Download Buprenorphine versus methadone for opioid dependence: predictor

Drug and Alcohol Dependence 75 (2004) 37–45
Buprenorphine versus methadone for opioid dependence:
predictor variables for treatment outcome
G. Gerra a,∗ , F. Borella a , A. Zaimovic a , G. Moi a ,
M. Bussandri a , C Bubici a , S. Bertacca b
a
Addiction Research Center, Servizio Tossicodipendenze, Azienda Unità Sanitaria Locale, Parma, Via Spalato 2, 43100 Parma, Italy
b Servizio Tossicodipendenze, Azienda Unità Sanitaria Locale, Parma, Italy
Received 23 May 2003; received in revised form 17 November 2003; accepted 25 November 2003
Abstract
The present study compared in a clinical non-experimental setting the efficacy of buprenorphine (BUP) and methadone (METH) in the
treatment of opioid dependence: all the subjects included in the study showed severe long-lasting heroin addiction. Participants (154) were
applicants to a 12 weeks treatment program, who were assigned to either METH (78) (mean doses 81.5 ± 36.4 mg) or BUP (76) (mean
doses 9.2 ± 3.4 mg) treatment. Aim of the study was to evaluate patient/treatment variables possibly influencing retention rate, abstinence
from illicit drugs and mood changes. METH patients showed a higher retention rate at week 4 (78.2 versus 65.8) (P < 0.05), but BUP and
METH were equally effective in sustaining retention in treatment and compliance with medication at week 12 (61.5 versus 59.2). Retention
rate was influenced by dose, psychosocial functioning and not by psychiatric comorbidity in METH patients. In contrast, BUP maintained
patients who completed the observational period showed a significantly higher rate of depression than those who dropped out (P < 0.01)
and the intention to treat sample (P < 0.05). No relationship between retention and dose, or retention and psychosocial functioning was
evidenced for BUP patients. The risk of positive urine testing was similar between METH and BUP, as expression of illicit drug use in
general. At week 12, the patients treated with METH showed more risk of illicit opioid use than those treated with BUP (32.1% versus 25.6%)
(P < 0.05). Negative urines were associated with higher doses in both METH and BUP patients. As evidenced for retention, substance
abuse history and psychosocial functioning appear unable to influence urinalyses results in BUP patients. Buprenorphine maintained patients
who showed negative urines presented a significantly higher rate of depression than those with positive urines (P < 0.05). Alternatively,
psychiatric comorbidity was found unrelated to urinalyses results in METH patients. Our data need to be interpreted with caution because
of the observational clinical methodology and non-random procedure. The present findings provide further support for the utility of BUP
in the treatment of opioid dependency and demonstrate efficacy equivalent to that of METH during a clinical procedure. BUP seems to be
more effective than METH in patients affected by depressive traits and dysphoria, probably due to antagonist action on ␬-opioid receptors.
Psychosocial functioning and addiction severity cannot be used as valuable predictors of BUP treatment outcome. High doses appear to predict
a better outcome, in term of negative urines, for both METH and BUP, but not in term of retention for BUP patients.
© 2004 Elsevier Ireland Ltd. All rights reserved.
Keywords: Buprenorphine; Methadone; Heroin; Depression; Psychosocial functioning; Treatment
1. Introduction
A review of clinical research including randomized, controlled trials has shown buprenorphine (BUP) to be equal
in effectiveness to methadone (METH) in the maintenance
treatment for opioid dependence (Raisch et al., 2002). Ac∗ Corresponding author. Present address: Dipartimento Nazionale
Politiche Antidroga, Via Quintino Sella 69, 00187 Roma, Italy.
Tel.: +39-06-42454251.
E-mail address: [email protected] (G. Gerra).
cordingly, BUP and METH did not show any significant
difference, with regard to urinalyses and retention, in a
multi-center study in our country (Pani et al., 2000) and
previous findings demonstrated BUP efficacy comparable to
METH in the therapy of heroin dependent patients (Johnson
et al., 2000; Strain et al., 1994).
Higher daily BUP and METH maintenance doses versus
lower doses appear to be more effective for reducing illicit
opioid use, when evaluated in a random double blind trial
(Schottenfeld et al., 1997). To this purpose, Ling findings
indicate BUP maintenance at 8 mg per day to be less than
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doi:10.1016/j.drugalcdep.2003.11.017
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G. Gerra et al. / Drug and Alcohol Dependence 75 (2004) 37–45
optimally efficacious (Ling et al., 1996) and, accordingly,
Eder suggests that lower retention in BUP patients may be
attributable to low doses BUP limit, particularly for those
subjects with high levels of dependence (Eder et al., 1998).
The number of days that a patient remained in treatment
in a randomized trial was reported significantly higher for
those receiving 16–32 mg of BUP three times a week and
daily high-dose METH (60–100 mg) than for those receiving
low-dose METH, without significant differences between
BUP and METH. Nevertheless, both the drugs were found
to substantially reduce the use of illicit opioids with similar
rates of negative urines (Johnson et al., 2000). In agreement
with these findings, a meta-analysis of controlled clinical
trials confirmed that the effectiveness of high doses of BUP
seems to be similar to high doses of METH for both retention
rates and illicit opioid use (Farre et al., 2002).
On the other hand, the difficulty to begin treatment with
BUP in comparison with METH in high dependent patients,
as reported by Uehlinger et al. (1998), and lower retention
rate in BUP patients evidenced by Mattick et al. (2003) have
suggested the need to induct patients more rapidly onto BUP
than METH, and start treatment at a higher BUP dose, but
also the opportunity to investigate other variables possibly
influencing the effects of BUP in particular subsets of addicts
was not excluded.
Accordingly, a meta-analytic evaluation of five randomized clinical trials comparing BUP to METH, with better
outcome for METH patients in term of retention and negative urinalyses, has indicated the need of further research to
determine if BUP treatment is more effective than METH
in particular settings or in particular subgroups of patients
(Barnett et al., 2001). The hypothesis that a specific subtype of addicted individuals may be benefiting from BUP
was also formulated by Fischer et al. (1999a,b), who reported better retention rate in the METH maintained group,
and significantly lower rates of illicit opiate consumption in
BUP patients.
The pronostic factors able to characterize patients-subtypes
and to predict BUP outcome, in comparison with METH,
are still unclear and confused. Administration of BUP has
been proposed to be reserved for patients addicted to opiates for less than 10 years, non-depressive and with low
disinhibition on Zukerman’s scale (Laqueille et al., 2001).
Levels of psychosocial functioning and global assessments
of functioning were significantly higher for BUP responders
than non-responders (Resnick et al., 1991) and patients who
dropped out from BUP treatment were reported to differ
significantly from those who stayed, in terms of a higher
level of psychopathological symptoms, and a lower level of
social integration (Pani et al., 2000). Finally, also gender
differences have been evidenced among the antecedents
of a positive outcome, being female gender with lifetime
sedative dependence associated with significantly better
retention (Schottenfeld et al., 1998).
For these reasons, in the present naturalistic observational
study we investigated the effectiveness of BUP, in rela-
tionship with different patient variables, particularly with
personality and behavioral traits, psychiatric comorbidity,
heroin addiction and previous treatment history, in comparison with METH maintenance treatment.
Aim of the study was to evaluate the possible factors
affecting the endpoints of retention rate, reduction of illicit drug use and psychiatric symptoms improvement, during BUP and METH treatment. The hypothesis was that
BUP treatment may differently influence outcome variables,
respect to METH, not only in relationship with addiction
severity or dose levels, but also with individuals personality
traits and comorbid disorders, due to its specific ␮-receptors
agonist/␬-antagonist profile.
The study was conducted to determine the responses to
BUP (76) and METH (78) of heroin dependent patients,
in the first 12 weeks of a maintenance treatment period,
measuring treatment and patient variables capacity to affect
retention rates, changes in psychometric measures, craving
scores and positive urine rates.
2. Materials and methods
2.1. Study population
Heroin-dependent subjects were selected from among patients participating in Parma Addiction Service Program
(Servizio Tossicodipendenze) of the public health system.
Addiction Services in Italy provide outpatients treatment
programs, with different therapeutic and rehabilitative strategies: METH, BUP and naltrexone are administered in association with possible psychosocial intervention, such as
psychotherapy, family therapy, group therapy, social support and medication for dually diagnosed patients. Most of
the patients in Italian Addiction Services are seeking treatment for heroin dependence, although the same Services
offer rehabilitative programs also for cocaine and alcohol
addiction. No exclusion criteria are applied to select patients in the public health system. All the patients have
been evaluated using a self-report and observer-rated questionnaire, a psychometric test, and a psychiatric diagnostic screening. Data describing a detailed history of the patients were also obtained from the drug addiction center
records.
To be eligible for the study, patients had to enter in METH
or BUP maintenance treatment during the 12 months of
2002. After we obtained informed consent, 78 METH patients (60 men and 18 women, mean age: 33 years) and 76
BUP patients (55 men and 21 women, mean age: 32 years)
were included in the study. The 12 weeks clinical evaluation
was conducted as an observational, non-randomized, study
that did not influence treatment choice decision, dosage,
psychosocial intervention and diagnostic assessment. Participants were heroin-dependent from at least 7 years (mean:
10.1 ± 3.2). Daily intake of heroin ranged from 1.5 to 3.0 g
of street heroin. Previous consumption of other drugs of
G. Gerra et al. / Drug and Alcohol Dependence 75 (2004) 37–45
Table 1
Buprenorphine
Heroin dependence years
Mean daily heroin
dose (g)
Previous cocaine use (%)
Good interpersonal
relationship (%)
Unemployed (%)
Legal problems (%)
Alcohol problems (%)
Previous methadone
treatment (%)
Previous residential
treatment (%)
Without psychiatric
comorbidity (%)
Depression (%)
Methadone
Significance
10.7 ± 3.5
2.3 ± 0.6
n.s.
n.s.
12.5
37.7
11.9
36.8
n.s.
n.s.
48.4
43.6
16.5
51
50.5
45.2
18.6
59
n.s.
n.s.
n.s.
n.s.
38
40.4
n.s.
53.8
52.5
n.s.
19.7
17.9
n.s.
9.5 ± 2.8
2.1 ± 0.9
abuse and psychotropic agents or excessive alcohol intake
was recorded.
No significant difference in heroin exposure extent (years
and dosage), or other psychotropic drugs use (11.9 and
12.5% of cocaine; 9.2 and 8.8% of ecstasy and 28.1 and
26.4% for benzodiazepines, respectively for METH and
BUP), was evidenced between BUP and METH patients.
Among the patients selected for the study, 56% had been
submitted to previous METH treatment, respectively 59%
in METH group and 51% in BUP group.
Other characteristic of the patients are included in Table 1:
no significant differences between BUP and METH groups
have been evidenced at baseline.
Previous residential treatment was reported in 39.1% of
the sample prior to their beginning the study (respectively
40.4 and 38.0% for METH and BUP). Benzodiazepines were
prescribed to 10.2% of the MMT patients and 11.8% of the
BMT patients; 6.4% of the METH patients and 5.2% of the
BUP patients were prescribed antidepressant agents and 2.4
and 3.3% neuroleptic agents, in association respectively to
METH and BUP treatment.
METH or BUP treatment was integrated with psychosocial support, including weekly individual counseling and
money vouchers, for all the patients. Counseling sessions
followed cognitive–behavioral methodology and the vouchers for a small amount of money were used as positive reinforce to obtain negative urines. Patients with significant psychiatric comorbidity were also referred to a weekly meeting
with the psychiatrist and possible psychotropic medication.
The procedures followed were in accord the Helsinki declaration of 1975. Following the criteria of the program of
Parma, no patient was discharged because of consecutive
positive urine test results.
39
METH or BUP was reached on the first week of treatment:
the patients treated with BUP received a first dose of 2 mg,
8 h after the last injection of heroin, or 24 h after the last
METH administration; then they received other 2 or 4 mg
of BUP, when did not present withdrawal symptoms, during
the first day. Adjunctive BUP doses were administered to
rapidly reach high doses: in some cases, first day BUP was
limited to 2 mg because withdrawal symptoms were clearly
BUP-induced. METH patients received 40 mg on the first
day, in refracted doses of 20 mg. Other changes in METH
or BUP doses have been permitted on the first week of the
treatment: then stable doses were administered for 12 weeks.
Flexible dosing schedule was applied in the first week of
treatment, but rarely in the following 3 months (5–10 mg of
METH or 2 mg of BUP in two and three patients respectively), for clinical reasons: after obtaining an agreement
about appropriate doses with the patients, they were asked to
evaluate their behavioral reaction to stable doses for at least
3 months, without focusing continuously on medication.
METH was administered daily in the outpatient center
for 64% of the subjects; 36% of the patients were permitted to bring their METH home three times a week. BUP
was administered daily in the outpatient center for 61% of
the patients and three times a week for 39% of the patients.
Weekly take home METH or BUP was not permitted in the
first three months of treatment. The “three times a week”
schedule was not used as a behavioral privilege, but independently from negative urines.
All the patients were submitted to self-report and
observer-rated questionnaire, Symptoms Check List 90
(SCL-90), craving 100 mm Visual Analog Scale (VAS),
DSM IV clinical psychiatric assessment and Minnesota
Multiphasic Personality Inventory (MMPI 2) (Hathaway
and McKinley, 1989) on week 1. Retention rates, SCL-90
scores, VAS craving scores were measured again on week
4 and week 12, at the end of the study.
The main measure available for assessing illicit drug use
was urinalysis. The week immediately before and during
the three month of the study, urine samples were screened
twice a week on random days for amphetamines, methamphetamines, morphine, METH, cannabis, cocaine, barbiturates, benzodiazepines and alcohol. Urinalyses were performed with immunoenzymatic methodology (polyclonal
antibodies with glucose-6-phosphate dehydrogenase: EMIT,
Syva, Italy) and positive results were confirmed by thin layer
chromatography, using commercial kits (Toxi-lab; ANSYS
Technologies, Lake Forest, CA). A total of 26 urine samples (2 before admission and 24 during the 12 weeks) have
been collected for each patient: missing urinalyses have been
counted positive.
2.3. Data collection strategy
2.2. Study design
All the patients were evaluated for 12 weeks after the beginning of the opioid substitution therapy. Stable dosage of
The data collection strategy consisted of a seven-page
form for BUP and METH maintenance program counselors
to complete for each patient in the outpatient program who
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G. Gerra et al. / Drug and Alcohol Dependence 75 (2004) 37–45
entered substitution treatment during 2002. The patient
survey form requested the following information: treatment
identification (BMT or MMT); patient identification; previous treatment; employment status; highest school grade
completed; quality of interpersonal relationships; marital
status; legal problems; commitments; time in prison; number of arrests; number of violent crimes; perception of
alcohol as a current problem. New selective psychopharmacological treatment associated with METH or BUP was also
recorded. The quality of interpersonal relationships was defined as bad (no affective relationship with family members
or friends), good (close affective relationships with family
members or friends), or maintained with difficulties (visual
analog score of 100 mm: good = more than 70; bad = less
than 30; maintained with difficulties = between 31 and 70).
Employment status was defined as unemployed, stable job
(the same company during the year, regularly paying taxes),
or unstable job (different short-term jobs during the last 12
months). Alcohol-correlated problems were defined as having been drunk frequently during the last month (weekly or
more frequently), behavioral changes, health consequences,
or automobile accidents related to ethanol consumption.
Alcohol levels in urines were also utilized to screen severe
alcohol abusers, being urines positive in the morning interpreted as a sign of heavy ethanol use in the night before.
Legal problems were classified with or without violence.
The counselors and the psychiatrist of the program of
Parma had been trained to collect research data on BUP and
METH dose, administration frequency (daily in the outpatients center, or three times a week), measures of previous
illicit drug use and problematic alcohol use, social status and
employment condition, educational status, interpersonal relationships levels, criminal activities, health status, and possible DSM Axis I and Axis II comorbid diagnoses.
Relevant data were requested, for the 6 months preceding the study, concerning substance abuse other than heroin,
activities, and stressful events. Previous psychosocial treatment and previous residential treatment were also recorded
on the form.
2.4. Personality assessment
DSM-IV clinical evaluation and psychometric measures
were performed by trained psychiatrists at baseline. Axis I
and II disorders were evaluated using the Structured Clinical Interview (SCID) for Axis I disorders (Spitzer et al.,
1990) (Italian version: Intervista Clinica Strutturata per il
DSM-III-R, Fava et al., 1993) and the Structured Interview
for DSM-IV Personality Disorders (SIDP) for Axis II disorders (Pfohl et al., 1989) (Italian version: Maggini et al.,
1994). Personality was assessed with the MMPI 2 (Hathaway
and McKinley, 1989).
All METH and BUP patients completed the Symptom
Check List 90 scale (SCL-90) for the evaluation of a broad
range of psychological problems and symptoms of psychopathology. Primary symptom dimensions measured by
SCL-90 included somatization, obsessive compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism (Derogatis,
1977). The patients repeated SCL-90 evaluation at week 4
and week 12.
2.5. Methadone and buprenorphine doses
The patients included in the study were treated with
METH average dose of 81.5 ± 35.4 mg, or BUP average
dose of 9.2 ± 3.4 mg. The decision about doses was independent from the inclusion in the observational protocol.
Stable doses were utilized during the first 12 weeks for
both groups of patients, with minimal flexibility in relationship with patient requests. No missed doses and missed
clinic visits were reported, both for METH and BUP, in the
patients who remained in treatment.
2.6. Statistical analysis
The variables were compared between treatment arms utilizing standard Chi-square tests. A survival analysis, on an
intention-to-treat basis (Kaplan–Meier), was used to measure the efficacy of BUP and METH in term of retention.
Positive urine samples for heroin were analyzed with a
Chi-square test and ANOVA for repeated measures to evaluate the changes over time. SCL-90 psychometric measures
were compared utilizing multiple ANOVA and t-test. Missing urine specimens were counted positive.
The intention-to-treat sample (ITT-Analysis) was 78 in
the METH and 76 in the BUP group (154 patients).
3. Results
3.1. Sample characteristics
No significant differences in mean age (32 ± 3.8 years for
BUP versus 33±5.3 years for METH), gender (males: 72.3%
(55) for BUP versus 76.9% (60) for METH), daily heroin
dose (2.1 ± 0.9 for BUP versus 2.3 ± 0.6 for METH), years
of heroin addiction history (9.5 ± 2.8 years for BUP versus 10.7 ± 3.5 years for METH), interpersonal relationships
quality, job performance, legal problems, alcohol problems
and previous METH and residential treatment rates were evidenced between BUP and METH patients included in the
study (Table 1).
DSM-IV evaluation of the subjects revealed no comorbid
diagnosis for 52.5% (41) of the subjects included in METH
treatment and 53.8% (41) of the subjects included in BUP
treatment.
3.2. Retention rate
Survival analysis showed that the rate of BUP maintained
patients who dropped out during the first four weeks were
G. Gerra et al. / Drug and Alcohol Dependence 75 (2004) 37–45
41
Fig. 1. Surviving rates at the intention to treat analysis (Kaplan–Meier)
in METH maintenance treatment group (MMT) and BUP maintenance
treatment group (BMT).
significantly higher, respect to the intention to treat sample,
in comparison with METH maintained patients (Fig. 1).
The risk for retention failure was similar between BUP
and METH at week 12. Retention rates in BUP and METH
groups at week 12 were respectively 59.2 and 61.5%, with
no significant difference (45/76; 48/78) (Fig. 1).
METH maintained patients who dropped out had significantly lower doses of METH than the completers (44 ±
4 versus 76 ± 12; F(d.f. = 1, 77) = 8.9, P < 0.01).
No significant difference in doses was found between the
intention-to-treat sample and the completers in the BUP
group (8.8 ± 2.9 versus 9.4 ± 3.7).
METH maintained patients who dropped out had significantly worse interpersonal relationships and employment
status respect to completers (F(d.f. = 1, 77) = 4.12, P <
0.05; F(1, 77) = 8.6, P < 0.05). No significant difference
in interpersonal relationships and employment status was
found between the Intention-to-treat sample and the completers in the BUP group.
No difference in term of comorbid depression rates was
evidenced between the intention-to-treat sample and the
completers in the methadone group. In contrast, response to
buprenorphine treatment, in term of retention, was related
to the existence of comorbid psychiatric disorders (Fig. 2a
and b). Buprenorphine maintained patients who completed
the observational period showed a significantly higher rate
of depression than the patients who dropped out (31.1%
versus 6.5%; χ(1) = 6.7, P < 0.01) and the Intention to
treat sample (21.1%; χ(1) = 2.34, P < 0.05).
No significant differences in age (32 ± 3.8 versus
31.2 ± 2.8 for BUP and 33 ± 5.3 versus 29.6 ± 3.4 for
METH), gender (males 72,3% versus 73.3% for BUP;
76.9% versus 72.9% for METH), substance abuse history (years of addiction) (9.5 ± 2.8 versus 8.6 ± 3.6 for
BUP and 10.7 ± 3.5 versus 11.3 ± 2.6 for METH), legal problems history (43.4% versus 46.67% for BUP;
44.9% versus 43.75% for METH), psychotropic medication associated to substitution treatment (23.7% versus
26.67% for BUP; 25.6% versus 22.9% for METH), previous methadone treatment (51.3% versus 48.88% for BUP;
59.00% versus 45.83% for METH) and residential treatment (38.2% versus 31.11% for BUP; 41.0% versus 31.25%
Fig. 2. Surviving rates at the intention to treat analysis (KaplanMeier) in
depressed and non depressed patients treated with BUP (a) (upper panel)
and METH (b) (lower panel).
for METH) were evidenced between the Intention-to-treat
sample and the completers both in BUP and METH
groups.
3.3. Psychiatric comorbidity
The rates of patients with Axis I diagnosis in METH and
BUP groups were 25.6% (20) and 23.7% (18), respectively
and the rates of patients with Axis II diagnoses were 34.6%
(27) and 35.4% (27), respectively. The rate of depressed
individuals was 21.1% (16) among BUP patients and 17.9%
(14) in the METH group. No significant baseline difference
was evidenced in Axis I and Axis II diagnoses rates between
BUP and METH groups.
SCL-90 data were consistent with DSM diagnoses, with
a close correspondence between SCL-90 scores and Axis I
and personality disorders criteria. No significant differences
in baseline SCL-90 and MMPI 2 scores have been demonstrated between BUP and METH groups.
The rates of psychotropic medication associated to substitution treatment did not show any difference between BUP
and METH groups.
BUP maintained patients who dropped out had significantly lower SCL-90 “depression” subscale scores at
baseline than the completers (1.2 ± 0.4 versus 2.3 ± 0.5,
P < 0.005, t = 3.50, d.f. = 1). In contrast, BUP maintained patients who dropped out had significantly higher
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G. Gerra et al. / Drug and Alcohol Dependence 75 (2004) 37–45
SCL-90 “hostility”, “obsessive compulsive”, “paranoid
ideation”, and “psychoticism” subscales scores at baseline
than the completers (2.2 ± 0.3 versus 1.4 ± 0.3, P < 0.005,
t = 3.48, d.f. = 1; 1.9 ± 0.5 versus 1.0 ± 0.2, P < 0.05,
t = 2.14, d.f. = 1; 2.6 ± 0.7 versus 1.2 ± 0.4, P < 0.01,
t = 2.45, d.f. = 1; 1.5 ± 0.2 versus 0.9 ± 0.3, P < 0.05,
t = 2.16, d.f. = 1, respectively).
No significant difference in SCL-90 subscales scores were
found between the Intention-to-treat sample and the completers in the METH group.
The same was true for baseline MMPI 2 results that
showed significantly higher depression (D) subscale scores
in BUP patients who completed the 12 weeks treatment
(MMPI 2 “D”: 58.87 ± 3.2 versus 45.4 ± 1.4, P < 0.005,
t = 3.44, d.f. = 1), in comparison with the patients who
dropped out earlier.
No significant difference in MMPI 2 subscales scores
were found between the intention-to-treat sample and the
completers in the METH group.
ANOVA for repeated measures showed a significant decrease in SCL-90 depression scores in both METH and BUP
patients who completed the study (F = 7.4, d.f. = 2 P <
0.01; F = 15.6, d.f. = 2 P < 0.001), with a significantly
more consistent decrease in BUP completers, in comparison with METH completers. ANOVA for repeated measures
showed a significant effect of time (F = 19.6, d.f. = 2,
P < 0.001), group (F = 8.6, d.f. = 1, P < 0.005) and
group per time (F = 6.9, d.f. = 3, P < 0.05).
3.4. Urinalysis
The risk for positive urine testing was similar between
BUP and METH at week 4 and week 12, as expression of
illicit drug use in general. Positive urines in general in BUP
and METH groups at week 4 were 40.8 and 38.4%, and at
week 12 44.7 and 46.2%, respectively, with no significant
difference between groups.
The rates of opioid positive urines (morphine metabolites) were not significantly different at week 4 between BUP
(21.5%) and METH (24.4%) groups. In contrast, patients
treated with BUP showed a significantly lower rate of positive urines for morphine metabolites (25.0%), as expression
of heroin use, than those treated with METH (32.1%) at
week 12, in the patients who remained in treatment. ANOVA
for repeated measures showed a significant effect of time
(F = 9.3, d.f. = 2, P < 0.01), group (F = 6.3, d.f. = 1,
P < 0.05) and group per time (F = 6.4, d.f. = 3, P < 0.05)
in opioid positive urine changes (Fig. 3).
Both methadone and buprenorphine maintained patients
who showed morphine positive urines, and continued illicit
opioid use, had significantly lower doses than the patients
with negative urines (88.4 ± 25.9 versus 48.1 ± 4.4; t =
5.3, P < 0.001, d.f. = 1) (7.7 ± 0.6 versus 11.3 ± 0.5
t = 2.53, P < 0.05, d.f. = 1). High doses of METH were
more effective than low doses in reducing illicit opioid use
(F = 12.4, P < 0.01). Similarly, high doses of BUP were
more effective than low doses in reducing illicit opioid use
(F = 9.7, P < 0.05).
METH maintained patients who showed positive urines
for morphine metabolites had significantly worse interpersonal relationships and employment status respect to the
patients with negative urines (F(76) = 4.12, P < 0.05;
F(76) = 8.6, P < 0.05). No significant difference in interpersonal relationships and employment status was found
between the opioid-positive and the opioid-negative urines
patients in the BUP group.
No significant difference in term of comorbid depression rates was evidenced between the patients with negative urines and those with opioid positive urines in the
METH group. In contrast, response to BUP treatment, in
term of negative urines, was related to the existence of comorbid psychiatric disorders. Buprenorphine maintained patients who showed negative urines presented a significantly
higher rate of depression than those with positive urines
(26.3% versus 5.3%; χ(1) = 3.8, P < 0.05) (Table 2).
No significant differences in age, gender, substance abuse
history (years of addiction and heroin doses), legal problems history, psychotropic medication associated to substitution treatment and previous METH and residential treatment
were evidenced between the negative urines patients and
Fig. 3. Urinalyses positive for opioid drugs at week 4 and week 12 in patients treated with METH and BUP.
G. Gerra et al. / Drug and Alcohol Dependence 75 (2004) 37–45
43
Table 2
Depression diagnosis rate in METH patients (%)
Depression diagnosis rate in BUP patients (%)
Opioid negative urines
Opioid positive urines
Significance
16.9
26.3
24.0
5.3
χ = 3.8, P < 0.05
the opioid-positive urines patients both in BUP and METH
groups.
BUP maintained patients who showed negative urines
had significantly higher SCL-90 “depression” subscale and
MMPI 2 depression (D) subscale scores at baseline than
those with positive urines (SCL-90 1.9 ± 0.3 versus 0.80 ±
0.5, P < 0.005, t = 3.50, d.f. = 1) (MMPI 2 “D”: 58.87 ±
3.2 compared with 45.4 ± 1.4, P < 0.005, t = 3.44, d.f. =
1). Mean SCL-90 and MMPI 2 scores at week 1 were not
found significantly different between METH patients who
did not use heroin during treatment and those who continued to inject.
METH maintained patients who showed positive urines
for cocaine had significantly lower METH doses than those
with negative urines (t(1) = 3.12, P < 0.05; t(1) = 3.25,
P < 0.05). No significant difference in doses was found
between the cocaine-positive and cocaine-negative urines
patients in the BUP group.
4. Discussion
The present study showed that BUP and METH were similar in term of retention in treatment at 12 weeks, but BUP
was less effective to retain patients in the early phase. Our
findings are in agreement with previous studies that evidenced no differences in retention measures between METH
and BUP (West et al., 2000; Farre et al., 2002), but significantly higher retention rate in METH patients during the
early phase of treatment (6 weeks) (Petitjean et al., 2001).
The percentage of patients retained at 12 weeks was comparable with rates reported elsewhere for these medications
(Johnson et al., 2000; Schottenfeld et al., 1997; Strain et al.,
1994).
In contrast, treatment retention better for METH was
demonstrated by other authors, probably due to the low doses
of BUP utilized in comparison with appropriate doses of
METH (Kosten et al., 1993; Fischer et al., 1999a,b).
Early drop out in BUP group patients in our study seems
to be unrelated to dosage levels, that were not different in
the subjects who let the treatment during the first weeks, respect to those who stayed, suggesting that other factors may
have influenced retention. Accordingly, high dose BUP was
found to suppress heroin use better than low doses, without
influencing retention rate (Mattick et al., 2003). Nevertheless, BUP capacity to completely counteract heroin effects
perception at high doses, evidenced in human laboratory
studies (Comer et al., 2001), could have represented a fac-
tor reducing compliance in the early phase of maintenance
treatment.
On the other side, higher retention in BUP treatment
seems to be associated with depression and dysphoria, with
a significant improvement of psychiatric symptoms in this
subgroup of patients. The association between affective disorders and higher retention in BUP group was not unexpected. In a double blind investigation BUP induced strong
antidepressant effects in patients with endogenous depression (Emrich et al., 1983) and in an open-label study, subjects with treatment-refractory, unipolar major depression
showed clinical improvement in both subjective and objective measures of depression after BUP treatment (Bodkin
et al., 1995). Our data are in contrast with Laqueille findings
(Laqueille et al., 2001), suggesting that negative outcome of
BUP treatment was related with depression. This discrepancy may be due to the difference in diagnostic methodologies, being Laqueille evidence supported by psychometric
measures only, and not by clinical DSM evaluation.
Better outcome in depressed patients may tentatively be
attributable to the specific pharmacological profile of the
drug, being BUP a partial ␮-agonist/␬-antagonist: in fact,
␬-receptors agonist, such as butorphanol and enadoline have
been reported to increase dysphoria, confusion, sedation
and to produce feelings of depersonalization in humans
(Greenwald and Stitzer, 1998; Walsh et al., 2001), supporting the hypothesis that BUP may counteract in depressed
subjects the emotional and perceptual effects of ␬-receptors
system.
Accordingly, BUP capacity to control dysphoria, as a
possible consequence of a dysfunction of the endogenous
␬-opioid system, has been suggested also by combining BUP
with naltrexone, theoretically leaving ␬-antagonism as the
major medication effect, and obtaining positive responses
to treatment that exceeded those expected from naltrexone
alone (Rothman et al., 2000).
The significant reduction of SCL-90 depression-subscale
scores obtained in our depressed subjects treated with BUP,
and not in METH patients, again indicates a possible specific
action of ␮-agonist/␬-antagonist drug on affective symptoms
and their relationship with addictive behavior. In agreement
with these findings, depressive symptoms were reported to
decrease significantly in the patients who were depressed at
intake to BUP treatment (Kosten et al., 1990).
Although BUP has been reported as a useful treatment
for moderate dependence and more motivated subjects (Eder
et al., 1998; Ling et al., 1994), the patients submitted to
BUP who remained in treatment in the present observational
44
G. Gerra et al. / Drug and Alcohol Dependence 75 (2004) 37–45
study were not affected by less severe disorders, in term of
addiction history (heroin dependence duration and doses),
self-disruptive behavior, interpersonal relationships and social integration. In contrast, retention in METH patients was
not related with specific comorbid diagnoses, but with social
integration, good inter-personal relationships and job stability, as previously demonstrated in a recent multi-centric
study including long-term MMT patients (Gerra et al., 2003).
In the present study, BUP and METH obtained similar
results, in term of illegal drugs use in general, but a significantly lower rate of opioid positive urines was found in BUP
patients on week 12, apparently indicating a higher effectiveness of BUP in counteracting heroin injection, in comparison
with METH. Similarly, an open-label, non-randomized study
evidenced, at the first 8 weeks follow up, significantly less
additional consumption of opioids in the BUP-maintained
group, in comparison with the METH group (Giacomuzzi
et al., 2003).
Because of the limitations of this observational clinical
study definite conclusions are not allowed: patients included
in BUP and METH groups, without a random schedule,
may have been influenced by their motivational status at the
beginning of the study with different intention to abstain
from illicit opioids. At the present evaluation, both BUP
and METH groups showed that negative urines in general
and negative urines for illicit opioid drugs corresponded to
higher doses treatment, as repeatedly evidenced in previous
trials (Johnson et al., 2000; Ling et al., 1996; Maxwell and
Shinderman, 1999; Preston and Bigelow, 2000; Strain et al.,
1999).
Our data increase the evidence suggesting that BUP
might be as effective as METH in the treatment of heroin
dependence, with lower rates of illicit opiates consumption,
particularly in subjects affected by depression and mood
disorders. More consistent risk of discontinuing treatment
in BUP patients and more positive urine analyses evidenced
by other authors (Barnett et al., 2001), in comparison
with METH patients, might be attributable to the different sample of patients, possibly including non-comparable
subgroups of personality traits and comorbid disorders. Different rates of dually diagnosed patients in the other studies,
that did not report detailed information concerning psychiatric symptoms, could have significantly influenced the
outcome, with a higher rate of opioid-positive urinalyses in
BUP patients respect to METH patients (Strain et al., 1994,
1996).
Cocaine-positive urines appear unrelated to low doses in
BUP patients, indicating, at least in clinical conditions, BUP
inability to counteract cocaine use among heroin addicts,
also at high doses. Accordingly, previous experimental evaluation of BUP capacity to reduce cocaine craving in humans
did not evidence encouraging results (Foltin and Fischman,
1994; Kamien and Spealman, 1991).
The lack of relationships between psychosocial functioning, substance abuse history and BUP treatment outcome
suggests that addiction severity, and its social consequences,
cannot be used per se as valuable predictors of BUP
treatment effectiveness, in contrast with previous reports
(Resnick et al., 1991; Pani et al., 2000)., indicating the need
of further research to define predictor variables of BUP
outcome. Our findings need to be interpreted with caution
because of the methodological limitations of the survey: in
fact, the study used a descriptive approach, with short-term
measurements, non-standard doses, in a naturalistic clinical setting, and non-random procedure that do not permit
certain conclusions on BUP and METH effectiveness.
In conclusion, METH seems to obtain higher retention
in the early phase of treatment, with an effective action in
maintaining the relationship with the patient at the beginning
of the program, and worse results in term of opioid-positive
urines, in comparison with BUP. BUP effectiveness was
higher, both in term of retention and negative urinalyses, in
depressed subjects. Continued research is needed to better
investigate the possible psychobiological traits characterizing addicted individuals with better responses to BUP treatment, not necessarily associated to addiction severity and
psychosocial functioning.
Acknowledgements
The study was supported by internal funds of Addiction
Research Center of Parma (Local Public Health Unit, AUSL,
Emilia-Romagna Region). No private companies were included among the sources of financial support for the present
study.
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