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Sees KL, Delucchi KL, Masson C, et al. Methadone Maintenance vs 180-Day Psychosocially Enriched Detoxification for Treatment of Opioid DependenceA Randomized Controlled Trial. JAMA. 2000;283(10):1303–1310. doi:10.1001/jama.283.10.1303
Context Despite evidence that methadone maintenance treatment (MMT) is effective
for opioid dependence, it remains a controversial therapy because of its indefinite
provision of a dependence-producing medication.
Objective To compare outcomes of patients with opioid dependence treated with
MMT vs an alternative treatment, psychosocially enriched 180-day methadone-assisted
Design Randomized controlled trial conducted from May 1995 to April 1999.
Setting Research clinic in an established drug treatment service.
Patients Of 858 volunteers screened, 179 adults with diagnosed opioid dependence
were randomized into the study; 154 completed 12 weeks of follow-up.
Interventions Patients were randomized to MMT (n = 91), which required 2 hours of
psychosocial therapy per week during the first 6 months; or detoxification
(n = 88), which required 3 hours of psychosocial therapy per week, 14 education
sessions, and 1 hour of cocaine group therapy, if appropriate, for 6 months,
and 6 months of (nonmethadone) aftercare services.
Main Outcome Measures Treatment retention, heroin and cocaine abstinence (by self-report and
monthly urinalysis), human immunodeficiency virus (HIV) risk behaviors (Risk
of AIDS Behavior scale score), and function in 5 problem areas: employment,
family, psychiatric, legal, and alcohol use (Addiction Severity Index), compared
by intervention group.
Results Methadone maintenance therapy resulted in greater treatment retention
(median, 438.5 vs 174.0 days) and lower heroin use rates than did detoxification.
Cocaine use was more closely related to study dropout in detoxification than
in MMT. Methadone maintenance therapy resulted in a lower rate of drug-related
(mean [SD] at 12 months, 2.17 [3.88] vs 3.73 [6.86]) but not sex-related HIV
risk behaviors and in a lower severity score for legal status (mean [SD] at
12 months, 0.05 [0.13] vs 0.13 [0.19]). There were no differences between
groups in employment or family functioning or alcohol use. In both groups,
monthly heroin use rates were 50% or greater, but days of use per month dropped
markedly from baseline.
Conclusions Our results confirm the usefulness of MMT in reducing heroin use and
HIV risk behaviors. Illicit opioid use continued in both groups, but frequency
was reduced. Results do not provide support for diverting resources from MMT
into long-term detoxification.
In 1997, the most recent year for which data are available, treatment
program admissions for opioid dependence surpassed admissions for cocaine
abuse in the United States.1 As heroin use
resurfaces, evaluation and improvement of the treatment of opioid abuse are
increasingly urgent needs. Methadone maintenance treatment (MMT) has been
shown to improve life functioning and decrease heroin use; criminal behavior;
drug use practices, such as needle sharing, that increase human immunodeficiency
virus (HIV) risk; and HIV infection.2,3
However, variations in efficacy have been reported, and high illicit drug
use rates in those undergoing treatment have been observed.4,5
Most data about MMT efficacy are from program evaluation efforts, including
the Drug Abuse Reporting Project,6 the Treatment
Outcome Prospective Study,7 and a nationwide
study completed by the Department of Veterans Affairs,8
all of which reported reduction in drug use and criminality following treatment.
Despite such evidence that MMT is a useful treatment for opioid dependence,
it remains controversial because of the indefinite provision of a dependence-producing
medication. An effective alternative treatment that did not involve indefinite
opioid use would be a valuable addition to the limited array of options available
to treat heroin dependence.
Short-term methadone detoxification treatment, usually 21 days in duration,
was proposed as an alternative to MMT but had poor retention and high relapse
detoxification (up to 180 days) was approved in 1989 as a treatment option
for opioid-dependent individuals who either do not meet the federal guidelines
for MMT or who reject this treatment.12
The present study was done to determine whether 180-day methadone-assisted
detoxification (M180), when enriched with intensive psychosocial services
and aftercare, could provide an efficacious alternative to MMT. Data indicate
that psychosocial services increase methadone treatment efficacy.13,14 We reasoned that adding such services
to M180 would provide a reasonable alternative to MMT.
If M180 exceeded or matched MMT in efficacy, it might provide a viable
alternative treatment. On the other hand, if M180 did not equal MMT in efficacy,
this study would provide additional and convincing evidence for the value
The study was publicized by notices, word-of-mouth, and written information.
Participants met Diagnostic and Statistical Manual of Mental
Disorders, Revised Third Edition (DSM-III-R)
criteria for a diagnosis of opioid dependence and had an initial urine screening
test result positive for an opioid other than methadone and negative for methadone.
Potential participants were excluded if they had medical conditions that contraindicated
methadone treatment or a psychiatric condition that interfered with treatment,
were enrolled in substance abuse treatment, had been in a methadone treatment
program within the previous week or were in the follow-up phase of a previous
methadone detoxification research protocol, could not be expected to remain
in the study for 12 months, did not have signs of opioid withdrawal on 3 occasions,
or were younger than 18 years. Women of childbearing age were required to
be practicing birth control. A pregnancy test was administered, and those
pregnant or breastfeeding were excluded. Participant disposition from initial
contact to trial completion is shown in Figure
The research took place at the San Francisco Veterans Affairs Medical
Center, San Francisco, Calif. Veterans were not eligible because MMT is available
on request for clinically appropriate veterans at the same site. The study
was approved by the University of California, San Francisco, Committee on
Participants were assessed at baseline and monthly for 12 months. A
urine specimen was collected at each assessment.
During the first 6 months, urine samples were collected weekly from
participants in both study groups. In the second 6 months, 1 urine specimen
was collected monthly in the M180 group and weekly in the MMT group. The differential
collection of urine specimens during the second 6 months in the 2 groups reflected
the anticipated difficulty of obtaining weekly urine specimens from participants
in the M180 group, who no longer had the incentive of methadone to encourage
them to return to the clinic. In both groups during both 6-month blocks, 1
urine sample per month from each participant was selected for data analysis.
Urine specimens were analyzed by enzyme-multiplied immunoassay technique
for the presence of cocaine, heroin, amphetamines, barbiturates, benzodiazepines,
tetrahydrocannabinol, and methadone.
Opioid use was coded as negative if the participant indicated no illicit
opioid use in the last 30 days and the urine screening test result was negative
for opioids other than methadone. Cocaine use was coded as negative if the
participant indicated no cocaine use in the last 30 days and the urine screening
test result was negative for cocaine.
The Addiction Severity Index (ASI)8,15
assesses functioning in employment, drug use, alcohol use, legal, family,
and psychiatric problem areas. It was administered monthly by research interviewers.
The computerized Diagnostic Interview Schedule16-19
was administered at baseline. We obtained DSM-III-R
lifetime diagnoses for alcohol and drug abuse or dependence disorders, posttraumatic
stress disorder, major depressive disorder, dysthymic disorder, and antisocial
The Risk of AIDS Behavior (RAB) scale20
assesses drug use and sexual behaviors that increase risk for HIV infection
over a 6-month period. It was administered at enrollment and 6 and 12 months.
The Treatment Services Review (TSR)21
is a structured interview that provides information on the type and number
of services received in each ASI problem area. We developed 2 parallel forms,
1 for services received from the research program (in-program) or from an
outside provider (out-of-program). The TSR was scored by summing the number
of services received in-program and out-of-program separately.
Individuals who met screening criteria, gave written informed consent,
and completed enrollment procedures were further evaluated by medical history
and physical examination. If eligibility criteria were met, participants completed
a baseline assessment. They then came to the clinic on the day before the
admission day to provide a urine specimen. Those who returned the following
day in opioid withdrawal were stratified by sex and ethnicity, randomly assigned
from stratified blocks to either M180 or MMT, and began treatment. The randomization
assignments were generated via computer software by the project statistician
using varying block sizes known only to the statistician and were kept in
Participants in both groups were required to attend an HIV risk reduction
education class and a session describing the program. They were given a detailed
community resource manual and appropriate referrals.
Research interviewers located and assessed participants. Individuals
who missed appointments were contacted by telephone and mail. When necessary,
interviewers used contact information to find participants and interview them
in the community. Interviews took 35 to 90 minutes to complete. Respondents
were paid $15 for each of the first 5 interviews, $35 for assessments occurring
in months 6 through 11, and $50 for the 12-month interview. If participants
completed all assessments for months 6 through 11, a $50 bonus was given at
12 months; thus, participants could earn $100 for the final interview. To
increase the probability of locating participants, participants were paid
$20 for verified changes in locator information.
In both groups, the initial methadone dosage was 30 mg/d, increased
to 80 mg/d within the first 3 treatment weeks. The maximum methadone dosage
was 100 mg/d, reached by day 44. Participants could be evaluated for an increase
in methadone dosage at any time if the current dosage was less than 100 mg/d
or for a lower dosage if the participant had consistent opioid-free urine
screening test results. Methadone dosages were adjusted based on test results.
Breath tests for alcohol content were conducted if alcohol intoxication was
Dosing occurred 7 days a week, with take-home medication provided on
holidays. Participants who missed medication for 3 consecutive days were reevaluated
before restarting treatment. Participants who missed medication for 7 consecutive
days were discharged from treatment.
Counselors had master's degrees in social work or behavioral sciences
and a minimum of 4 years of counseling experience and were supervised by a
psychiatrist and psychologist. The same staff treated patients in both groups.
Assessments were conducted by research interviewers.
Early discharge occurred if a participant violated program rules (eg,
criminal behavior on hospital grounds), failed to attend treatment program
activities, requested discharge or transfer, or was incarcerated.
In the MMT group, participants were eligible for 14 months of methadone
maintenance, followed by a 2-month detoxification. Fourteen months of maintenance
were provided to assess the effects of maintenance (at month 12) before the
potential psychological effects of impending detoxification. Participants
were required to attend 1 hour per week of substance abuse group therapy for
the first 6 months of maintenance and 1 hour per month of individual therapy.
After the first 6 months, group attendance was optional. Participants who
failed to comply with treatment requirements were discharged.
Twenty-four MMT participants were discharged for failure to attend clinic
or comply with program rules. Eleven were jailed, 1 elected a self-taper,
and 1 transferred to another program. Of the 24 discharges, 15 applied for
and were readmitted at least once.
In M180, participants were eligible for 14 months of substance abuse
treatment. During months 1 through 6, 120 days of induction or maintenance
were followed by 60 days of dosage reduction. During the first 6 months of
treatment, participants were required to attend 2 hours per week of substance
abuse group therapy, 1 hour per week of cocaine group therapy if cocaine was
noted on their admission urine screening test result and 2 subsequent screening
test results (continued attendance was required until urine specimens tested
cocaine-free for a month), a series of 14 weekly 1-hour substance abuse education
classes, and weekly individual therapy sessions.
During months 7 through 14, participants were offered 8 months of aftercare
(nonmethadone) treatment that included weekly individual and group psychotherapy
and liaison services with the criminal justice system, medical clinics, and
social service agencies.
Forty M180 participants were discharged for failure to attend clinic
or comply with program rules. Ten were jailed and 6 transferred. Most discharges
were participants who failed to appear for the last few detoxification doses.
Participants who failed to comply with treatment recommendations or
requested early detoxification were not eligible to restart methadone treatment.
However, they were eligible to receive nonmethadone substance abuse treatment,
and 14 did so.
Sample size was based on a type I error rate of .05, a type II error
rate of .20, nondirectional testing, and effect sizes found in relevant literature
and pilot data. Analyses were based on an intent-to-treat model with all collected
data used in analyses—complete-case-only analyses were not used.
Treatment retention was the number of days between study enrollment
and the last day a participant received any psychosocial service. Heroin and
cocaine use was measured by self-report of abstinence or use, with abstinence
confirmed by the monthly urinalysis screening tests. For participants who
had provided more than 1 urine specimen per month, the specimen collected
nearest to the interview (within 4 days before or after the scheduled monthly
assessment) was tested.
The RAB subscale scores assessing HIV-related drug and sexual risk behaviors
over the past 6 months served as measures of HIV risk behaviors. The number
of times a participant reported using a needle to inject drugs in the week
before the assessment was used as a second indicator of drug-related HIV risk
behavior. Psychosocial functioning was determined by ASI composite scores
in 5 problem areas: psychiatric, family, legal, employment, and alcohol use.
Treatment services used, both in-program and out-of-program, were assessed
using the TSR.
Retention in treatment was tested using Kaplan-Meier survival estimates
and a Wilcoxon signed rank test to compare the groups. For all other hypotheses,
a treatment group by assessment generalized linear model was the prototypical
model. While all participants were scheduled for monthly assessments, the
actual time they were interviewed varied around the scheduled date by 7 days.
In the data-analysis models, the assessment point (days from enrollment) was
treated as a continuous time-varying covariate. Study participants dropped
out of treatment and from assessment interviews over time. The resulting missing
data were not imputed; rather, the models used all observed data at each assessment
for parameter estimation. Tests were based on the marginal effects using the
generalized estimating equation approach22
with a 1-step autoregressive covariance structure. SAS, version 6.12, GENMOD
procedure (SAS Institutes, Cary, NC) was used to estimate and test all models.
For models with a dichotomous outcome (eg, drug use), a binomial distribution
with logit link function was used; for counts, a Poisson distribution with
log-link function was used (α = .05 for all tests).
As shown in Table 1, there
were no significant differences between groups at baseline for demographic,
drug use, diagnostic, HIV-risk, or psychosocial functioning variables, with
1 exception: alcohol abuse or dependence (χ21, 5.54; P = .02).
The M180 participants were more likely to be diagnosed as having an
alcohol abuse or dependence disorder. Alcohol disorder was not a significant
predictor of any outcome variable. Comparison of baseline values of outcome
measures among participants who dropped out before the final assessment vs
those who remained produced only 1 significant difference: dropouts had lower
mean RAB drug risk scores (P = .05).
Across groups, cocaine use at enrollment was nonsignificantly related
to less time in treatment (P = .09). Also, the greater
the percentage of cocaine positive assessments, the fewer the days in treatment
(P = .02), an association that was significantly
stronger in the M180 (r = 0.35; P<.001) than in the MMT group (r = 0.06; P = .59).
To compute the average methadone dose received by each participant,
we excluded doses before day 17 (the induction phase) and, for the M180 group,
doses received after day 120 (the taper phase). Also excluded were doses taken
under an early taper (eg, a taper due to rule violations) and clinic-withheld
doses. We assumed that unobserved doses such as take-home or hospital inpatient
doses were taken as scheduled. Eight individuals who participated only in
the induction phase (4 in each group) were omitted. Mean methadone dose in
the 2 groups did not differ (M180 group [n = 84], mean [SD], 85.3 [12.01]
mg/d; MMT group [n = 87], mean [SD], 86.3 [12.88] mg/d; t169, 0.52; P = .60).
The number of services used in each group was computed to determine
whether, as planned, M180 participants did receive more in-program services
than MMT participants during the first 6 months of the study. As shown in Figure 2, group, assessment, and group-by-assessment
effects for the TSR in-program score were all statistically significant. The
significant interaction reflected the fact that the M180 group used more services
during months 1 through 4 than the MMT group, and fewer during months 5 through
12. Assessment and group-by-assessment effects were significant for out-of-program
scores, but the group main effect was not. Participants in the 2 groups did
not differ markedly in out-of-program services during the first 5 months of
the study, but beginning at month 6, the M180 participants reported more use
of out-of-program services.
As shown in Figure 3, group
time in treatment differed. The MMT participants remained in treatment longer
(median days, 438.5; 95% confidence interval [CI], 413-441) than the M180
participants (median days, 174.0; 95% CI, 161-181).
The 2 conditions also differed in the proportion of participants available
at each monthly assessment (Wilcoxon χ2, 8.58; P = .01). Sample size available at each monthly assessment declined
over time to a low at the month 11 assessment (75/91 MMT [82.4%] and 52/88
M180 participants [59.1%]). At the month 12 assessment, there were 77 MMT
and and 57 M180 participants.
At each time point (t) there was no correlation between the results
of the urine screening test for heroin and the probability of the participant
being present for assessment (t + 1). There was a negative relationship between
the proportion of heroin-positive urine screening test results and the number
of days in treatment (r2, 0.10; P<.001) that, while statistically significant, explained
so little of the variance that it was unimportant for clinical purposes. Given
the consistently high levels of continued heroin use and the lack of a lag-1
correlation between heroin use and the probability of dropout, we treated
the missing data as random in the sense that they were not related to the
unobserved outcome variable.
Neither group nor assessment effect was significant for opioid use.
Group-by-assessment interaction reached the P<.05
level of significance. As Figure 4
shows, participants in the 2 treatment groups differed little until month
5, when use rates for the M180 group increased markedly and remained greater
than that of the MMT group until month 12. Reanalyzing these data under the
assumption that the missing data were drug-positive did not produce any important
differences from the analysis that did not impute heroin use. Illicit opioid
use rates were greater than 50% for both groups at any assessment.
As a second index of heroin use, we analyzed days of heroin use in the
previous month, as reported on the ASI. Effects for assessment, group, and
group-by-assessment were significant. Heroin use in both groups markedly decreased
from baseline, but the decrease was greater in the MMT group during the last
6 months of treatment (Figure 4).
The RAB drug-risk subscale scores indicated a significant group by assessment
interaction; at months 6 and 12, the level of HIV drug-risk behavior reported
by MMT participants was lower than that reported by M180 participants. Group
and assessment main effects were not significant. There were no significant
effects on the RAB sex-risk behaviors scale (Table 2).
For the number of times participants reported injecting heroin in the
week before each assessment, neither the main effects for group or assessment
were significant, but the group-by-assessment interaction was significant
and favored less needle use in the MMT group during months 6 through 12.
No significant effects for group-by-assessment were found for the ASI
psychiatric and family composite scores, which were uniformly low across time,
or the employment composite score, which was uniformly high. The ASI legal
composite score was uniformly low with a mean of 0.20 or less at all assessments.
There were no significant assessment or group main effects for legal composite
scores, but the assessment-by group interaction was significant. From 6 months
on, the M180 participants reported significantly higher legal composite scores
than did the MMT participants, although the magnitude of differences and the
low absolute level suggest that the finding may be of little clinical importance.
Statistically significant differences were found for assessment and
assessment by group. During months 4 through 7 and 9 through 12, M180 participants
had lower cocaine use rates than MMT participants. Main effects for group
were not significant. Interpretation of these data was confounded by differences
between the 2 groups in the strength of the relationship between days in treatment
and cocaine use, with cocaine users more likely to drop out of M180 than MMT.
There is little basis for assuming that a missing assessment should
be counted as positive for cocaine for all missing participants. To examine
the stability of differences between group and cocaine use given the missing
assessment data, we reestimated the statistical model by setting the missing
assessments to cocaine-positive use under 3 assumptions: positive enrollment
cocaine test, more than half of assessments cocaine-positive, and any assessment
cocaine-positive. Under all 3 assumptions, the difference between the groups
was no longer significant, suggesting that the difference initially observed
resulted from the higher probability of cocaine users dropping out of M180
than MMT. At each assessment, only 30% to 50% of participants assessed in
either group were abstinent from cocaine.
The average ASI alcohol use composite score was low. On a scale from
0 to 1, with 1 the most problematic, mean scores were 0.11 or less at all
assessments. There were no significant effects.
Methadone maintenance was found to increase retention and be more effective
in decreasing heroin use than M180. Methadone maintenance treatment resulted
in a lower level of drug-use HIV risk behavior and lower ASI legal composite
scores scores during the second 6 months of the assessment period, when provision
of methadone to M180 participants had ended. The ASI psychiatric, family,
employment, and alcohol use composite scores and the RAB HIV-related sex behavior
subscale score were not affected. Heroin and cocaine use rates were high in
both groups over the entire 12-month period. There was evidence that participants
using cocaine were more likely to drop out of M180 than MMT.
The rate of continued use of heroin in both groups is of concern. Methadone
dosages were adequate by current practice standards. Dosages could reach 100
mg/d if warranted and averaged well over 80 mg/d. Too low a methadone dose,
therefore, does not appear to be the reason for the failure of either treatment
to markedly curtail heroin use. Persistent use may reflect the participants'
goals when they entered treatment—only 50% of the sample reported to
us that they had a goal of total abstinence from illicit opioids.
The dropout rate from M180 was high throughout the course of the study.
This may reflect more stringent requirements about attendance at psychosocial
treatment than in the MMT group. An acceleration in dropout occurred at around
120 days, the point at which methadone dosage began to be decreased in this
The M180 group received psychosocial treatment for continued cocaine
use; nevertheless, this group failed to suppress cocaine use rates. Psychosocial
treatments have been shown to be effective in reducing cocaine use.23,24 However, successful treatments were
manualized and adapted from psychotherapeutic interventions, rather than the
generic drug counseling provided by drug counselors in the present study.
Methadone maintenance treatment was more successful in retaining cocaine
users in the treatment system than M180; however, it did not appear to affect
the level of cocaine use because the 2 groups did not differ under several
reasonable assumptions about cocaine use in participants with missing data.
Neither treatment had a marked effect on psychosocial functioning. It
may be that the psychosocial services provided were inappropriate. For example,
while most patients were marginally employed, no vocational rehabilitation
services were available.
This study has implications for the treatment of opioid dependence.
First, improvement is needed. That 50% of participants used an illicit opioid
at least once a month is not encouraging. Given that methadone doses were
adequate, failure may rest in the realm of psychosocial treatment. Neither
program in this study provided extensive legal, employment, family, or psychiatric
services. Participants showed little change in these areas. A cost-effectiveness
study of the benefits of adding these services to methadone treatment is needed.
Second, cocaine use remains a problem in methadone maintenance programs. While
a pharmacological treatment for cocaine dependence has not emerged, there
is considerable evidence that cocaine use is responsive to a variety of psychological
interventions, including group drug counseling,25
group-administered cognitive behavior therapy,23
individual relapse prevention interventions,26
and contingency management.27 Such specific,
promising interventions need to be integrated into methadone treatment programs
for cocaine users.
The generalizability of the results in the current study is limited
in that the study represents only 1 clinical trial. The participants were
a small subset of those who originally contacted the project and may differ
from other methadone maintenance patients in unknown ways. However, the current
study does not provide support for diverting resources from methadone maintenance
to long-term detoxification, no matter how ideologically attractive the notion
of a time-limited treatment for opioid abusers is.
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