Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue1.2000:

Thrice-Weekly versus Daily Buprenorphine
Maintenance
Richard S. Schottenfeld, Juliana Pakes, Patrick O’Connor, Marek Chawarski,
Alison Oliveto, and Thomas R. Kosten
Background: Buprenorphine is a promising alternative to
methadone or levo-acetyl alpha methadol for opioid agonist maintenance treatment, and thrice-weekly dosing
would facilitate its use for this purpose.
Methods: After a 3-day induction, opioid-dependent patients (n 5 92) were randomly assigned to daily clinic
attendance and 12-weeks maintenance treatment with sublingual buprenorphine administered double blind either daily
(n 5 45; 16 mg/70 kg) or thrice weekly (n 5 47; 34 mg/70
kg on Fridays and Sundays and 44 mg/70 kg on Tuesdays).
Outcome measures include retention, results of 33/week
urine toxicology tests, and weekly self-reported illicit drug
use.
Results: There were no significant differences at baseline
in important social, demographic, and drug-use features.
Retention was 71% in the daily and 77% in the 33/week
conditions. The proportion of opioid-positive urine tests
decreased significantly from baseline in both groups and
averaged 57% (daily) and 58% in 33/week. There were
no significant differences between groups in self-reported

number of bags of heroin used for any day of the week,
including Thursdays (48 –72 hours following the last
buprenorphine dose for subjects in the 33/week condition), or in medication compliance (92%, 91%) and
counseling attendance (82%, 82%).
Conclusions: At an equivalent weekly dose of 112 mg/70
kg, thrice-weekly and daily sublingual buprenorphine
appear comparable in efficacy with regard to retention
and reductions in illicit opioid and other drug use. These
findings support the potential for utilizing thrice-weekly
buprenorphine dosing in novel settings. Biol Psychiatry
2000;47:1072–1079 © 2000 Society of Biological
Psychiatry
Key Words: Buprenorphine, clinical trial, heroin dependence treatment, opioid agonist maintenance treatment,
opioid dependence, opioid treatment

From the Departments of Psychiatry (RSS, JP, MC, AO, TRK) and Internal
Medicine (PO), Yale University School of Medicine, New Haven, Connecticut.
Address reprint requests to Richard S. Schottenfeld, M.D., CMHC/SAC S204, 34
Park Street, New Haven CT 06519.
Received April 23, 1999; revised September 20, 1999; accepted October 4, 1999.

© 2000 Society of Biological Psychiatry

Introduction

D

espite the effectiveness of methadone maintenance
treatment (Cooper 1992; Dole 1988, 1989; Newman
1987; Schottenfeld and Kleber, in press), there are critical
needs to develop alternatives to methadone for opioid
agonist maintenance treatment (Blaine 1992). Problems
with methadone maintenance include its limited availability, the need for daily dosing, possible diversion of
take-home doses, potential for opioid overdose for patients
who use illicit opioids, and difficulty withdrawing from
methadone. The need for daily dosing and consequent
initial requirement for daily clinic attendance may deter
many heroin users from seeking treatment and contribute
to the costs and limited reach of treatment. Currently,
fewer than one in five heroin users receive treatment for

drug dependence (National Institutes of Health 1998).
Levo-acetyl alpha methadol (LAAM) is currently the
only other opioid agonist approved by the U.S. Food and
Drug Administration (FDA) for maintenance treatment of
opioid dependence. One important advantage of LAAM
over methadone is its efficacy when administered on a
thrice-weekly dosing schedule (Eissenberg et al 1997a),
which permits reduced clinic attendance, obviates the need
for take-home bottles, and reduces dispensing costs. Like
methadone, however, LAAM acts as a pure agonist at the
m receptor, and it shares many of the problems found with
methadone, including the potential for overdose and the
difficulty of withdrawal from maintenance treatment
(Greenstein et al 1992). Buprenorphine, a partial m agonist
and k antagonist, represents a promising alternative to
either methadone or LAAM (Blaine 1992; Lewis and
Walter 1992; Johnson et al 1992). Ceiling effects at higher
buprenorphine doses result in a lower risk of overdose
compared with methadone (Walsh et al 1994, 1995b), and
buprenorphine may also have a reduced abuse liability in

opiate-dependent individuals (and thus less likelihood of
diversion) because its use may precipitate withdrawal
symptoms (Strain et al 1995; Walsh et al 1995a, 1995b).
Withdrawal symptoms following abrupt discontinuation of
buprenorphine are also usually relatively mild (Amass et
al 1994; Eissenberg et al 1997b; Fudala et al 1990; Negus
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Thrice-Weekly vs. Daily Buprenorphine

and Woods 1995; San et al 1992). Results of double-blind
randomized clinical trials generally support the safety and
dose-dependent efficacy of daily sublingual buprenorphine (Johnson et al 1992; Kosten et al 1993; Ling et al
1996; Schottenfeld et al 1997; Strain et al 1994a, 1994b).
In conjunction with previous dose-ranging studies (Bickel
et al 1988; Mello et al 1980, 1981; Schottenfeld et al
1993), these studies suggest that sublingual buprenorphine
doses of 12–16 mg daily lead to the greatest reductions in
illicit opioid use. Because of its demonstrated safety and

efficacy, a new drug application has been submitted to the
FDA for use of buprenorphine sublingual tablets for
opioid agonist maintenance treatment.
A number of recent studies suggest that buprenorphine,
like LAAM, may be suitable for thrice-weekly administration during maintenance treatment. Buprenorphine has a
high binding affinity and dissociates very slowly from the
m receptor (Boas and Villiger 1985, Kajiwara et al 1986),
leading to dose-dependent and long duration of attenuation
of both opioid withdrawal and opioid self-administration
(Bickel et al 1988; Fudala et al 1990; Schottenfeld et al
1993). In general, patients experience no problems with
withdrawal symptoms or increased agonist effects during
alternate-day or every third, fourth, or fifth day administration of buprenorphine at sublingual doses of 8 – 40 mg
(Amass et al 1994; Bickel et al 1995, 1996, 1997;
Eissenberg et al 1997b; Fudala et al 1990; Johnson et al
1995). Patients also generally report a preference for
alternate-day or even less frequent dosing (Bickel et al
1995, 1997). Results of several studies suggest that higher
doses of buprenorphine (12–24 mg SL) are needed to
attenuate or block hydromorphone effects for 48 –72 hours

(Amass et al 1996; Bickel 1988; Rosen 1994; Walsh
1995b). Johnson et al (1995) compared daily and alternateday dosing with 8 mg SL buprenorphine under doubleblind conditions and found no significant differences (but
a trend favoring daily dosing) in the primary outcome
measures of retention in treatment or rates of opioidpositive urine samples.
This randomized, double-blind, 12-week clinical trial
compared daily and thrice-weekly administration of buprenorphine for the maintenance treatment of opioid dependence. The study specifically evaluated the clinical
efficacy of thrice-weekly versus daily buprenorphine dosing, while controlling for clinic attendance across both
conditions. Doses were chosen to provide an optimal daily
dose (16 mg/70 kg) and a thrice-weekly dose providing an
equivalent weekly buprenorphine dose (112 mg/70 kg,
administered as 34 mg/70 kg on Sunday and Friday and 44
mg/70 kg administered on Tuesday). Pilot studies conducted before beginning the clinical trial found that the
thrice-weekly dose schedule was well tolerated by patients, and buprenorphine plasma levels 48 hours follow-

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2000;47:1072–1079

1073

ing the 34 mg/70 kg dose and 72 hours following the 44

mg/70 kg dose were comparable to plasma levels 24 hours
following a daily dose of 16 mg/70 kg (Chawarski et al
1999).

Methods and Materials
Subjects
Subjects were recruited from individuals seeking opioid agonist
maintenance treatment at the APT Foundation’s Legion Avenue
Program or from respondents to word-of-mouth advertisements
about the availability of an experimental agonist maintenance
program. Subjects were eligible for the study if they met FDA
criteria for methadone maintenance, had a urine toxicology test
positive for opioids, and met DSM-IV criteria for opioid dependence. Signs of opiate withdrawal (pulse or blood pressure elevations, piloerection, lacrimation, rhinorhea, vomiting, yawning, pupil
dilation) following intramuscular injection of naloxone 0.8 mg were
used to verify current physiologic opioid dependence in subjects
with no prior history of methadone maintenance (n 5 40 or 43.5%).
One patient out of 41 tested failed to demonstrate evidence of opioid
withdrawal and was not admitted to the study. Exclusion criteria
included current psychosis or major depression, suicide risk, current
dependence on cocaine, alcohol, or sedatives, pregnancy, and the

inability to read or understand rating forms. Women of childbearing
age who agreed to adequate contraception and monthly pregnancy
tests were eligible for the study. The study protocol was approved
by the Human Investigations Committee of Yale University School
of Medicine.
After giving written informed consent, 97 subjects began
buprenorphine; 92 subjects completed three days of buprenorphine induction (4 mg, 8 mg, and 12 mg sublingual liquid) and
were randomly assigned to one of the two maintenance groups.
An urn randomization procedure, which uses a computer-calculated algorithm to modify ongoing randomization probabilities
based on prior composition of treatment groups (Project Match
Research Group 1993; Crits-Christoph et al 1997), was used to
balance groups by gender, employment status, and history of
alcohol dependence.

Maintenance Medications
Maintenance medications were dispensed daily, and ingestion
observed by nursing staff. To maintain double-blind conditions,
subjects receiving thrice-weekly buprenorphine received identical-appearing placebo doses on Mondays, Wednesdays, Thursdays, and Saturdays. The highest dose of buprenorphine in the
thrice-weekly schedule was administered on Tuesdays to avoid
the possibility of confounding the effects of placebo administration for 2 consecutive days and differences between weekend and

weekday drug use. A research pharmacist prepared all medications and was the only person with knowledge of drug assignment. Buprenorphine solutions were prepared in 30% ethanol
(vol/vol), and doses were weight adjusted (16 mg/70 kg), with a
maximum weekly dose equivalent to 21.3 mg daily and the
maximum dose administered on any day in the thrice-weekly
schedule limited to 64 mg. The 30% ethanol solution used as the

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2000;47:1072–1079

vehicle for dissolving buprenorphine served as the placebo. All
patients received identical volumes of buprenorphine solution on
all study days and were instructed to hold the liquid under their
tongue for 5 minutes. Average weight-adjusted weekly doses
were 17.9 mg daily in the daily schedule and 36.4 mg (on
Sundays and Fridays) and 47.1 mg (on Tuesdays) in the
thrice-weekly group.

Beginning Day 4, subjects assigned to daily dosing continued
to receive 12 mg daily until the first Monday following Day 4, at
which time the dose was increased to 16 mg daily. Subjects
assigned to thrice-weekly received 16 mg, 22 mg, and 28 mg on
Days 4, 5, and 6 before beginning the regular thrice-weekly
schedule. After completing 12 weeks of maintenance treatment
with either daily or thrice-weekly buprenorphine, buprenorphine
doses were tapered during a 2-week period prior to discharge or
transferring subjects to methadone maintenance or another treatment program. During the tapering period, all subjects received
buprenorphine daily, and buprenorphine doses were reduced in
increments of 4 mg from 16 mg/day to 4 mg/day at 2-day
intervals; subjects were then maintained on 4 mg/day for 9 days
prior to discontinuing buprenorphine.
All subjects were required to participate in a one-hour weekly
manual-guided group counseling session to enhance motivation
for abstinence from illicit drugs and to develop coping skills and
behavioral techniques to prevent relapse. Subjects were not
discharged from the study for continued illicit drug use. They
were discharged from the study for medical reasons, for missing
three consecutive days of medication or three consecutive counseling sessions, and for physical or verbal abuse at the clinic.

Assessments
At baseline, trained research interviewers assessed subjects using a
structured drug use interview, the Addiction Severity Index (McLellan et al 1992), and sections of the Structured Clinical Interview for
DSM-IV (First et al 1996) evaluating lifetime and current substance
use and affective disorders. Supervised urine samples for toxicology
testing were obtained at baseline, and thrice weekly on Mondays,
Wednesdays, and Fridays. All urine samples were tested for opioids
and the cocaine metabolite, and one sample per week from each
subject was also tested for benzodiazepines. The Abbott Tdx system
(Abbott Laboratories, Abbott Park, IL) was used for toxicology
testing, with cutoffs of 200 ng/mL for opioids and benzodiazepines
and 300 ng/mL for cocaine metabolite.
Research staff collected weekly self-report ratings of drug and
alcohol use and opiate withdrawal symptoms, using the Weekly
Drug Use Inventory and the Opiate Withdrawal Symptom
Checklist. (Copies of all instruments are available from the
authors on request.) In the Weekly Drug Use Inventory, subjects
are asked to report drug use each day of the week, the routes of
administration used for each drug, and the average amount used
each day in grams or dollar value. The Opiate Withdrawal
Symptom Checklist is a 20-item questionnaire rating withdrawal
symptoms experienced in the past 24 hours (e.g., “My nose has
been runny”) on a scale from 1 (“not at all”) to 4 (“very much”).
Ratings of withdrawal symptoms were collected before medication dosing on Monday mornings. Data were collected from
subjects during the time they participated in the study.

Table 1. Characteristics of the Study Population
Subjects (n 5 92)

Daily
(n 5 45)

Thrice-weekly
(n 5 47)

% Male
% White
Mean (SD) years age
% Married
Mean (SD) years education
% Employed
% Current IV users
% Cocaine positive utox
% No cocaine use last 30 days
Mean (SD) years heroin use

71.1
75.5
36.2 (7.2)
13.6
11.9 (1.6)
42.9
43.9
24.4
71.1
10.1 (8.8)

74.5
74.5
37.6 (7.9)
17.8
11.6 (2.6)
36.2
56.1
23.4
74.5
9.9 (7.4)

Statistical Analysis
Chi-square and t tests were utilized to compare groups on baseline
characteristics. Differences in retention were analyzed using the
Kaplan-Meier product limit method and the generalized Wilcoxon
test (Allison 1995; Selvin 1991). Chi-square was used to analyze
treatment group effects on the proportion of subjects achieving 3 or
more consecutive weeks of abstinence in each condition. Random
regression models (RRM) were used to examine the effects of
treatment group on repeated urine toxicology results and self-report
data regarding daily drug use and opioid withdrawal symptoms
(Gibbons et al 1993; Hedeker and Mermelstein 1996; Littell et al
1996). RRM provide p values for the Wald statistics, expressed as
x2. To develop a continuous outcome measure with regard to urine
toxicology results, the results of urine toxicology testing during the
12 weeks of maintenance were aggregated into four successive
3-week periods. The proportion of tests positive for illicit opioids or
cocaine during induction and each successive 3-week period were
then calculated for each subject and used in the RRM. During the
time subjects remained in the study, 2.3% (72/3092) of scheduled
urine toxicology samples were not obtained and were coded as
positive. Leaving missing values as missing or imputing them to the
average value for the subject over the preceding weeks did not affect
the significance of the major findings. Urine toxicology data were
available for 412 aggregated measurements, or 89.6% of the total
460 expected 3-week aggregates, had all 92 subjects remained in
treatment for the 12 maintenance weeks and 1 induction week. A
total of 1009 weekly assessments were collected during treatment,
out of a total possible 1196 assessments (84.4%), had all 92 subjects
provided information for 13 weeks.

Results
Randomization and Retention in Treatment
Characteristics of study sample are shown in Table 1. The
two treatment groups were comparable across baseline
demographic, social, drug abuse, and psychiatric factors.
The percentage of subjects completing 12 weeks of
maintenance treatment did not differ between the two
treatment groups (76.6% vs. 71.1%), and the average
number of weeks (SD) in treatment was 11.0 (4.0) in 3

Thrice-Weekly vs. Daily Buprenorphine

BIOL PSYCHIATRY
2000;47:1072–1079

1075

Figure 1. The proportion of
opioid-positive toxicology
tests at baseline, during induction, and during the four
successive 3-week periods
of maintenance treatment in
the daily (diamonds) and
thrice weekly (squares)
groups. Error bars represent
standard errors.

3/week and 11.2 (3.7) in daily (Wilcoxon x2 5 0.102,
df 5 1, p 5 .64). Reasons for premature termination
included missing medications 3 days in a row (12 in daily
and 6 in thrice weekly); missing 3 consecutive groups
(n 5 1), exacerbation of pre-existing medical problems
(n 5 2), depression requiring medication treatment (n 5
1), incarceration (n 5 2), and abusive behavior (n 5 1).
No patients reported adverse medication effects. Of the 67
patients who completed the maintenance phase of the
study, 10 elected medical detoxification, 12 transferred to
methadone maintenance, and 45 elected transfer to another
buprenorphine research protocol.

Effects on Illicit Opioid Use
As shown in Figure 1, the proportion of opioid-positive urine
tests declined substantially over time (Wald x2 5 76.7, df 5
4, p , .001) but did not differ between treatment groups
(57% vs. 58% in daily and 33/week, respectively; Wald
x2 5 0.04, df 5 1, p 5 .84), and there was no significant
interaction between treatment group and time (Wald x2 5
5.4, df 5 4, p 5 0.25). Three or more consecutive weeks of
abstinence from illicit opioids, as documented by urine
toxicology testing, was attained by 42.6% in the thriceweekly group and 37.8% in the daily group (x2 5 0.22, df 5
1, p 5 .64). There were also no significant differences in the
mean length of longest period of continuous opioid abstinence (if abstinent) among subjects medicated 33/week
(7.8 6 3.0) compared to the daily group (6.5 6 3.1, t 5 1.25,
df 5 35, p 5 0.22). Analyses based on self-report measures

of illicit opiate use were consistent with analyses of urine
toxicology data. As shown in Figure 2, there were significant
reductions in self-reported days per week using heroin over
time for both treatment groups (Wald x2 5 1187.3, df 5 12,
p , .001) but no differences between the two treatment
group (1.3 6 0.23 vs. 1.7 6 0.22; Wald x2 5 1.2, df 5 1, p 5
.27), and no significant interactions between treatment group
and time (Wald x2 5 19.4, df 5 2, p 5 .08). Bags of heroin
used on any day of the week, including Thursdays (48 –72
hours following the highest medication dose in the thriceweekly group) also did not differ between groups. Withdrawal scores decreased significantly over time in both
groups (Wald x2 5 112, df 5 12, p , .001), but opioid
withdrawal ratings collected 48 hours following buprenorphine dosing in patients in the thrice-weekly group also
showed no difference (Wald x2 5 0.54, df 5 1, p 5 .46).

Effects on Cocaine Use
Although cocaine dependence was an exclusion criterion,
almost half of the subjects (46.7%) were unable to abstain
from cocaine for at least 3 weeks. As shown in Figure 3,
cocaine use increased over time in both groups (Wald
x2 5 13.4, df 5 4, p , .001). The proportion of subjects
achieving 3 or more consecutive weeks of abstinence from
cocaine was 51.1% and 55.3% in the daily and thriceweekly groups, respectively (x2 5 0.16, df 5 1, p 5 .69).
There were no significant effects of dosing condition on
the proportion of cocaine-positive urine samples (Wald
x2 5 1.2, df 5 1, p 5 .26) and averaged 38.1% and 31.2%.

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R.S. Schottenfeld et al

Figure 2. Reported
days of heroin use
per week at baseline,
during
induction,
and during the 12
weeks of maintenance treatment in
the daily (diamonds)
and thrice weekly
(squares) groups. Error bars represent
standard errors.

Three consecutive weeks abstinence from cocaine during the trial was significantly associated with greater
reductions in opioid-positive urine samples (Wald x2 5
6.26, df 5 1, p , .012), with rates of opioid-positive
samples averaging 49% and 66%, respectively, among
subjects who were or were not cocaine abstinent (Wald
x2 5 8.8, df 5 1, p 5 .003).

Adherence to Medication Dosing and Counseling
and Maintenance of the Double Blind
Medication compliance (92%, 91%) and attendance at
counseling sessions (82%, 81%) were comparable between patients in the thrice-weekly and daily dosing
conditions. Medication compliance on placebo medication

Figure 3. The proportion of
cocaine-positive toxicology
tests at baseline, during induction, and during the four
successive 3-week periods
of maintenance treatment in
the daily (diamonds) and
thrice weekly (squares)
groups. Error bars represent
standard errors.

Thrice-Weekly vs. Daily Buprenorphine

days (Mondays, Wednesdays, Thursdays, and Saturdays)
averaged 90% and 89%, respectively, in the daily and
thrice-weekly groups. Self-report data available from the
last 53 subjects enrolled in the study also suggest that
subjects did not reliably identify whether they were
receiving thrice-weekly or daily dosing: At Week 4, 44%
of subjects receiving thrice-weekly buprenorphine and
54% of subjects receiving daily dosing reported thinking
that they were receiving daily dosing.

Discussion
This study provides strong support for the efficacy of
thrice-weekly compared to daily buprenorphine dosing,
when patients in both conditions receive relatively high
and equivalent total weekly buprenorphine doses. Illicit
opioid use declined substantially and comparably in both
groups during maintenance treatment and are comparable
to those of patients treated with methadone 65 mg daily in
a previous study (Schottenfeld et al 1997). The comparable efficacy of daily and thrice-weekly buprenorphine
dosing is also consistent with recently reported results
supporting the comparable efficacy of thrice-weekly buprenorphine and LAAM (Chutuape et al, in press). The
lack of differences in self-reported daily illicit opioid use
for any day of the week suggest that subjects did not detect
or respond adversely to placebo medication days in the
thrice-weekly condition. The two groups were also comparable in medication compliance (92%, 91%) and counseling attendance (82%, 82%), and patients were as likely
to attend the clinic and ingest the daily dose whether
receiving a thrice-weekly buprenorphine, daily buprenorphine, or placebo dose. Thus, patients receiving thriceweekly buprenorphine did not detect or respond differently to placebo buprenorphine days. The comparable
efficacy of thrice-weekly and daily buprenorphine dosing
for reducing illicit opioid use extends previous findings
that patients tolerate and prefer less than daily buprenorphine dosing (Amass et al 1998; Bickel et al 1995, 1997).
Relatively high buprenorphine doses (total weekly dose
of 112 mg/70 kg) were used in this study in both the daily
and thrice-weekly groups. Although preventing withdrawal symptoms is an important criterion for evaluating
the efficacy of opioid agonist maintenance treatment, the
“gold standard” for assessing efficacy remains the elimination or reduction of illicit opiate use. Relatively low
daily doses of methadone (20 –35 mg) are generally
sufficient to prevent withdrawal, but higher doses are more
effective in reducing illicit opioid use. Thus, the pharmacologic targets of opioid agonist maintenance treatment
include attenuating the reinforcing effects of illicit opioid
use and reducing craving, in addition to preventing withdrawal (Amass et al 1996; Chutuape et al, in press). In

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order to block opioid effects for 48 –72 hours, buprenorphine doses of 12–24 mg are needed. Thus, we used higher
doses to effect reductions in illicit opioid. Previous studies
have established the dose-dependent efficacy of buprenorphine during daily administration, with optimal daily
doses appearing to range from 8 –16 mg using a sublingual
liquid preparation. In an earlier study, we found that
plasma buprenorphine concentrations 72 hours following a
44-mg dose and 48 hours following a 34-mg dose during
thrice-weekly dosing at a schedule providing a total
weekly dose of 112 mg were comparable to concentrations
24 hours following daily administration of a 16 mg-dose
(Chawarski et al 1999). Plasma concentrations 24 hours
following the 16-mg daily dose were considerably higher
than concentrations 72 hours following a 32-mg dose and
48 hours following a 16-mg dose during thrice-weekly
dosing with a total weekly buprenorphine dose of 64 mg.
Although these findings support the use of relatively high
buprenorphine doses for thrice-weekly dosing, the efficacy
of lower thrice-weekly doses has not been systematically
evaluated. Despite the substantial reductions in illicit
opioid use found with the buprenorphine doses used in the
current study, 52% of urine samples tested positive for
illicit opioids during maintenance treatment. A longer
period of treatment and additional pharmacologic and
behavioral interventions may be needed to reduce use even
more.
Buprenorphine was well tolerated by patients in this
study. There were no reports of serious adverse effects of
buprenorphine among patients in either treatment group.
No patient requested dose adjustments or medication
discontinuation due to medication side effects, and no
patient needed to be withdrawn from the study protocol
because of medical complications associated with buprenorphine. Given that there are reports of dose-related
hepatotoxicity associated with some opioid agonists and
antagonists (Mitchell et al 1987; Pfohl et al 1986), it is also
of note that despite the relatively high buprenorphine
doses used in the thrice-weekly condition, there was no
evidence of liver toxicity associated with thrice-weekly
dosing. Five of the 92 patients developed elevations of
liver function enzymes that did not necessitate discontinuation from the study. Three of these patients had hepatitis
C (1 in daily dosing and 2 in thrice weekly). For the other
two patients, serum g-glutamyltransferase (g-GTP) increased from 14 at baseline to 144 at study completion
(normal range , 37) for a thrice-weekly patient, and gGTP increased from 29 at baseline to 73 and serum
glutamate pyruvate transaminase increased from 43 to 144
(normal , 50) for a daily patient.
Although dosing condition did not differentially affect
cocaine use, the cocaine use of patients in this study is
particularly notable, because cocaine dependence was an

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exclusion criterion for study participation, and 70 of the 92
patients tested negative for cocaine at baseline. The
proportion of cocaine-positive urine samples increased
over time in both groups; and less than half of the patients
abstained from cocaine for 3 or more consecutive weeks
during the 12-week trial. The high prevalence of cocaine
use in the study sample suggests that using diagnostic
criteria for cocaine dependence, based on patient selfreport only, will need to be augmented by repeated urine
toxicology results negative for cocaine in future studies
directed at opioid-dependent patients without heavy cocaine use. Additionally, the higher rates of illicit opioid
use among patients with cocaine abuse points to the
importance of evaluating potential differential effects of
treatments on patients with and without cocaine abuse or
dependence.
A limitation of this study is the relatively limited power
to prove comparability of the two doses and exclude the
possibility of a Type II error. The findings of nearly
identical proportions of opioid-positive urine tests and
self-reported heroin use in the two groups makes it highly
unlikely that significant differences would have resulted
from a larger sample size. The effect size (Cohen’s d 5
0.037) calculated from the observed data regarding opioidpositive urine tests is extremely low, and a sample size of
19,000 would be needed to have a power of 0.80 to detect
a significant difference between treatments with p , .05
(Cohen 1988). In this study, buprenorphine doses were
calculated on a mg/70-kg basis in an attempt to optimize
buprenorphine doses at the outset of treatment, because the
protocol did not permit dose adjustments during the
maintenance period. In clinical practice, mg/kg dosing
may not be necessary, because doses can be adjusted
according to the response of the individual patient. Additionally, subjects in this study attended the clinic daily to
ingest active medication or placebo under double-blind
conditions. The results of thrice-weekly dosing may differ
if patients attend the clinic less frequently or are aware of
the days they do not receive buprenorphine. Nevertheless,
the results of this study support the clinical efficacy of
thrice-weekly dosing and use of this dosing schedule.
Thrice-weekly dosing reduces the costs to clinics and the
inconvenience to patients, and the efficacy of thrice
weekly dosing will also facilitate use of buprenorphine
outside of traditional narcotic maintenance treatment programs, such as in primary care clinics and physician
offices.

This study was supported by NIDA grant DA09803 (Richard S.
Schottenfeld).

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