A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence

DRUGand ALCOHOL@ DEPENDENCE Drug and Alcohol Dependence 40 (1995)17-25

A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence Rolley E. Johnson*, Thomas Eissenberg, Maxine L. Stitzer, Eric c. Strain, Ira A. Liebson, George E. Bigelow Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, Behavioral Pharmacology Research Unit, 5510 Nathan Shock Drive, Baltimore, MD 21224-6823. USA

Received9 February1995;accepted26 July 1995

Abstract Large-scaleplacebo controlled clinical trials assessingthe efficacy of medications for the treatment of drug dependencehave generally been limited to alcohol, cocaine and nicotine dependent populations. The purpose of the present study was to assessthe early (l-2 week) clinical effectiveness of buprenorphine versus placebo in an opioid dependent population. The study used a parallel-group design with a behavioral choice component to compare buprenorphine (a mu-opioid partial agonist) to placebo for the treatment of opioid dependence.Opioid dependent volunteer patients participated in a ICday study to assessthe effectiveness and patient acceptanceof this new pharmacotherapy for the treatment of opioid dependence.Patients were randomly assignedto placebo (n = 60) or 2 mg (n = 60) or 8 mg (n = 30) daily sublingual buprenorphine. All doseswere administered double-blind. On days 6-13 all patients could request a dose change, knowing that their new dose would be randomly chosen from the remaining 2 alternatives. Compared to placebo, patients given buprenorphine (independent of dose) showed greater time on initial dose, requested fewer dose changes, used less illicit opioids (assessedby urinalysis), and rated dose adequacy higher. These results demonstrate that a placebo controlled study with a behavioral choice component is an effective means of assessingthe potential efficacy and acceptability of new pharmacotherapies for opioid dependence. Keywords: Buprenorphine; Clinical trial; Placebo; Efficacy; Acceptability

1. Introduction The parallel-group, placebo controlled clinical trial is one of the five treatment evaluation designs generally recognized as adequate and well controlled (Food and Drug Administration, 1988), and has been called the ‘gold standard’ of the Food and Drug Administration (FDA) (Rothman and Michels, 1994). Generally, FDA officials have argued in favor of placebo controlled studies so long as life is not threatened (Temple, 1982). In at least one case, FDA has withheld the approval of a new drug because no data from placebo controlled trials were available (Temple, 1982). Large-scale placebo controlled clinical trials assessing the efficacy of medications for the treatment of drug dependence have * Correspondingauthor. Fax: (410)5500030.

generally been conducted with alcohol (e.g., Fuller et al., 1986), cocaine (e.g., Alterman et al., 1992; Kosten et al., 1992; Wolfsohn et al., 1993; Carroll et al., 1994), and nicotine dependent populations (e.g., Fagerstrom et al., 1993; Tonnesen et al., 1993). No controlled study of a treatment for opioid dependence has been reported where patients were initially randomized to a placebo condition. Studies have been reported using a placebo maintenance group (following methadone withdrawal) to evaluate the efficacy of differing methadone doses (Senay et al., 1977; Newman and Whitehall, 1979; Strain et al., 1993) in opioid-dependent populations. Buprenorphine, a mu-opioid partial agonist under development as a pharmacotherapy for treatment of opioid dependence, was selected for comparison to placebo. Several lines of research support the use of buprenorphine as a pharmacotherapy for opioid abuse. First, the

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subjective effects of buprenorphine are opioid-agonistlike (Jasinski et al., 1978; Bigelow and Preston, 1992; Weinhold et al., 1992; Pickworth et al., 1993;Walsh et al., 1994) suggesting that individuals dependent on opioids may find the drug an acceptable alternative to illicit opioids. Second, buprenorphine maintenance blocks or greatly attenuates the self-reported drug effects of concurrently administered opioids (Jasinski et al., 1978;Bickel et al., 1988b;Fudala et al., 1988;Rosen et al., 1994).Third, the withdrawal syndrome following discontinuation of daily buprenorp.hine is relatively mild (Jasinski et al., 1978; Kosten and Kleber, 1988; Fudala et al., 1990). Fourth, buprenorphine appears to be a safer pharmacotherapy than pure mu agonists, such as methadone and levo-alpha acetylmethadol (LAAM), becauseagonist effects such as respiratory depression reach a ceiling at sub-toxic and clinically useful doses (Budd, 1981;Lewis, 1985;Walsh et al., 1994). Fifth, the long duration of action of buprenorphine (Jasinski, 1978;Lewis, 1985;Johnson et al., 1989) may make less than daily dosing feasible without loss of efficacy (Fudala et al., 1990; Resnick et al., 1993; Amass et al., 1994). Several randomized, double-blind, parallel-group, trials short-term maintenance clinical have demonstrated the efficacy of buprenorphine to be comparable to that of methadone on outcomes such as decreasedopioid-positive urine rates and retention in treatment (Bickel et al., 1988a; Johnson et al., 1992; Strain et al., 1994). One study failed to demonstrate comparable efficacy betweenbuprenorphine and methadone on these outcome measures(Kosten et al., 1993). Importantly, all of these clinical trials involved lengthy maintenance periods, and none involved a placebo control. Rather, these trials compared buprenorphine to methadone, an existing effective treatment for this population (e.g., Bickel et al., 1988a;Johnson et al., 1992; Kosten et al., 1993; Strain et al., 1994) and/or different dosesof buprenorphine (Kosten et al., 1993;Ling et al., 1993). While no placebo controlled clinical trials of buprenorphine have been reported, there are several reports using placebo to evaluate factors related to the clinical efficacy of buprenorphine. For example, Mello and Mendelson (1980; also see Mello et al., 1982) used a placebo controlled laboratory procedure to demonstrate that buprenorphine suppressedheroin selfadministration in heroin-dependent men. Others have used placebo administration within the context of buprenorphine maintenance to study the effective buprenorphine inter-dose interval (Fudala et al., 1990; Amass et al., 1994) and withdrawal symptomatology (Seow et al., 1986). Thus, except for assessingoperant behavior, inter-dose intervals, or withdrawal symptomatology, buprenorphine has not been compared to a placebo treatment condition.

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The purpose of the present study was to assessthe early (l-2 week) clinical effectivenessof buprenorphine versus placebo in an opioid dependent population. The study incorporated traditional measuresof efficacy (e.g., time on initial dose-retention, illicit opioid use). In addition, an option to change dosesfollowing short-term exposure to a randomly assigned dose provided a behavioral method to assessearly treatment acceptability, while limiting exposure to placebo. 2. Materials and methods 2.1. Patients

Participants were 150 male and female volunteers admitted to a short-term opioid treatment research clinic. Patients were enrolled in a two part, 20-week study of buprenorphine. The first study, the results of which are reported here, lasted two weeks. The second study, reported in this issue (Johnson et al., 1995), began following 1 week of stabilization (week 3). In study I (the present study), patients were informed that they would be randomly assigned to one of three treatment conditions, and that one of these conditions was placebo while the other two were different dosesof buprenorphine. All patients met the following criteria for study participation: (a) pre-admission urine specimen negative for methadone and positive for opioids; (b) 18-50 years of age; (c) negative pregnancy test for females; (d) absence of major medical illness; (e) no chronic medications; (f) no history of serious psychiatric illness (e.g., bipolar depression, schizophrenia); (g) met federal guidelines for methadone treatment; (h) DSMIII-R diagnosis of opioid dependence(E module of the SCID; Spitzer and Williams, 1987); (i) no prior drug abuse treatment with buprenorphine; and (i) three months sincelast treatment at the clinic. Ineligible applicants were assisted in seeking alternative treatment. Table 1 summarizesdemographic information by group. Though group membership was assignedrandomly, the groups differ with respect to gender (a significantly larger proportion of females are in the 8-mg buprenorphine group as compared to the 2-mg buprenorphine group). Groups do not differ significantly on any other demographic characteristic. Some analyses contained below are based upon the subset of patients who completed the 1Cday study (n = 110). These patients also differed on one demographic characteristic: employment (0 mg = 47.5%; 2 mg = 33.3%;8 mg = 13.6%).Significantly fewer patients assignedto the 8-mg group were employed as compared to the placebo group. No other significant differences were identified for this subset of patients. While this clinical trial was on-going, gender differenceswere of increasing interest in regulatory decision-making (Institute of Medicine, 1994) and clinical treatment (e.g., LAAM-Package Insert). Therefore, upon study comple-

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Table 1 Demographic characteristics of 150opioid dependent patients assigned to placebo or buprenorphine treatment Demographic characteristics Characteristics

Female (%) Non-white (%) Marital status (%) Single Married Widowed Separated Divorced Employed (%) Legal problems (%) Education Mean SD. Age Mean SD. Past 30 days drug use (days) Alcohol Mean SD. Cocaine Mean S.D. Heroin (i.v.) Mean S.D. Lifetime drug use (years) Alcohol Mean SD. Cocaine Mean S.D. Heroin (iv.) Mean SD. Previous treatment episodes Mean SD.

Initial buprenorphine dose 0 m8 (n =60)

2 m8

28 51

25 53

50' 40

40 28

50 15

47

0

0

17 37 38

17 18 30 33

3 21 13 13 40

11.52 1.84

II.45 1.69

11.07 1.62

34.99 6.18

33.70 6.45

31.65 6.51

6.30 8.43

6.02 8.58

4.47 8.09

6.72 10.14

7.90 11.08

9.83 11.45

29.22 3.43

29.20 2.58

29.93 0.25

3.31 6.04

4.69 7.01

3.15 6.44

1.75 3.58

2.09 3.63

2.70 4.12

8.75 7.19

9.28 1.23

1.76 6.07

1.53 1.51

1.37

1.17 1.26

IS

8 mg (n= 60) (n = 30)

1.44

10

*Group differences were significant (P < 0.05) for Female (%).

tion, a post-hoc analysis was conducted to assessgender differences. The study was approved by the local institutional review board, and each patient gave written, informed consent prior to participation. 2.2. Drug and drug administration

Buprenorphine hydrochloride was provided by Reckitt and Colman (Hull, England) through the Research Technology Branch, National Institute on Drug

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Abuse (Rockville, MD). Drug solutions were aseptically prepared in 30% ethanol (v/v) and stored under refrigeration (2- 1Y’C). Placebo solution consisted of vehicle only. All solutions were administered daily by the sublingual route in a volume of 1 ml using Ped-Pod oral dispensers(SoloPak Laboratories, Franklin Park, Ill). Patients were instructed to refrain from speaking and to hold the solution under their tongue for 5 min, and were observed and timed by nursing staff to ensure compliance. 2.3. Procedures

This 1Cday study used a randomized, double-blind, parallel-group design. Participants were randomly assigned among three treatment conditions: placebo (n = 60), 2 mg buprenorphine (n = 60), or 8 mg buprenorphine (n = 30) in a 2:2:1 ratio. The assumption that the 8-mg condition would produce a larger effect (i.e., fewer patients would opt for a dose change) than the other 2 conditions guided the decision to assign unequal numbers of patients to the 3 groups. Patients assignedto the placebo and 2-mg groups received that dose on days l-6 of treatment. Patients assignedto the S-mggroup received 2 mg on day 1,4 mg on day 2, and 8 mg on days 3-6. On days 6-13 all patients could request a dose change. Dose changesrequested on a given day became effective the following day and continued through study day 14. Patients were informed that the new dose would be randomly chosen from the two to which they had not been originally assigned.That is, if a patient originally receiving 2 mg of buprenorphine opted for a dose change, that patient would have an equal chance of receiving 8 mg buprenorphine or placebo. Patients were reminded (on day 6, the beginning of the dose change period) that they could request a dose change on day 6, or on any day up to and including day 13.Only one dose change was permitted. Both the original and the changed dose were delivered under double-blind conditions (i.e., patients requesting a dose change were assured their request was honored, but remained uninformed of both their original and new dose). Patients were required to come to the clinic daily to receivetheir medication. Participants who missed 5 consecutive days of medication were dropped from the study. No take-home medication was provided. 2.4. Other treatment

Patients were admitted using a rapid intake procedure and assignedan individual counselor who set treatment goals and developed an individualized treatment plan. Six problem areas were evaluated and addressed by counseling staff: physical/nutritional, emotional/behavioral (these first two included drug and alcohol use), social/family, activity/recreation, legal, and educational/ vocational. In addition, patients were required to attend

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group therapy sessionsa minimum of once per week. Group therapy sessionsconcentrated on educational issuesassociatedwith drug use and on relapse prevention. On-site medical services were provided by a full-time internist. 2.5. Primary outcome measures Percent of patients on initial dose is defined as the percent of patients (n = 150) in each group who remained on the doseto which they were originally randomized for each day of this 1Cday study. Patients were no longer on their originally randomized dose when they either dropped out of the study, or opted for a dose change (on or after day 6). Percentof patients requesting a dosechange is defined as the percent of patients within a group that requested a dose change between days 6 and 13. In this measure, a drop-out is not counted. Thus, only patients who remained in the study at day 14 (the final dose change assessment day) are included in this calculation (n = 110).

are included from patients who remained in the study through day 14, and who had at least one data point for this measure (n = 108). 2.7. Data analysis Data reflecting the percent of patients remaining on their initial dose were compared, by group, using the Lee-Desu statistic (Lee and Desu, 1972).All other measures were analyzed using a two-factor analysis of variancewith gender and buprenorphine dose (0,2 or 8 mg) as the independent variables. Tukey’s honestly signilicant difference procedure was used for pairwise comparisons following a significant F test. Comparisons for which P < 0.05 are reported as significant. Tests of proportions (urine results) were analyzed as raw data, and following an arcsine transformation, in order to clarify meaningful differences for observations at the extremes of the distribution (Snedcor and Cochran, 1989). Because the two analyses did not differ, the raw data are presented for clarity. 3. Results

2.4. Secondaryoutcome measures Percent of urine specimenspositive for opioids and cocaine is defined as the percent of all urine specimens provided by a patient that tested opioid-positive or cocaine-positive in separate analyses using the enzymemultiplied immunoassay technique (EMIT; Syva Corp, Palo Alto, CA). Results from urines collected on days 3-7 are included in this measure to equalize the duration of exposure each patient had to a given dose of buprenorphine. Day 7 is included because results of urinalysis on that day reflect drug usage on days prior to day 7 (e.g., day 6). Becausesupervised urines were collected on Mondays, Wednesdaysand Fridays, a maximum of three urines could be collected in this interval. These urine samples reflect illicit drug use after randomization to treatment, but before the dosechange option could be exercised and implemented. Data are included from patients who remained in the study through day 14, and who provided at least one urine specimen during days 3-7 (n = 103). Dose adequacy is defined as a response on a visual analog scale (VAS). Patients were instructed to make a vertical mark on a 100~mmlong line in responseto the question ‘How well has this dose of medicine been holding you?‘. The line was anchored by ‘too low’ on the left and ‘too high’ on the right. The measurewas scored as distance (in mm) from the left end of the line to a vertical mark made by a patient. Patients completed the VAS daily on days 3-7. Day 7 is included becausethis measure reflects the previous 24-h period. The mean VAS score for a patient for days 3-7 was calculated using all available data (e.g., if available, days 3,4, 5, 6 and 7 of an individual were averaged).Thus each patient contributed a single averagedscore to the analysis. Data

A total of 40 patients dropped out of the study through day 14,20 (33%) from the 0-mg group, 12 (20%) from the 2-mg group, and 8 (27%) from the 8-mg group. Of the 40 patients who dropped out, 15 were female. Thirty-two percent of the females who participated dropped out before the study was completed; 24% of the males dropped out. In separateone-factor analysespercent drop-out did not significantly differ across groups (F(2,147) = 1.36, n.s.) or by gender (F < 1). Data from patients who dropped out of the study are included in the percent of patients on initial dose measure, but are omitted from the other measures to avoid confounds (e.g., patients who dropped out of the study could not request a dose change). 3.1. Primary outcome measures 3.1.1. Percent ofpatients on initial dose.Fig. 1 presents the percent of patients in each group who remained on their initial dose by day, independent of gender. The data of all 150 patients are summarized. The data from two patients (both assigned to placebo dosing) were coded as ‘censored’ becausethey were incarcerated during the study. The days a patient stayed on initial dose ended either with a dose change request or drop-out from the study. Survival analysis revealed that the percent of patients remaining on their initial dose through the 1Cday study differed across treatments (LeeDesu = 18.64,df = 2, P < 0.001). Pairwise comparisons revealed that the two active drug conditions differed from the placebo condition, but did not differ from each other. 3.1.2. Percentofpatients requestinga dosechange.Fig. 2 presentsthe percent of patients who requested a dose

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Percent

Patients

on Initial

Dose

Dose p change option in loogo80 70 60 PERCENT 50 40 30 20 loOT 1 1 012345678

’

I

I

1

I

I 9

--t-

Placebo (n = 60) 2 mg (n = 60) 8 mg (n = 30)

I I 10 11

I 12

f I 13 14

Day Fig. 1. Percent of patients on initial dose, by group (0 mg, 2 mg or 8 mg buprenorphine) and day for all patients (n = 150).

change between days 6 and 13, independent of gender. This graph displays data from patients (n = 110)who remained in treatment to day 14 and therefore had the option to request a dose change through day 13. In addition, 3 patients requested a dosechange and subsequently dropped out of the study (2 originally assigned to 0 mg, 1 originally assignedto 2 mg; all 3 of these patients were reassigned to 8 mg). Two-factor ANOVA revealed a significant main effect of dose (F(2,104) = 5.57, P < 0.01). Neither the main effect of gender, nor the interaction of gender and dose were significant. Collapsed across gender, a greater percentage of patients in the placebo group requesteda dosechange (65%), as compared to either the 2-mg (27%) or 8-mg (32%) active buprenorphine groups. Pairwise comparisons revealed that the two active drug conditions differed from the placebo condition, but did not differ from each other.

3.2. Secondary outcome measures 3.2.1. Mean percent of urine specimens positive for opioids and cocaine. Fig. 3 presents the percent of urine

specimenspositive for opioids in the 72 male patients Urine Specimens Positive for Opiates Males

100

75 PERCENT 50

25

0

8 BUPRENORPHINE

DOSE (MG)

Females 100

Patients Requesting Dose Change 75

100 PERCENT

80

50

PERCENT

60 40

25

20 Ci

8 2 BUPRENORPHINEDOSE (MG)

0

Fig. 2. Percent of patients who requested a dose change by group (0 mg, 2 mg or 8 mg buprenorphine) for patients who completed the study through day 14 (n = 110). Brackets indicate S.E.M.

!

2

8

BUPRENORPHINE

DOSE (MG)

0

Fig. 3. Percent of urine samples positive for opioids by group (0 mg. 2 mg or 8 mg buprenorphine) for patients who completed the study through day 14and who contributed at least one urine sample between days 3 and 7 (n = 103). Brackets indicate S.E.M.

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and the 31 female patients who completed the study through day 14, and who provided at least one urine specimen between days 3 and 7. Two-factor ANOVA revealed a significant main effect of dose (fl2,97) = 3.14, P < 0.05) and a significant main effect of gender (F(1,97) = 4.97, P < 0.03). The interaction of gender and dose was not significant. As can be seen from Fig. 3, male patients showed the greater decrease in percent of urine specimenspositive for opioids. Indeed, pairwise comparisons revealed that, for males, the two active drug conditions differed from the placebo condition, but did not differ from each other. In contrast, pairwise comparisons revealed no significant differencesacross doses for females. The urine specimensof the same 103 patients were analyzed for evidence of cocaine use. As above, a percent positive scorewas determined for each patient. The two-factor ANOVA revealed no significant effects on this measure (all Fs < 1). 3.2.2. Dose adequacy (hold)

visual analog scale

(FM). Fig. 4 presentsthe results of the dose adequacy VAS, averaged by group, independent of gender. Data collected on days 3-7 of treatment are included for all patients who completed the study through day 14, and who contributed at least one data point for this measure (n = 108). Two-factor ANOVA revealed a significant main effect of dose (F(2,102) = 5.28, P < 0.01). Neither the main effect of gender, nor the interaction of gender and dose.were significant. Pairwise comparisons revealed that eachbuprenorphine group differed from placebo but not from each other. Dose Adequacy VAS .

100 J

--r-

0

8

2 BUPRENORPHINE

DOSE (MG)

Fig. 4. Mean response,in millimeters, on the analog scale item ‘How well has this dose of medicine been holding you?’ by group (0 mg, 2 mg or 8 mg buprenorphine) for patients who completed the study through day 14 and who contributed at least one data point between days 3 and 7 (n = 108). Brackets indicate S.E.M.

4. Discussion The methodology used in this study provided for a placebo controlled assessment of the clinical effectiveness and acceptability of buprenorphine during the initial stageof treatment for opioid dependence.The results from both primary outcome measuresindicate that buprenorphine is more effective than placebo for the treatment of opioid dependence.Patients maintained on active buprenorphine (2 or 8 mg s.l.), remained on their assigned dose longer and were less likely to request a dose change than were patients maintained on placebo. The behavioral choice component of this study allowed for the opportunity to assessthe acceptability of a medication in a clinical setting. Over 60% of the patients in the placebo group opted to change their dose, while only 27% (2 mg) or 32% (8 mg) of the patients assigned to the active medication (buprenorphine) opted to change their dose. One interpretation of these results is that the majority of patients maintained on active medication (buprenorphine) found their treatment acceptable, while those maintained on placebo did not. Treatment acceptability is an important component of clinical efficacy, as the practical effectiveness of any treatment is limited by patient compliance. For example, the pharmacological activity of naltrexone as an opioid antagonist is unquestioned, but opioid dependent individuals assigned to naltrexone treatment show poor retention (e.g., National Research Council Committee on Clinical Evaluation of Narcotic Antagonists, 1978). Similarly, alcoholics who take disulliram show dramatic increases in alcohol abstinence, but many alcoholics given disulfiram fail to comply with the treatment regimen (Fuller et al., 1986). In both casesthe medication is pharmacologically effective, but its unacceptability to the target population results in limited clinical efficacy. In the present study, acceptability of the three dosesof buprenorphine (0, 2 or 8 mg) was assessedby offering all patients one chance to change from their initial dose (under double-blind conditions) to one of the other two doses. The fact that most buprenorphinemaintained patients opted to continue on their initial dose while most placebo patients opted for a dose change supports the conclusion that buprenorphine is an acceptable treatment for an opioid-dependent population. The results of the behavioral choice component are open to at least one other interpretation. The outcome of controlled studies employing ‘inactive’ placebo may be influenced by a non-specific difference between active and inactive drugs that can impact on patient expectancy. That is, if patients detect the absence of an active drug effect, they may conclude that they have been assignedto placebo and leave the study or show other undesirable outcomes (e.g., illicit drug use) as a consequenceof low expectation of treatment efficacy. Indeed,

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the problem has led some researchersto call for the use of an active placebo (Greenberg and Fisher, 1994). An active placebo is a compound with detectable effects but not specifically effective in altering targeted outcome measures.The use of an active placebo in clinical trials, especially those using experienceddrug usersas patients, would add further refinement to controlled treatment evaluations. Results from both secondary outcome measuresalso support the effectivenessof buprenorphine as a treatment for opioid dependence.Male patients receiving buprenorphine had significantly fewer opioid positive urines, as measured by urinalysis, during days 3-7 of treatment; the low number of femalesin each group may have contributed to the observed gender difference. To our knowledge, the observation of gender differences in trials of buprenorphine has not previously been reported. Additionally, patients maintained on buprenorphine reported higher dose adequacy ratings than patients maintained on placebo. All dose adequacy means displayed in Fig. 4 are low. However, other investigators using this measurein a comparison of methadone dosesof 50,20 and 0 mg report that patients rated thesethree doseswith a mean score (acrossweeks- not days) of approximately 44, 42 and 35, respectively (Strain et al., 1993).The short-term effectivenessof buprenorphine, as measured by decreased opioid use, is particularly noteworthy, since urine results are a relatively insensitive index of drug-use behavior change (i.e., when drugs are used frequently, a reduction in the frequency of use may not be reflected in urinalysis measures), and often 4-5 weeks of treatment are necessary before urinalysis differences are observed (e.g., Johnson et al., 1992; Strain et al., 1993). Overall, results of this study support the use of buprenorphine as a treatment for opioid dependence,although the early effectiveness of buprenorphine, as measuredby decreasedopioid use, may be gender specific. A noteworthy feature of the present results is the similarity of the two buprenorphine groups on almost every outcome measure- i.e., the lack of dose-related effects. The failure to observe dose-responsivenessis most likely due to the shallow dose-responsecurve of buprenorphine which is indicative of a partial agonist. Factors contributing to a lack of dose-responsiveness with buprenorphine may include: (a) the dependent measurein question (measuresof agonist- or antagonistlike effects) and intersubject variability (the ceiling for maximum agonist- and antagonist-like effects may vary); and (b) the study design (a short observation period may better measure agonist-like activity). The first of these factors may have contributed to other reports indicating that the effects of buprenorphine are sometimes dose-dependent and sometimes non-dosedependent. Jasinski et al. (1978) reported dose-related acute agonist effects, but noted that the relative potency

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(compared to morphine) declined as the buprenorphine dose increased- fitting a partial agonist profile. Walsh et al. (1994) reported a ceiling on the magnitude of acute opioid agonist effects produced by buprenorphine, such that further dose increasesdid not result in more intense drug effects. This ceiling occurred at 16 mg s.l. for ratings of ‘any drug effect’ and ‘high’, but at 2 mg s.l. for ratings of ‘good effects’ and ‘liking’. Also, in a trial of buprenorphine maintenance Kosten et al. (1993) reported 6 mg/day s.l. buprenorphine to be equivalent to 2 mg/day on treatment retention and on urinalysis measures of opioid use, but to be more effective on selfreported opioid use(using an end-point analysis) and on withdrawal suppression. Finally, Bickel et al. (1988b) reported that buprenorphine produced dose-related blockade of acute opioid challenge effectsup to dosesof 16 mg/day (s.1.).Given the complex pharmacodynamic and pharmacokinetic profile of buprenorphine, the lack of dose responsivenessfollowing the administration of large doses ( > 8- 16 mg/day) must be considered when assessingoverall treatment efficacy. Such consideration is especially important given that larger doses of buprenorphine primarily increasethe duration of blockade and suppressionof the opioid withdrawal syndrome. In effect, larger doses of buprenorphine may autoantagonize (Kareti et al., 1980) the agonist effects perceived as positive by the patient. Second, the lack of dose-responsivenessobserved in this study could also have resulted from the study design. For example, the behavioral choice contingencies faced by the patients may have decreasedthe probability of observing dose-responsivenessin both primary outcome measures,particularly on the percent of patients requesting a dose change. Specifically, patients in the 2mg buprenorphine group may have been reluctant to request a dose change becauseof the 5O?hpossibility of being assigned to placebo. A 2-mg dose of buprenorphine should have been efftcacious for some patients in this group, as Bickel et al. (1988a) reported 2 mg s.1.buprenorphine to be equi-eficacious to 30 mg p.o. methadone in opioid-dependent patients (see Amass et al., 1994). Also, the relatively brief observation period for stable dosing effects (5 days) may have limited doseresponsiveness,particularly on the urinalysis measure. A longer period before the dose change option might have increased the likelihood of observing dosedependent effects without jeopardizing the efficiency and safety of the placebo controlled design. Overall, buprenorphine appears to produce doserelated effectsover a wider dose range on indices assessing its ability to block exogenously administered opioids (Bickel et al., 1988b), and over a more narrow dose range on indices assessing its opioid agonist effects. Thus, larger dosesof buprenorphine may not influence acceptability of the medication, but will influence its overall clinical effectivenessin reducing drug use by in-

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creasing the duration of blockade and suppression of opioid withdrawal symptomatology. Many of the outcome measuresin the present study (e.g., days on initial dose) are related to acceptability, and may have been influenced primarily by the agonist effects of buprenorphine. We believe the current study presentsan effective and ethically acceptable methodology to assessshort-term treatment effectivenessusing a parallel-group, placebo controlled clinical trial design. Studies using parallelgroup placebo controls provide scientific rigor, but in somecontexts may seemmedically or ethically inappropriate when an efficacious treatment already exists (Rothman and Michels, 1994).This study used an intake procedure that addressedmedical and ethical considerations by providing, at a minimum, medical and psychological servicesto patients who ordinarily would be waiting for treatment. Lack of group differences on retention supports the ethical acceptability of the procedure in that assignment to placebo dosing for a short time, under double-blind conditions, did not produce differential drop-out. The behavioral choice component was incorporated in this design to address ethical concerns raised about placebo controlled clinical trials (e.g., Rothman and Michels, 1994). Evidence that some ethical concerns were addressedcomesfrom a consideration of the retention data from days l-7 (Fig. 1). That is, a large proportion (approximately 25”h) of the placebo group were removed from their initial dose on the first day of the dose-changeperiod (days 6-7), compared to a cumulative total of approximately 19% on the 5 days prior to the dose-changeperiod. This result suggeststhat some subjectsin the placebo condition may have remained in treatment until day 6 in order to exercise their dosechange option. In placebo controlled studies without a dose-change option, these same subjects may have withdrawn from the study in the first 6 days. Thus the inclusion of a dose-changeoption allowed patients who would otherwise not reeive any treatment (due to dropout) to receive active drug treatment following the onset of the dose-changeperiod. Becausepatients who opted for a dose change were randomly assigned to 1 of the 2 remaining doses, patients who were originally assigned to placebo dosing were assignedto active drug following their dosechange request. In contrast, patients originally assigned to either 2 or 8 mg buprenorphine had a 50% chance of being assigned to placebo if they requested a dose change. A clinical concern with this methodology was that patients who changed from active drug to placebo may have dropped out of the study once assigned to placebo dosing. In fact, 20 subjects originally assigned to active drug (13 originally assignedto 2 mg; 7 assigned to 8 mg) opted for a dose change. Of these 20, 14 were assigned to placebo, and only 2 of these 14 patients

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subsequently left the study before day 14. This result supports the notion that assignment to placebo dosing following a request for a dose change does not lead to a significantly higher drop-out rate. Another factor influencing retention throughout the 1Cday study may have been the fact that all patients were aware that, following study completion, they would begin receiving active medication. In addition, the dose change option procedure offers a methodology for revealing important features of clinical efficacy, including treatment acceptability. One advantage of this methodology is that it can be used to examine the effect size of a pharmacotherapy, while giving patients the opportunity to change doses (and thus remain in the study) if their current dose is unacceptable. Becauseof the short-term nature of the study, and the support servicesthat are offered to all patients, this methodology may prove valuable for investigating new pharmacotherapies where parallel-group placebo controls might otherwise seem problematic. The methodology provides a rapid clinical screen for potential treatments for opioid dependencebefore undertaking long-term clinical trials. Acknowledgments This research was supported by USPHS grant R18 DA 06165. We thank Ms. Nicolette Chios, Ms. Joy Fisher, Mr. Tim Mudric, Ms. Michelle Petrecca, Ms. Ginger Rafferty, the Dispensary-Nursing, Pharmacy, and Toxicology staffs for their excellent technical support. References Altetman, AI., Droba, M., Antelo, R.E., Corriish, J.W., Sweeney, K.K., Parikh, GA. and O’Brien, C.P. (1992) Amantadine may facilitate detoxification of cocaine addicts. Drug Alcohol Depend. 31, 19-29. Amass, L., Bickel, W.K., Higgins, ST. and Badger, G.J. (1994) Alternate-day dosing during buprenorphine treatment of opioid dependence.Life Sci. 54, 1215-1228. Bickel, W.K., Stitxer, M.L., Bigelow, G.E., Liebson, LA., Jasinski, D.R. and Johnson, R.E. (1988a)A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts. Clin. Pharmacol. Ther. 43, 72-78. Bickel, W.K., Stitaer, M.L., Bigelow, GE., Liebson, I.A., Jasinski, D.R. and Johnson, R.E. (1988b) Buprenorphine: dose-related blockade of opioid challenge effects in opioid dependent humans. J. Pharmacol. Exp. Ther. 247, 47-53. Bigelow, G.E. and Preston, K.L. (1992)Assessmentof buprenorphine in a drug discrimination procedure in humans. In: Buprenorphine: An Alternative Treatment for Opioid Dependence (Blame, J.D., ed.), pp. 28-37. NIDA Research Monograph Series No. 121, DHHS Publication No. (ADM) 92-1912.Government Printing Office, Washington, DC. Budd, K. (1981)High dosebuprenorphine for postoperative analgesia. Anaesthesia 36, 900-903. Carroll, K.M., Rounsaville, B.J., Gordon, L.T., Nich, C., Jatlow, P., Bisighini, R.M. and Gawin, F.H. (1994) Psychotherapy and phar-

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