadditional concern over increased risk for spreading the HIVinfection and AIDS (O'Connor et al., 1988; Robertson, Rob-erts, Black, Davitt, & Stewart, 1987; Strang, 1985,1991). In theUnited States, alternative routes of administration have beenexplored as a way of limiting buprenorphine's abuse potential.Although the subcutaneous preparation was investigated inearly clinical studies (Jasinski et al., 1978; Mello, Mendelson,& Kuehnle, 1982), noninjectable sublingual formulations arenow advocated as a better drug delivery system because they

are more convenient to administer, will minimize illicit diver-sion relative to the injectable formulation, and may be moreeconomical to manufacture (Jasinski, Fudala, & Johnson,1989). However, 6 out of 8 heroin-dependent individuals onlong-term buprenorphine maintenance in New York whoreceived sublingual buprenorphine (range 0.6-3.9 mg) forself-administration at home administered the solution intrana-sally, as this route reportedly produced a stronger drug effect;the other 2 individuals receiving the highest doses claimed thatthe drug volume precluded sublingual administration andcontinued to self-administer their buprenorphine subcutane-ously (Resnick, Resnick, & Galanter, 1991). Interestingly, thepharmacokinetic profile of intranasal buprenorphine (Eriksenet al., 1989) resembles that of intramuscular administration(Bullingham, McQuay, Moore, & Bennett, 1980), a routewhich is approximately twice as potent as sublingually adminis-tered buprenorphine (Wallenstein, Kaiko, Rogers, & Houde,1986). Thus, the formulation used is important in mitigatingbuprenorphine's abuse potential, and caution is recommendedwith the use of take-home medication.

Finally, buprenorphine's reinforcing effects are reflected byits ability to maintain compliance rates comparable to metha-done across several outpatient maintenance treatment studies.Retention rates of 72% were reported for 39 patients receivingbetween 2 and 6 mg SL buprenorphine daily for 1 month(Kosten, Morgan, & Kleber, 1991). These findings extendthose of an earlier report with 16 patienfs maintained on dailysublingual buprenorphine (2,4, or 8 mg), where retention ratesof 81% over the 1-month maintenance period were reported(Kosten & Kleber, 1988). Higher retention rates (i.e., 96%)have been observed in patients maintained for 28 days on 8 mgSL buprenorphine, when continued participation was contin-gent on an individual never missing more than two consecutiveclinic visits (Amass, Bickel, Higgins, & Hughes, 1994). Direct,controlled comparisons of sublingual buprenorphine with oralmethadone (2 mg buprenorphine versus 30 mg methadone and8 mg buprenorphine versus 60 mg methadone) have demon-strated comparable retention rates during maintenance anddetoxification treatment for periods up to 25 weeks (Bickel etal., 1988a; Johnson et al., 1992).

In conclusion, buprenorphine has reinforcing effects thathave been exhibited in studies with nonhumans, are evidencedby abuse patterns of buprenorphine by humans in a variety ofcountries, and are consistent with the retention data obtainedwith buprenorphine when compared with methadone. Bu-prenorphine's abuse liability highlights the need to exercisecaution and maintain regulatory control over this compound,but it also indicates buprenorphine's acceptability as a treat-ment agent for opioid-dependent patients.

Duration of agonist effects and dosing schedules. Identifyingthe range of buprenorphine doses and interdosing intervalsthat maintain agonist activity may significantly increase theoptions available to clinics providing buprenorphine treat-ment. Currently, methadone must be administered at leastonce daily to suppress withdrawal signs and symptoms. Take-home doses must be provided to patients when they cannotattend the clinic on a daily basis, which in turn increases therisk for medication diversion (e.g., Goldman & Thistel, 1978;Kirn, 1988). Alternatively, /-alpha-acetylmethadol (LAAM), a


long-acting full efficacy (j, agonist recently approved by theFDA for the treatment of heroin dependence, permits dosingthree times a week without increased withdrawal signs andsymptoms and thereby obviates the problems inherent withtake-home medication (Bigelow & Preston, 1995). Althoughinitial tests of longer interdosing intervals with buprenorphinedid not support its feasibility for this use (Fudala et al., 1990),more recent information suggests that buprenorphine is closerto LAAM than may have originally been thought (Amass,Bickel, Higgins, & Badger, 1994).

The first study examining whether addicts could be main-tained on buprenorphine less frequently than once dailystudied 19 heroin-dependent males residing on a residentialtreatment unit (Fudala et al., 1990). Patients were assignedrandomly to receive an 8-mg SL buprenorphine dose eitherdaily or every 48 hr for 18 days using a double-blind, placebo-controlled design. Self-reported drug and withdrawal effectsand physiologic responses (except pupil diameter) did notdiffer significantly between the 2 groups, but clinically relevantbehavioral effects were present between drug and nondrugdays for patients receiving buprenorphine on alternate days.These individuals reported greater "urge for opioid" andsignificantly higher ratings on the LSD (dysphoria) subscale ofthe Addiction Research Center Inventory short form (Jasinski,1977; Martin, Sloan, Sapiro, & Jasinski, 1971) during placeboas compared with buprenorphine days and correctly identifiedplacebo doses 70% of the time. Moreover, self-reported opioidwithdrawal effects and pupil responses oscillated as a functionof drug and nondrug days, such that increased withdrawalrating scores and pupil dilation covaried with placebo adminis-tration. This profile of withdrawal effects on nondrug days forindividuals receiving buprenorphine on alternate days mightincrease susceptibility to illicit opioid use (Fudala et al., 1990).Therefore, the more stable withdrawal scores obtained withonce daily dosing supported using daily dosing in clinicalsettings.

However, another and perhaps more effective approach tousing buprenorphine in an alternate-day dosing schedule wassuggested in a recent clinical pharmacology study. In thatreport, the acute substitution of 16 mg per 70 kg of sublingualbuprenorphine was more effective than the 8 mg per 70 kgmaintenance dose at suppressing withdrawal symptoms for 24hr (Amass et al., 1993). These data suggest that administeringdouble the maintenance dose of buprenorphine may extendwithdrawal suppression beyond 24 hr and thereby support asuccessful alternate-day dosing regimen. A double-dose regi-men is feasible because of the ceiling on buprenorphine'sagonist activity. High doses of buprenorphine are medicallysafe, produce minimal intoxication, and do not interfere withroutine patient management (Amass et al., 1993; Walsh et al.,1994).

To further investigate this possibility, Amass, Bickel, Hig-gins, and Badger (1994) used a double-blind, placebo-controlled, crossover trial to examine alternate-day buprenor-phine administration in 13 opioid-dependent outpatients usingdouble the daily maintenance dose of buprenorphine. Patientswere maintained on either 2, 4, or 8 mg per 70 kg SLbuprenorphine and received their maintenance dose daily for2] days and then received twice their maintenance dose every

other day (with placebo on the interposed day) for another 21days. Participation was contingent on daily attendance andopioid abstinence. Opioid abstinence was verified by on-siteurinalysis testing conducted under observation three times perweek. Seventy-seven percent of the participants (10 out of 13)completed the study (n = 6, 4 mg per 70 kg; n = 4, 8 mg per 70kg). No differences were observed between alternate-day anddaily dosing in terms of opioid intoxication, opioid withdrawal,the ability to discriminate placebo doses, retention, or positiveurinalysis results for nonopioid drugs. The only significantdifference observed was in participant-rated agonist effects,which were lower during alternate-day than daily administra-tion. These data suggest that buprenorphine can be adminis-tered safely and effectively every 48 hr by doubling themaintenance dose. Moreover, this dosing schedule may becost-effective for programs and be useful in settings (e.g., ruralareas) where travel is a barrier to treatment. This observationwas extended in subsequent studies showing that this alternate-day dosing procedure functions as a reinforcer (Amass et al.,1995). Perhaps most significantly, the maintenance dose canalso be tripled, permitting patients to attend the clinic everythird day without risk of overdose or withdrawal (Bickel et al.,1995). Thus, like LAAM, buprenorphine has the potential tobe dispensed three times per week by administering doubledoses Monday and Wednesday and a triple dose on Friday.Data from a current outpatient clinical trial indicate this 3-daya week dosing procedure is acceptable to patients and ispreferred to a 4-day a week regimen (Bickel & Amass, 1994).

Although a large-scale clinical trial to assess carefully theefficacy of alternate-day dosing with buprenorphine is war-ranted, these findings illustrate that buprenorphine has somesimilarities to LAAM and represent an advance over metha-done in the treatment of opioid dependence. Double mainte-nance doses every 48 hr allow patients to attend the clinic lessfrequently without the use of take-home doses and theconsequent risk for diversion of medication, a risk which isparticularly relevant given the numerous reports of buprenor-phine abuse. This procedure may also enhance compliance inpatients whose work, parental responsibilities, or commutetime to the clinic make daily attendance difficult.

Antagonist Properties and Duration of Opioid Blockade

One of buprenorphine's most desirable clinical actions is itsability to block the effects of opioid agonists such as heroin.Buprenorphine (16 mg SC) blocked the self-reported andphysiological effects of 120 mg SC morphine administered 1.5hr after buprenorphine administration (Jasinski et al., 1978).Buprenorphine (2, 4, 8, and 16 mg SL) has also produced adose-related blockade of the effects of hydromorphone (18 mgSC) 24 hr after the last buprenorphine administration (Bickelet al., 1988b). Buprenorphine blockade of self-reports at 24 hrwas greater than its blockade of physiological measures ofopioid-agonist effects. This selective blockade is similar to thatobserved during the dissipation of naltrexone blockade (Vereby,Volavka, Mule, & Resnick, 1977). Thus, these data suggest theblockade produced by the maintenance dose of buprenorphinemay be dissipating at the end of the 24-hr period.

The extent to which that blockade will extend beyond 24 hr


when double the maintenance dose has been administeredremains to be determined and may impact on how alternate-day dosing regimens are implemented into treatment pro-grams. For example, if blockade extends for the entire interdos-ing interval, then these dosing schedules could be applicable tomost patients. However, if these dosing schedules fail toprovide blockade throughout the dosing interval, then suchdosing schedules may need to be restricted to patients whohave achieved appreciable periods of abstinence from streetopioids.

Efficacy as a Treatment Agent

Buprenorphine appears as efficacious as methadone insuppressing opioid intake across both nonhumans and hu-mans. Chronic intravenous buprenorphine and methadone, atroughly equivalent doses according to potency estimates (i.e., 1mg/kg/day buprenorphine and 24 mg/kg/day methadone,Jaffe & Martin, 1990), suppressed similar levels of morphineand heroin self-administration to the same degree in rhesusmonkeys (Harrigan & Downs, 1981). However, another pre-clinical report of the effects of buprenorphine and methadoneon opiate self-administration in rhesus monkeys found bu-prenorphine more effective than methadone (Mello, Bree, &Mendelson, 1983). The reason for the different outcomes isunknown.

Laboratory studies in humans have shown that buprenor-phine produces a 69% to 98% suppression of heroin self-administration in opioid-dependent humans receiving dailysubcutaneous doses of 8 mg (Mello & Mendelson, 1980; Melloet al., 1982). Dose-dependent decreases in illicit opioid usehave also been reported with sublingual buprenorphine main-tenance in a small sample. Approximately 30% of urinecollected during 2-mg maintenance was opiate-positive com-pared with only 10% during 16-mg maintenance (Bickel et al.,1988b).

Similar results were reported in several controlled, outpa-tient studies. Patients maintained for 17 weeks on eitherbuprenorphine (8 mg SL) or methadone (60 mg PO) hadcomparable rates of illicit opiate use (47% and 56%, respec-tively; Johnson et al., 1992). In another study, patients main-tained for 16 weeks on either buprenorphine (average dailydose 8.9 mg SL) or methadone (average daily dose 54 mg PO)also had comparable rates of illicit opiate use (55% and 47%,respectively; Strain, Stitzer, Liebson, & Bigelow, 1994). Inpatients completing 1 month of outpatient treatment withbuprenorphine (2 and 6 mg SL daily), illicit opioid usedecreased by 50%, although not dose-dependently (Kosten etal., 1991). When opioid abstinence was reinforced with vouch-ers exchangeable for retail items, 87.5% of urine samples wereopioid-negative in outpatients maintained on daily 8 mg SLbuprenorphine (Amass, Bickel, Higgins, & Hughes, 1994).Thus, buprenorphine appears to be at least as effective asmethadone at suppressing illicit opioid use in both laboratorysettings and during outpatient treatment.

Discontinuing Buprenorphine Treatment

If buprenorphine becomes widely available as an opioidtreatment agent, knowledge of the extent of withdrawal

occurring following abrupt and gradual discontinuation withbuprenorphine will be important for patient management.Further, because of its unique" pharmacology, buprenorphinemay permit patients to transition directly from buprenorphineto naltrexone (an opioid antagonist) treatment. Such a transi-tion would be beneficial since naltrexone greatly reduces therisk for relapse in this population (Kleber, 1985).

Abrupt Discontinuation

Buprenorphine can induce physical dependence (Fudala etal., 1990; Jasinski et al., 1978). Therefore, knowledge of thedegree of physical dependence resulting from abrupt discontin-uation of chronic buprenorphine treatment will dictate thetype of dose taper regimens used for both inpatient andambulatory detoxification of opioid-dependent patients.

A withdrawal syndrome of a mild-to-moderate magnitudehas been reported following abrupt discontinuation of bu-prenorphine in opioid-dependent humans. This result suggeststhat physical dependence develops to some limited degreeduring chronic treatment (Fudala et al., 1990; Jasinski et al.,1978; Kosten & Kleber, 1988; Lukas et al., 1984). Mild,antagonist-precipitated withdrawal signs have also occurred inresponse to high-dose naloxone challenge following mainte-nance with 3 mg SL buprenorphine (Kosten et al., 1990).

In contrast, withdrawal signs were not observed whenbuprenorphine was discontinued over a 5-day period in heroinaddicts who were maintained on an 8 mg SC dose for 10 days(Mello & Mendelson, 1980; Mello et al., 1982). Similarly,abstinence signs have not been documented in preclinicalstudies with patas (Cowan, 1974) and macaque (Lukas, Mello,Bree, & Mendelson, 1988) monkeys when buprenorphine wasdiscontinued following a month of chronic treatment (see alsoMello etal., 1981).

These inconsistent findings must be evaluated carefully withthe recognition that increased withdrawal symptoms may beassociated with higher buprenorphine doses and longer treat-ment regimens. For example, in an outpatient study, buprenor-phine was abruptly discontinued in opioid-dependent patientsfollowing 1 month of 2, 4, or 8 mg SL buprenorphine (Kosten& Kleber, 1988). In the 24 hr following discontinuation,withdrawal symptoms increased in a dose-dependent fashionwith minimal withdrawal observed in patients receiving eitherthe 2- or 4-mg dose, while withdrawal scores doubled, increas-ing from mild to moderate, in patients maintained on 8 mgbuprenorphine. Observations were not reported beyond the24-hr period following discontinuation. Unfortunately, be-cause of the brief duration of the observations, this study mayhave failed to measure peak withdrawal symptoms. In anotherstudy, mild withdrawal symptoms were observed during a10-day period of saline treatment in opioid-dependent patientspreviously maintained for 45 days on 2 mg SC buprenorphine(Lukas et al., 1984), a dose that is equivalent to approximately3 mg SL (Jasinski et al., 1989). This 10-day assessment periodwas consistent with the typical 10-day observation period usedto characterize withdrawal from prototypic opiates (Eraser,Van Horn, Martin, Wolbach, & Isbell, 1961).

Withdrawal signs were sufficient to warrant therapeuticintervention in 53% of 15 participants withdrawn from bu-


prenorphine in another study (Fudala et al., 1990). Theseparticipants were abruptly withdrawn and maintained onplacebo after receiving 8 mg SL buprenorphine administereddaily for 16 days followed by another 18 days of 8 mg SLbuprenorphine administered either daily or on alternate days.Of the remaining 7 participants, withdrawal signs appearedwithin the first 72 hr, peaking between 3 and 5 days anddiminishing over 8 to 10 days following the last buprenorphinedose. This time-course of withdrawal differs from a report of amore gradual and delayed abstinence period following 54 daysof daily 8 mg SC buprenorphine administration (Jasinski et al.,1978). In that study, administration of buprenorphine to 3opioid-dependent humans was abruptly terminated via double-blind substitution of saline for 10 days. Observations werecontinued for another 13 days. Himmelsbach abstinence scores(Himmelsbach, 1939) gradually increased and peaked 15 dayspostbuprenorphine and continued through Day 23. Partici-pants rated the overall withdrawal syndrome as mild tomoderate although, at its peak, marked effects includedvomiting, chills and sweating, rhinorrhea, diarrhea, restless-ness, joint pain, and insomnia. Moreover, maximum Himmels-bach abstinence scores and symptoms were qualitatively simi-lar to those observed by Fraser et al. (1961) during the first48-72 hr of withdrawal from codeine and propoxyphene butwere lower than those observed for morphine. However,Jasinski et al. (1978) allowed supplemental doses of morphineand valium that may have compromised the characterization ofbuprenorphine withdrawal.

Differences in the time-courses for abstinence signs andsymptoms were likely related to dose, supplemental medica-tion, and length of treatment regimen. That is, Fudala et al.(1990) maintained participants on 8 mg SL buprenorphine for34 days, while Jasinski et al. (1978) maintained participants ona subcutaneous dose of buprenorphine equivalent to 13.3 mgSL (Jasinski et al., 1989) for an additional 20 days.

Although there is some inconsistency, the data generallysupport the observation that buprenorphine can induce physi-cal dependence, and discontinuation of chronic treatmentresults in opioid withdrawal. However, the magnitude of thatwithdrawal appears less than that observed with full efficacyagonists such as morphine. Finally, because both dose andlength of treatment regimen may modulate buprenorphinewithdrawal symptomology, these factors are important toconsider when developing a detoxification schedule.

Detoxification Scheduling

The decreased magnitude of opioid withdrawal observedfollowing abrupt discontinuation of buprenorphine relative tofull efficacy agonists may result from buprenorphine's slowdissociation from opiate receptors and long duration of action.These qualities may impact positively on detoxification out-comes by permitting accelerated buprenorphine detoxifica-tions to be used without inducing significant withdrawaldistress. In designing a buprenorphine detoxification program,three main objectives should be met. First, patient complianceshould be maintained. Second, opioid abstinence should beachieved. Third, minimal abstinence symptomology should

result from the dose reduction schedule to minimize the riskfor relapse.

Some insight as to whether withdrawal from buprenorphinecan be best achieved by a gradual or rapid dose-reductionschedule can be gleaned from two controlled studies. Arandom assignment 90-day outpatient study compared sublin-gual buprenorphine (2 mg) to oral methadone (30 mg) in 45heroin dependent individuals by using double-blind, double-dummy procedures (Bickel et al., 1988a). Following 3 weeks ofmaintenance at the 2-mg dose, the dose was reduced (1.34,0.67, 0.34, and 0.17 mg) at weekly intervals over 4 weeksfollowed by 6 weeks of placebo medication. There were nosignificant differences between methadone and buprenorphineon retention, illicit drug use, or withdrawal symptoms. Thepercentage of patients continuing in both treatments afterWeek 6 declined rapidly, and illicit opiate use steadily in-creased through the detoxification, suggesting that this rapidtaper schedule was not optimal.

A random-assignment 66-day outpatient study demon-strated that a 36-day gradual buprenorphine dose reductionwas superior to a 12-day rapid buprenorphine dose reductionwhen incentives for opioid-negative urine samples were of-fered and counseling was mandated (Amass, Bickel, Higgins,& Hughes, 1994). Participant retention was lower, and opioiduse and participant-rated withdrawal increased to a greaterextent during rapid buprenorphine detoxification. For thegradual and rapid dose reductions, respectively, 100% versus0% of patients were retained in treatment for the entire 9weeks, and 33.3% versus 61.3% of urine was positive foropioids during detoxification. Participant-rated withdrawalincreased at a rate 6 times higher during rapid as opposed togradual detoxification. Taking both studies together, the avail-able data indicate that rapid buprenorphine dose reduction isassociated with poorer treatment outcome. Nonetheless, morestudies are necessary to understand how to best use buprenor-phine as a detoxification agent.

Buprenorphine-Naltrexone Interactions

The literature published to date suggests that buprenor-phine is not antagonized by opioid antagonists except at highdoses of the antagonist, differentiating it from full efficacyagonists. This characteristic may benefit three treatment areas.First, it may be possible to transfer patients directly frombuprenorphine to naltrexone, thereby eliminating the need fordetoxification before naltrexone treatment. Second, a combina-tion buprenorphine-naltrexone product might be developed toextend buprenorphine's duration of blockade and further limitits abuse liability. Third, by developing a range of combinationmixtures in which the buprenorphinemaltrexone ratio is gradu-ally adjusted, a seamless transition to naltrexone treatmentmay be possible.

Preclinical data suggest that opioid antagonists do notdisplace buprenorphine from receptors and therefore do notprecipitate withdrawal (Woods et al., 1985). For example,when naloxone (0.3 mg/kg) was administered before buprenor-phine, the effects of buprenorphine were completely blocked(i.e., buprenorphine did not displace naloxone). However,when buprenorphine was administered first, naloxone doses


up to 100 mg/kg did not reverse buprenorphine's effects (i.e.,naloxone did not displace buprenorphine; Shannon, Cone, &Gorodetzky, 1984). Thus, the dose of an opioid antagonistnecessary to reverse the actions of buprenorphine is substan-tially greater than the dose necessary to block the effects of thiscompound (France, Jacobson, & Woods, 1984; Ranee &Dickens, 1978). Buprenorphine's high affinity for opioid recep-tors undoubtedly prevents naloxone from displacing buprenor-phine already bound to these sites (Hambrook & Ranee,1976), while also limiting the intensity of antagonist-precipi-tated withdrawal.

Clinical reports further confirm that very large doses ofnaloxone are required to antagonize the effects of buprenor-phine. For example, 4 mg SC naloxone administered 3.5 hrafter buprenorphine failed to precipitate withdrawal in 3participants maintained on 8 mg SC buprenorphine for 38 days(Jasinski et al., 1978). In fact, precipitating withdrawal frombuprenorphine when naloxone is administered 24 hr after thelast buprenorphine dose requires at least 25 times the intrave-nous naloxone dose (i.e., 0.4 mg) necessary to precipitatemarked or severe withdrawal from full agonists such asmorphine (Kosten et al., 1988, 1989, 1990; Quigley et al.,1984). Only a remarkable dose of naloxone (35 mg IV)produced a mild withdrawal response in patients maintainedon 3 mg SL buprenorphine (Kosten et al., 1990). In healthyvolunteers, reversal of buprenorphine-induced (0.3 mg IV)respiratory depression by naloxone was dose-dependent andhad gradual onset, with maximal reversal effects taking 3 hrfollowing a 10-mg IV dose (Gal, 1989). The lack of the abruptreversal effect, typical of most naloxone-opioid interactions,again underscores naloxone's difficulty in displacing buprenor-phine already bound to opioid receptors (Hambrook & Ranee,1976).

The previous observations suggest that buprenorphine mayresult in an easier and more expedient transition to naltrexonethan is currently possible with methadone. Such a transitionmay improve patients' compliance with naltrexone treatment.The question of how to most effectively transfer patients frombuprenorphine to naltrexone must await more research, butthe possibilities could vary across a broad range. At oneextreme, detoxification with buprenorphine may decrease thenumber of days required without medication before startingnaltrexone. The transition from methadone to naltrexonerequires patients to be completely detoxified from methadone,to cope with the methadone withdrawal syndrome, and toremain abstinent from opioids for up to 10 days beforereceiving naltrexone (Kleber, 1989). This delay between ago-nist and antagonist therapy substantially increases an individu-al's susceptibility to relapse (Kleber, 1989). Other techniqueshave been developed to shorten the period between agonistand antagonist therapy, but these procedures require hospital-ization and the coadministration of other agents such asclonidine and benzodiazepines (Brewer, Rezae, & Bailey,1988; Charney, Heninger, & Kleber, 1986; Kosten et al., 1990,1991; Loimer, Lenz, Schmid, & Presslich, 1991; Vining, Ko-sten, & Kleber, 1988). However, because buprenorphine is noteasily antagonized by opioid antagonists, the transition frombuprenorphine to naltrexone may be easier. Thus, perhaps

naltrexone could be administered at the end of a detoxificationwith a limited delay.

At the other extreme, buprenorphine and naltrexone couldbe coadministered at certain doses and permit a seamlesstransition from buprenorphine to buprenorphine-naltrexoneto naltrexone. For example, perhaps a series of mixturesvarying in net agonist effect could be used.to gradually taperthe agonist actions over time, while slowly fading patients intonaltrexone treatment. Moreover, a combination buprenorphine-naloxone or buprenorphine-naltrexone mixture may limitbuprenorphine's abuse potential and may be one strategy formitigating against illicit diversion (Preston, Bigelow, & Lieb-son, 1988; Weinhold, Preston, Farre, Liebson, & Bigelow,1992). Of course, the alternate-day dosing schedules, discussedearlier, may minimize many concerns about diversion viatake-home doses. However, there still may be occasions wheresuch a combination mixture is useful, such as for travel oremergencies that extend beyond the limits of the alternate-daydosing effect.

A sublingual buprenorphine-naloxone combination tablet isin fact being developed by NIDA (D. Segal, personal commu-nication, December 8, 1994). This sublingual combinationtablet may be particularly useful because of the differentparenteral to sublingual potency profiles for buprenorphineand naloxone. While buprenorphine has an approximately 2:1parenteral to sublingual potency ratio (McQuay, Moore, &Bullingham, 1986), studies with opioid-dependent participantsindicate a parenteral to sublingual potency ratio of approxi-mately 10:1 to 20:1 for naloxone (Preston, Bigelow, & Liebson,1990). Sublingual naloxone doses up to 5 times the intravenousdose that reverses toxic opioid overdose can be administeredsafely to opioid abusers without precipitating withdrawal(Preston et al., 1990). Thus, the possibility exists that acombination mixture could be developed that would permitbuprenorphine's agonist actions to operate when administeredsublingually but would precipitate withdrawal in opioid-dependent individuals when administered parenterally andhence help mitigate against unauthorized use of buprenor-phine. This strategy for limiting abuse has been successfullyachieved with pentazocine-naloxone combinations (Legros,Khalili-Varasteh, & Margetts, 1984), and initial studies withbuprenorphine are encouraging. For example, the concurrentadministration of buprenorphine and naloxone to nondepen-dent postaddicts produced less agonist effects than buprenor-phine alone (Weinhold et al., 1992). In participants main-tained on 50 mg/day of oral methadone, naloxone (0.2 mg IM)alone and in combination with buprenorphine (0.2 and 0.3 mgIM) precipitated withdrawal (Preston et al., 1988). Althoughthe combination product was identified as an opioid antago-nist, buprenorphine somewhat "blunted" naloxone's effects onwithdrawal scores. Importantly, this buprenorphine-naloxonemixture (i.e., 0.3/0.2 IM) did not compromise the analgesicefficacy or safety of buprenorphine when administered for thetreatment of postoperative pain (Roily, Poelaert, Mungroop,& Paelinck, 1986; Vanacker, Vandermeersch, & Tomassen,1986). More research is necessary to determine the extent towhich a sublingual combination mixture can mitigate againstparenteral abuse of buprenorphine. Although prior researchsuggests that a combination mixture would precipitate with-


drawal in methadone-maintained individuals, studies areneeded to assess directly the effects of a combination mixturein those populations most likely to abuse buprenorphine onceit is available for widespread clinical use: buprenorphine-maintained individuals, opioid-dependent individuals not seek-ing treatment, and nondependent opioid abusers. The degreeto which a combination mixture limits buprenorphine abusewill most likely depend on the extent to which naloxone eitherantagonizes opioids or blunts buprenorphine's effects whendoses of buprenorphine indicated for opioid dependencetreatment are used.

Finally, a combination product, assuming there is a compat-ible formulation, may enhance the acceptability of naltrexone.Naltrexone's limited acceptability among patients is reflectedby the fact that few individuals suitable for naltrexone treat-ment ever receive the first dose (KJeber, 1989). One factorcontributing to this limited acceptability is the absence ofagonist effects. If buprenorphine and naltrexone could becoadministered at certain doses, then the agonist effects ofbuprenorphine might support self-administration, while naltrex-one would blunt the effects of illicit opioids. Of course, doseselection of the two agents would be very important. Ideally,the buprenorphine dose would need to be sufficiently low sothat it did not produce any clinically significant physicaldependence, but it would need to be sufficiently high foragonist effects to be experienced. The naltrexone dose wouldneed to be sufficiently low so as to not block buprenorphine'seffects but sufficiently high so as to blunt the effect of any illicitopioid. This raises the important question of whether blockadeneeds to be total to produce clinically important results (cf.Bickel et al., 1988b). Nonetheless, if successful, the combina-tion product would promote treatment compliance via bu-prenorphine's agonist effects, while naltrexone's antagonisteffects could enhance blockade and permit smaller buprenor-phine doses to be used (i.e., to block other opioids withbuprenorphine alone is expensive, requiring doses 25- to50-fold greater than the analgesic dose).

We do not know where along this range of potentialoutcomes the results of research will point. Nonetheless, any ofthese outcomes should minimize the likelihood of relapsefollowing buprenorphine before the initiation of naltrexonetreatment. Issues in transitioning patients from buprenorphineto naltrexone and the feasibility of the combination productalso raise numerous questions about the clinical pharmacologyof these two compounds. Significant questions include identify-ing doses of naltrexone that would permit the expression ofbuprenorphine's agonist effects, assessing the efficacy andduration of the blockade produced by the combination prod-uct, and evaluating the effects of the combination product ontreatment compliance. Such information is essential to deter-mine the feasibility of the combination mixture.

Summary and Future Directions

Buprenorphine is a promising alternative for the treatmentof opioid dependence, and it appears to compare favorably tomethadone for both maintenance and detoxification treat-ment. Buprenorphine can antagonize the effects of |j, opioids,is less likely to be associated with toxic overdoses, results in

milder withdrawal symptomology during gradual detoxifica-tion, and can support less than daily dosing regimens. How-ever, several clinical issues remain to be resolved beforebuprenorphine is accepted for widespread clinical use. Issuesthat await further research include developing protocols fortransferring patients from methadone to buprenorphine, deter-mining the proper buprenorphine maintenance dose, assessingthe feasibility of a combination buprenorphine-naltrexoneproduct, determining the most effective detoxification sched-ule, and evaluating buprenorphine's safety for long-termmaintenance. Although the lack of behavioral and physiologi-cal toxicity associated with large buprenorphine doses maysupport a longer interdosing interval, the extent to whichblockade of exogenous opioids is maintained over intervalsgreater than 24 hr also remains to be determined. Finally,although buprenorphine has a wider margin of safety thanmethadone, it still has the potential for abuse. Therefore,regulatory control should be maintained once buprenorphineis approved as a treatment agent. Ultimately, controlledoutpatient investigations designed to determine how buprenor-phine and other rehabilitative services can be combined toyield better treatment outcomes are necessary.

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Received November 13,1994Revision received April 17,1995

Accepted May 24,1995

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