Abstract
Background and aims
The Controlled Substances Act requires physicians in the United States to provide or refer to behavioral treatment when treating opioid-dependent individuals with buprenorphine; however no research has examined the combination of buprenorphine with different types of behavioral treatments. This randomized controlled trial compared the effectiveness of 4 behavioral treatment conditions provided with buprenorphine and medical management (MM) for the treatment of opioid dependence.
Design
After a 2-week buprenorphine induction/stabilization phase, participants were randomized to 1 of 4 behavioral treatment conditions provided for 16 weeks: Cognitive Behavioral Therapy (CBT=53); Contingency Management (CM=49); both CBT and CM (CBT+CM=49); and no additional behavioral treatment (NT=51).
Setting
Study activities occurred at an outpatient clinical research center in Los Angeles, California, USA.
Participants
Included were 202 male and female opioid-dependent participants.
Measurements
Primary outcome was opioid use, measured as a proportion of opioid-negative urine results over the number of tests possible. Secondary outcomes include retention, withdrawal symptoms, craving, other drug use, and adverse events.
Findings
No group differences in opioid use were found for the behavioral treatment phase (Chi-square=1.25, p=0.75), for a second medication-only treatment phase, or at weeks 40 and 52 follow-ups. Analyses revealed no differences across groups for any secondary outcome.
Conclusion
There remains no clear evidence that cognitive behavioural therapy and contingency management reduce opiate use when added to buprenorphine and medical management in opiates users seeking treatment.
Introduction
Worldwide, controlled clinical trials provide overwhelming support for the effectiveness of buprenorphine, a mu-opioid partial agonist approved in 2002 in the United States by the Food and Drug Administration (FDA) as a pharmacotherapy for opioid dependence (1-6). Buprenorphine has less potential for psychological and/or physical dependence than traditional full agonist opioids like methadone, has fewer side effects, and use in office-based settings allows patients to avoid the stigma sometimes attached to traditional opioid maintenance treatment programs. Buprenorphine treatment also allows patients to receive medication off-site by prescription, avoiding daily attendance at traditional opioid treatment programs.
The introduction of buprenorphine into the portfolio of treatment options was expected to substantially increase the number of patients seeking treatment for opioid dependence because of its ready availability at private office-based practices, less restrictive controls, and favorable safety profile (4,6-10). A possible barrier to prescribing buprenorphine may be the requirement that U.S. physicians treating opioid-dependent individuals with buprenorphine must provide ancillary treatment or referral to behavioral treatment, according to the Controlled Substances Act (11).
Because most private physicians may not have the training, time, space, or staff to provide on-site behavioral treatment, referrals are often made to local substance abuse treatment programs or 12-step programs. No research has assessed the true effectiveness of buprenorphine pharmacotherapy provided in conjunction with behavioral treatment as there has been no assessment of patients' acceptance and participation in behavioral programs. It remains unclear whether treatment outcome is improved by participation in behavioral treatments.
Controlled clinical trials have documented the efficacy of buprenorphine treatment (2,4,6,8,9) and of behavioral and cognitive therapies for optimizing pharmacotherapy outcomes (12-15). Currently popular and effective behavioral treatment methods for substance abusing populations include Cognitive Behavioral Therapy (CBT) and Contingency Management (CM).
Cognitive Behavioral Therapy (CBT) is associated with significant reductions in drug use (16-20), and in HIV-risk behaviors (21), and CBT benefits are sustained for significant durations after discontinuation of treatment (20,22). In a group or individual counseling session, CBT addresses intrapersonal and social/environmental influences that maintain substance use problems and provide coping skills training to prevent relapse. Sessions focus on behavior change principles including identifying relapse triggers, coping skills development, “breaking the cycle” of addictive behaviors, maintaining new lifestyle behaviors, and increasing self-efficacy.
Contingency Management (CM) interventions view behavior as controlled or shaped by its consequences (23-24), and drug use is maintained by positive reinforcement (25). As such, providing appropriate non-drug reinforcers should decrease substance use (26-30). CM procedures are successful in initiating periods of abstinence compared to standard treatment regimens (31) and have produced relatively long periods of abstinence (32-34). A variation of the CM procedure (35) provides opportunities to draw for prizes for meeting the target goal.
Although behavioral treatment methods have been found effective with opioid-dependent individuals, findings from research combining buprenorphine pharmacotherapy with different types of behavioral treatments are mixed. Bickel and colleagues (36) found that community reinforcement therapy with reinforcers for opioid-negative toxicology tests was associated with longer retention (p=0.03) and higher rates of abstinence (p=0.03) compared to a standard treatment group in a 26-week outpatient opioid detoxification study. Conversely, no differences in any drug use outcome were found between a voucher-based reinforcement group (n=20) and yoked control group that received no performance reinforcers (n=21)(37) in polydrug cocaine- and opioid-dependent participants.
In a 24-week randomized trial comparing standard medical management (MM) with once- and thrice-weekly dose dispensing and enhanced MM with thrice-weekly dispensing, Fiellin (38) found no difference among groups in opioid-negative toxicology tests or retention. The onceweekly dispensing group reported greater treatment satisfaction than either of the two thrice-weekly treatment groups regardless of whether the treatment was standard or enhanced (p=0.04). Similar negative findings were found in a recent randomized trial of 141 opioid-dependent patients provided with buprenorphine in a primary care clinic (39). No differences in outcome were found between groups receiving the standard MM with and without a CBT component.
These studies either compared a behavioral component to a control group, or a standard behavioral component to a more extensive behavioral component. To our knowledge, no study has directly compared the effectiveness of multiple behavioral treatment conditions. The current study examined whether behavioral treatment added to buprenorphine pharmacotherapy increases successful outcome. Participants were provided with 16 weeks of buprenorphine with MM and random assignment to one of four behavioral conditions: 1) Cognitive Behavioral Therapy (CBT), 2) Contingency Management (CM), 3) Both CBT and CM (CBT+CM), and 4) No additional behavioral treatment (NT). Outcomes include opioid use, retention, withdrawal and craving symptoms other drug use, and adverse events (AEs).
Methods
Design
This was a 16-week randomized controlled trial to compare the effectiveness of four behavioral treatment conditions provided with pharmacotherapy and MM for treatment of opioid dependence. MM was designed to approximate care provided by physicians when prescribing buprenorphine in private practice. Following the behavioral treatment phase, participants entered a 16-week medication-only phase with follow-up assessments at weeks 40 and 52.
Participants
Individuals in the Los Angeles area were recruited through advertising, word of mouth, study flyers, and referrals from local addiction treatment programs, outreach programs, primary care providers, and mental health centers. Eligibility criteria included being 15+ years of age, meeting DSM-IV-TR criteria for opioid dependence, good general medical and psychiatric health, no sensitivity to buprenorphine or naloxone, no dependence on alcohol, benzodiazepines or any other drug that would require immediate medical attention, or a pattern of benzodiazepine use that could be unsafe in the context of the study. Females could not be pregnant or nursing, and must have agreed to use an acceptable birth control method.
Gift cards worth $410 were provided for completing all assessments: $25 for screening, $5 for each clinic visit; $25 each for Weeks 18 and 40, and $55 for the Week 52 assessment.
Procedures
Appointments were made with individuals who met preliminary screening criteria. After the informed consent process, assessments collected eligibility and baseline information.
Induction onto sublingual buprenorphine occurred over three days. Suboxone, a combination of buprenorphine and naloxone in a 4:1 ratio was used in two doses, 8:2mg and 2:0.5mg buprenorphine:naloxone. Participants were instructed not to use opioids for at least 10 hours prior to first dose. A 4mg dose (expressed as buprenorphine) was dispensed in clinic and participants were monitored for an hour. An additional 4mg dose could be provided at the physician's discretion. The total Day 1 dose was typically 8mg, but may have been up to 16mg. Day 2 doses were between 8-16mg, and Day 3 doses were between 12-24mg. Dose could be adjusted throughout the trial as clinically indicated.
At the end of the 2-week Induction Phase, participants were randomized to behavioral condition using a computerized urn procedure managed by the UCLA Data Management Center, which included stratification by gender, in blocks of 8. Participants were provided a detailed description of their assigned condition.
During the 16-week behavioral treatment phase, twice weekly clinic visits were scheduled to collect data and urine (UA), meetings with the study physician, and to receive study medication. CM was provided at each visit, and CBT was scheduled once weekly. A 16-week behavioral treatment period was selected to mirror the typical 3-4 month treatment duration used by many addiction treatment providers (40).
Participants assigned to CBT (CBT, CBT+CM) met with a master's level trained counselor for 45-minute individual sessions once weekly to address topics relevant to drug use and recovery. A CBT manual addressed 16 weekly session topics, exercises, and homework. Therapists were trained and supervised by a lead therapist experienced in CBT for drug dependent patients. Sessions were audio-taped and reviewed to ensure therapist fidelity.
Participants assigned to CM (CM, CBT+CM) met with a trained CM technician at each clinic visit to review opioid urine test results and receive incentives if earned. A “fishbowl” included 100 chips each corresponding to 1 of 4 dollar amounts. Participants drew chips for each opioidnegative UA, increasing the number of draws with consecutive clean UA. Missed visits or opioidpositive UAs received no draws and reset the draws. Some aspects of the CM schedule were changed mid-study in order to contain CM costs (e.g., The maximum number of chips drawn at one session was reduced from 32 to 10, and from 528 to 230 across all sessions. Total amount possibly earned across all sessions initially ranged from $528-$2,196, but was reduced to $230-$1460). Analyses comparing the two schedules found no difference in opioid use or retention by CM schedule (41). CM booster training sessions ensured fidelity to the procedures.
Limited counseling as typically provided in private office-based practice settings was provided at weekly MM sessions by study physicians. An MM checklist was used to confirm that physicians addressed each component of the visit such as reviewing the UA result, medication dosage, and adherence to the dosing schedule.
Assessments
Screening assessments included medical and psychiatric assessments to ensure eligibility. Weekly assessments included safety and drug use measures. UA samples were tested at each visit, and a dose log was maintained. At the completion of the behavioral treatment phase, assessments were completed similar to the battery used at baseline. Assessments used in the current analyses include the Addiction Severity Index (ASI)(42); Visual Analog Craving Scale (VAS)(43-44); Clinical Opioid Withdrawal Scale (COWS)(45-46); Treatment Satisfaction, Substance Use Report; Dose Log, UA Drug Screen (opiates, oxycodone, propoxyphene, phencyclidine, barbiturates, benzodiazepines, cocaine, amphetamines, methamphetamines, marijuana, methadone, and ecstasy), and a dip test was used to confirm the presence of buprenorphine. All untoward events that occurred during the course of the study, whether or not deemed related to study drug or participation, were documented as adverse events (AEs) and categorized as to severity, relatedness, action taken, and resolution.
Analyses
Analyses include all randomized participants (47). Analyses of baseline characteristics were conducted using non-parametric univariate techniques to determine the adequacy of the randomization scheme. Analyses addressing opioid use during treatment compared opioid UA results by behavioral treatment condition. Analyses included univariate analyses of aggregate measures such as the Treatment Effectiveness Score (TES; 48) by condition for each treatment phase/follow-up. Chi-square tests were used to examine UA results across treatment conditions. Retention was analyzed using a Kaplan-Meier survival curve that tests the proportion of participants surviving by condition over the treatment phase. Listwise deletion was used for missing data. Distribution and composites of scores on drug craving and psychological tests were non-normal and analyzed by treatment condition using non-parametric Kruskal-Wallis test and Wilcoxon sign rank test for pre-post test comparisons. The statistical software used in the analysis includes SAS, version 9.3, and STATA 12.
Power analysis was conducted assuming a 70% follow up rate. Starting with a recruitment of 202 participants randomized into each condition allows us to determine a medium effect size difference between groups with a power of .80, and two-tailed alpha of .05. The study is therefore adequately powered at the behavioral treatment phase (n=202) and medication-only phase (n=143). The Weeks 40 and 52 follow-up samples (n≤100) are under-powered.
Results
Participants
A total of 366 individuals completed the consent process, 241 were inducted onto buprenorphine, and 202 were randomized to behavioral condition (figure 1). The first consent and randomization occurred in August, 2007, with the final follow-up assessment taking place in November, 2011.
Figure 1.
Consort Flow Diagram.
*Analyses for each phase included participants who began the phase;follow-up analyses include those who completed follow-up.
Baseline characteristics are shown in Table 1. Percentages of participants who reported main opioid of abuse (heroin or prescription opioids) are included. Days of heroin or prescription opioid use in the last 30 days at baseline are shown for only the participants who reported that drug as their main drug of abuse.
Table 1. Demographic and Drug Use Characteristics of Randomized Participants at Screening/Baseline by Treatment Condition.
| Characteristic | Treatment Condition | |||
|---|---|---|---|---|
| CBT (N = 53) | CM (N = 49) | CBT+CM (n= 49) | NT (N = 51) | |
| Mean Age (sd) | 35.2(12.4) | 39.5(12.9) | 38.8(12.2) | 34.9(12.7) |
| Percentage Sex (n) | ||||
| Male | 67.9 (36) | 71.4 (35) | 71.4 (35) | 66.7 (34) |
| Female | 32.1 (17) | 28.6 (14) | 28.6 (14) | 33.3 (17) |
| Percentage Race/Ethnicity (n) | ||||
| White | 54.7 (29) | 51.0 (25) | 53.1 (26) | 51.0 (26) |
| Hispanic | 17.0 (9) | 22.5 (11) | 16.3 (8) | 25.5 (13) |
| Black | 5.7 (3) | 8.2 (4) | 18.4 9) | 7.8 (4) |
| Asian | 9.4 (5) | 2.0 (1) | 2.0 (2) | 7.8 (4) |
| Am Indian | 1.9 (1) | 6.1 (3) | 2.0 (1) | 2.0 (1) |
| Other/unknown | 11.3 (6) | 10.2 (5) | 8.2 (4) | 5.9 (3) |
| Mean Yrs. Education (sd) | 13.3 (2.1) | 13.1 (2.3) | 13.5 (1.9) | 13.4 (2.0) |
| Employment (past 30 days) | ||||
| Full-time | 15.1 (8) | 22.5 (11) | 18.4 (9) | 11.8 (6) |
| Part-time | 30.2 (16) | 26.5 (13) | 26.5 (13) | 25.5 (13) |
| Student | 9.4 (5) | 2.0 (1) | 6.1 (3) | 13.7 (7) |
| Unemployed | 43.4 (23) | 34.7 (17) | 40.8 (20) | 35.3 (18) |
| Retired/Disabled | 1.9 (1) | 12.2 (6) | 8.2 (4) | 9.8 (5) |
| Other | 0 | 2.0 (1) | 0 | 3.9 (2) |
| Opioid+ Drug Screen* | 71.7% | 87.8 % | 87.8% | 74.5% |
| Mean VAS (sd) | 66.2 (31.3) | 60.0 (31.5) | 60.0 (31.5) | 59.0 (28.3) |
| Mean COWS (sd)** | 3.6 (3.5) | 1.7 (2.3) | 2.3 (2.7) | 2.1 (2.7) |
| % Reporting Heroin as main drug of abuse | ||||
| 56.6% | 57.1% | 61.2% | 62.0% | |
| % Reporting Prescription Opioids as main drug of abuse | ||||
| 39.6% | 38.8% | 34.7% | 30.0% | |
| # Days of Drug Use in Past 30 | ||||
| Alcohol | 3.8 (6.9) | 3.7 (5.7) | 2.6 (4.2) | 1.5 (1.9) |
| Heroin*** | 24.4 (8.9) | 27.6(5.9) | 24.6(9.2) | 22.5(11.2) |
| Methadone | 2.5 (7.3) | 2.9 (7.7) | 3.5 (8.2) | 3.6 (8.8) |
| Other Opiates**** | 13.6 (12.8) | 12.4 (14.1) | 12.0 (13.7) | 10.4 (12.5) |
results positive for opiate, oxycodone, propoxyphene, and/or methadone
p=0.01
for those reporting heroin as main opioid of abuse
for those reporting prescription opioids as main opioid of abuse
Opioid Use
The TES calculated opioid use (opiate, oxycodone, propoxyphene, and/or methadone) as a percentage of the number of opioid-negative urine tests over the number of tests possible. UA assessments of buprenorphine were not reported as positive opioid UA results. The number of missing tests did not differ statistically across groups: CBT=9.4(sd=10.5); CM=8.5(sd=10.1); CBT+CM=8.2(sd=9.9); and NT=9.7(sd=9.9).
During the induction phase, 4 UA tests were possible, 32 during the behavioral treatment phase, 16 during the medication-only treatment phase, and 1 at each follow-up. The TES did not differ across groups at any treatment phase or follow-up (Table 2).
Table 2.
Mean Opioid Use (TES), Withdrawal (COWS) and Craving (VAS) Symptom Scores by Treatment Condition for the 2-Week Induction Phase and 16-Week Combined Pharmacotherapy and Behavioral Treatment Phase.
| CBT (n=53) | CM (n=49) | CBT+CM (n=49) | NT (n=51) | ||
|---|---|---|---|---|---|
| Induction Phase (Weeks 1-2) | |||||
| TES | 0.54 (0.35) | 0.46 (0.39) | 0.42 (0.36) | 0.52 (0.33) | F=1.24, p=0.29 |
| COWS | 5.68 (1.93) | 5.76 (2.87) | 6.03 (2.10) | 5.72 (2.43) | F=.22, p=0.88 |
| VAS | 57.26 (22.90) | 51.94 (23.77) | 56.67 (18.09) | 49.14 (20.41) | F=1.28, p=0.28 |
| Behavioral Treatment Phase (Weeks 3-18) | |||||
| TES | 0.52 (0.38) | 0.56 (0.39) | 0.63 (0.37) | 0.53 (0.36) | F=0.41, p=0.75 |
| COWS | 1.25 (1.06) | 1.01 (1.16) | 1.16 (1.15) | 1.19 (1.17) | F=.48, p=0.69 |
| VAS | 26.59 (25.23) | 19.72 (21.88) | 19.86 (21.31) | 19.25 (18.24) | F=.37, p=0.78 |
| Medication-Only Treatment Phase (Weeks 19-34) | |||||
| TES | 0.64 (0.49) | 0.66 (0.47) | 0.73 (0.44) | 0.64 (0.47) | F=.34, p=0.79 |
| Week 40 Follow-Up | |||||
| TES | 0.62 (0.49) | 0.65 (0.48) | 0.73 (0.44) | 0.62 (0.48) | F=.32, p=0.81 |
| Week 52 Follow-Up | |||||
| TES | 0.61 (0.49) | 0.64 (0.48) | 0.72 (0.44) | 0.61 (0.48) | F=.29, p=0.83 |
Analyses found no group differences in other measures of opioid use assessed for the behavioral treatment phase. The percentage of participants with 3+ consecutive opioid-negative UA test results included: CBT=66.04%, CM=73.47%, CBT+CM=75.51%, and NT=70.59% (p=0.74), and the percentage with 6+ consecutive opioid-free UA results included: CBT=54.72%, CM=61.22%, CBT+CM=69.39%, and NT=58.82% (p=0.48). The mean number of consecutive opioid-negative UA results also did not differ significantly by group: CBT=9.96(sd=11.1), CM=14.04(sd=12.3), CBT+CM=14.10(sd=12.7), and NT=10.86(sd=10.7) (p=0.16).
Analyses compared the TES of participants who attended at least 50% of behavioral treatment sessions. Results show no difference by group for either behavioral or medication phase.
Although no differences were found in opioid use across treatment groups, all groups reported a significant reduction in heroin use in the last 30 days at the end of the behavioral treatment phase compared to baseline For behavioral treatment phase completers (n=141), days of heroin use in the last 30 days were significantly reduced from baseline for all groups (p<0.001): CBT=3.30(sd=6.9), CM=4.71(sd=6.7), CBT+CM=4.11(SD=8.3), NT=5.36(sd=8.0). For those who dropped out of this phase but completed the subsequent interview (n=19), days of heroin use are: CBT=25.7(sd=9.6), CM=29.8(sd=1.2), CBT+CM=28.7(sd=3.2), NT=21.67(sd=13.3).
Other Drug Use
No difference in self-reported other drug use was found across groups by specific drug (amphetamines, cannabis, cocaine, sedatives) for any timepoint (Table 3). Similarly, no difference was found for other drug use as measured with the TES for the behavioral (p=0.14) or medication-only (p=0.91) treatment phases.
Table 3. Self-Reported and TES Measures of Other Drug Use by Behavioral Treatment Group by Treatment Phase.
| Drug | Measure* | Treatment Phase | CBT | CM | CBT+CM | NT |
|---|---|---|---|---|---|---|
| Amphetamines | ASI | Screening | 0.7 (3.0) | 0.3 (0.8) | 1.6 (4.8) | 0.4 (1.0) |
| TES | Behavioral Treatment Phase | 0.95 (.16) | .91 (.19) | .92 (.20) | .91 (.21) | |
| ASI | End of Behavioral Treatment Phase | .09 (.62) | 1.08 (3.27) | 1.07 (6.96) | .69 (2.13) | |
| TES | Medication-Only Treatment Phase | .96 (.13) | .94 (.14) | .89 (.23) | .91 (.23) | |
| Cannabis | ASI | Screening | 5.6 (9.8) | 5.5 (9.8) | 2.1 (5.4) | 6.8 (10.4) |
| TES | Behavioral Treatment Phase | .72 (.36) | .78 (.33) | .83 (.31) | .62 (.43) | |
| ASI | End of Behavioral Treatment Phase | 5.71 (9.34) | 4.73 (9.41) | 1.86 (4.32) | 9.47 (12.69) | |
| TES | Medication-Only Treatment Phase | .72 (.40) | .81 (.33) | .88 (.29) | .65 (.43) | |
| Cocaine | ASI | Screening | 1.4 (4.8) | 3.4 (8.1) | 1.6 (3.0) | 1.2 (3.1) |
| TES | Behavioral Treatment Phase | .91 (.19) | .79 (.34) | .74 (.35) | .89 (.15) | |
| ASI | End of Behavioral Treatment Phase | .83 (3.2) | 2.01 (4.93) | 2.25 (5.78) | .53 (1.60) | |
| TES | Medication-Only Treatment Phase | .89 (.24) | 83 (.33) | .81 (.34) | .86 (.24) | |
| Sedatives | ASI | Screening | 3.4 (7.5) | 4.1 (8.6) | 3.1 (5.7) | 2.5 (5.3) |
| TES | Behavioral Treatment Phase | .78 (.29) | .79 (.29) | .76 (.32) | .83 (.27) | |
| ASI | End of Behavioral Treatment Phase | 5.4 (9.4) | 3.42 (7.76) | 4.44 (7.89) | 4.24 (8.79) | |
| TES | Medication-Only Treatment Phase | .73 (.34) | .82 (.29) | .74 (.38) | .77 (.35) |
ASI = self-reported days of use in the last 30 days; TES = Treatment Effectiveness Score
Retention
Study retention for the behavioral treatment phase was measured: 1) dichotomously by whether the participant completed the phase; 2) mean number of weeks retained (16 possible); and, 3) mean number of clinic visits attended (32 possible).
There were no differences in any retention measure across treatment groups. The percent of participants completing the behavioral treatment phase includes: CBT=71.7%, CM=69.4%, CBT+CM=73.5%, and NT=64.7% (p=0.79).
The mean number of weeks retained in this phase included: CBT=15.0(sd=5.1); CM=14.6(sd=5.3), CBT+CM=15.3(sd=5.0), and NT=14.6(sd=5.1)(p=0.89). The mean number of clinic visits included: CBT=22.4(sd=10.7), CM=22.3(sd=11.5), CBT+CM=23.6 (sd=10.1), and NT=21.5(sd=10.6)(p=0.81).
Withdrawal and Craving
No significant differences were found in withdrawal symptoms (COWS) or craving (VAS) across groups for the induction or treatment phases (Table 2).
ASI Domains
No significant difference was found across groups for any pre- or post-behavioral ASI composite score using non-parametric tests for non-normal distributions (not shown). No significant differences were found for pre-post scores within each group.
Adverse Events
A total of 253 AEs deemed possibly- or definitely-related to study drug were reported: CBT=29.2%, CM=24.5%, CBT+CM=24.1%, and NT=22.1%. Because the groups were similar, AE frequencies in Table 4 include the total sample: 31.6% occurred during the induction phase, before behavioral treatment was provided; and 68.4% occurred during the behavioral treatment phase. Assessing relation to study drug, 1.6% (4) were deemed definitely related to study drug, and 98.4% (249) were deemed possibly related. The severity of these AEs included 70.8% deemed mild; 29.2% moderate. No AEs were deemed serious or life-threatening. The majority of AEs did not require intervention (95.3%), whereas 3.6% were followed by a dose reduction, and 1.2% were followed by a dose increase. A total of 77.5% were resolved successfully, 2.4% were improving by study end; 10.3% had not changed; and 4.0 were worse or considered a chronic condition.
Table 4.
Frequencies of Adverse Events reported during induction and behavioral phases, deemed possibly or definitely related to study drug.
| Constipation | 51 |
| Insomnia | 40 |
| Sweating/hot flashes | 36 |
| Headache | 34 |
| Fatigue/Lethargy | 14 |
| Nausea/Vomiting | 9 |
| aches/pains | 8 |
| decreased appetite | 7 |
| runny nose | 5 |
| anxiety | 5 |
| Diarrhea | 4 |
| Stomach Cramps | 4 |
| urinary retention | 4 |
| increased appetite/weight gain | 3 |
| numbness/tingling | 3 |
| restless/irritability | 3 |
| dry mouth | 3 |
| blurred vision | 2 |
| heartburn/acid reflux | 2 |
| decreased libido | 2 |
| dizziness | 2 |
| sleep movement | 2 |
| irregular periods | 2 |
| depression | 1 |
| heart palpitations | 1 |
| feeling cold | 1 |
| rash | 1 |
| nightmares | 1 |
| itchiness | 1 |
| incontinent | 1 |
| swelling | 1 |
| Total | 253 |
Medication and Treatment Compliance
Mean prescribed dose, and dose reported as taken by participants were compared across treatment groups. No difference in prescribed daily dose was found (p=0.53): CBT=15.36 (sd=5.1), CM=15.22(sd=4.9), CBT+CM=15.40(sd=4.8), and NT=14.13(sd=5.3). There was no difference across groups for self-reported mean daily dose taken (p=0.61); CBT=15.13(sd=5.3), CM=15.23(sd=5.3), CBT+CM=15.32(sd=4.9), and NT=14.09(sd=5.4).
No difference was found across groups in percentages of time dose was taken as prescribed (p=0.77); CBT=84.8%, CM=85.0%, CBT+CM=85.6%, and NT=87.7%. Additional analyses found no statistical differences in the percentages of each group who complied with the prescribed dosing schedule at least 80% (p=0.85) and 90% (p=0.62) of the time. A total of 69.8% of the CBT group complied 80% of the time, CM=69.4%, CBT+CM=71.4%, and NT=76.5%.
No differences were found in the percentages of each group that complied with behavioral treatment attendance: CBT=73.1%, CM =72.6%, CBT+CM=75.4% of assigned CBT and 73.8% of CM sessions. No difference in attendance at assigned weekly MM sessions was found: CBT=70.2%, CM= 73.1%, CBT+CM=73.9%, and NT= 68.9%.
Treatment Satisfaction
Small cell sizes in the treatment satisfaction items (Table 5) limit the use of chi-square analyses, so ANOVA was used to compare responses for each item. Most participants reported being “very satisfied” with treatment, and 85% of participants reported that Suboxone was “very effective.” Fewer participants (60%) reported that their behavioral treatment was “very effective.” Importantly, 21% of the NT group reported that their behavioral treatment was “not effective” as compared to 3% of the CBT group and 0% of the CM and CBT+CM groups (p=0.007). Most participants (87%) reported that they would participate again in this study.
Table 5. Treatment Satisfaction Responses by Treatment Condition.
| CBT | CM | CBT+CM | NT | Total | |
|---|---|---|---|---|---|
| n= | 32 | 32 | 31 | 39 | 134 |
| How satisfied are you with the treatment you received? * | |||||
| Very satisfied | 78% (25) | 78% (25) | 81% (25) | 71% (27) | 77% (102) |
| Satisfied | 22% (7) | 19% (6) | 19% (6) | 26% (10) | 22% (29) |
| Dissatisfied | 0 | 3% (1) | 0 | 3% (1) | 2% (2) |
| Very dissatisfied | 0 | 0 | 0 | 0 | 0 |
| How much do you think the treatment you received helped you? | |||||
| Helped very much | 91% (29) | 78% (25) | 97% (30) | 79% (31) | 86% (115) |
| Helped somewhat | 9% (3) | 22% (7) | 3% (1) | 18% (7) | 13% (18) |
| Did not make a difference | 0 | 0 | 0 | 3% (1) | 1% (1) |
| Was Suboxone effective in treating your opioid dependence? | |||||
| Very effective | 94% (30) | 78% (25) | 90% (28) | 79% (31) | 85% (114) |
| Somewhat effective | 3% (1) | 16% (5) | 10% (3) | 15% (6) | 11% (15) |
| Not effective | 3% (1) | 6% (2) | 0 | 5% (2) | 4% (5) |
| Was the psychosocial treatment you received effective in treating your opioid dependence?** | |||||
| Very effective | 69% (22) | 62% (20) | 71% (22) | 44% (17) | 60% (81) |
| Somewhat effective | 22% (7) | 38% (12) | 29% (9) | 36% (14) | 31% (42) |
| Not effective | 9% (3) | 0 | 0 | 21% (8) | 8% (11) |
| Which treatment component do you think was most helpful? | |||||
| Suboxone | 62% (20) | 59% (19) | 48% (15) | 77% (30) | 63% (84) |
| Psychosocial | 0 | 3% (1) | 3% (1) | 0 | 1% (2) |
| Both equally helpful | 38% (12) | 38% (12) | 48% (15) | 23% (9) | 36% (48) |
| Neither helpful | 0 | 0 | 0 | 0 | 0 |
| If you had to do it over again, would you still choose to participate in this treatment study? | |||||
| Definitely | 91% (29) | 84% (27) | 96% (29) | 79% (31) | 87% (116) |
| Probably | 6% (2) | 9% (3) | 3% (1) | 15% (6) | 9% (12) |
| Possibly | 3% (1) | 6% (2) | 3% (1) | 3% (1) | 4% (5) |
| Probably not | 0 | 0 | 0 | 3% (1) | 1% (1) |
| Definitely not | 0 | 0 | 0 | 0 | 0 |
1 person did not respond;
p = 0.01
Discussion
Although all groups in our study reduced their opioid use significantly from baseline to the end of the treatment phase, the addition of a behavioral treatment component (CBT, CM, CBT+CM) did not increase positive treatment performance as compared to a group (NT) that received only the standard MM provided to all participants. Opioid use, withdrawal symptoms, craving, pre-post status and functioning, other drug use, and AEs did not differ across the treatment groups. Additional analyses documented no differences in daily buprenorphine dose or treatment compliance across groups.
It may be surprising that behavioral treatment did not increase positive outcome over no behavioral treatment, especially as the provision of psychosocial treatment is a condition in the U.S. for use of buprenorphine as a medical treatment for opioid addiction. CBT and CM are perhaps the two psychosocial treatments with the best supporting research data for clinical utility, however, there have been a number of controlled studies, systematic reviews and meta-analysis (37-39), including a recently published Cochrane review (49), showing that adding behavioral treatment adds little to medical management of agonist maintenance treatment. The current findings do not suggest that behavioral interventions are of no use to patients, but that it is very difficult to demonstrate any added benefits to patients undergoing pharmacotherapy in these treatment settings.
Addressing treatment compliance in this study increases the usefulness of these results. Showing that the groups did not differ in treatment participation assures us that the outcomes reported here are valid –there is no systematic difference in treatment compliance that may be responsible for the outcome results.
Similarly, it is becoming increasingly apparent that participant beliefs, in addition to behaviors, are vital to assess. Using a treatment satisfaction measure in the current study records participant beliefs about what is most important in their treatment. Importantly, although 60% of the study participants reported that psychosocial treatment was effective, only 1% of the participants reported that their psychosocial treatment was the most effective study component as compared to 63% who reported medication as the most effective study component for treating their opioid dependence, and 36% who reported both are important. These results suggest that treatment programs should either focus on the provision of pharmacotherapy for increasing treatment satisfaction and positive outcome, or develop more effective psychosocial treatments satisfying to patients.
Importantly, the majority of our participants complied with treatment, attended study visits, reduced their opioid use, and reported satisfaction with treatment. Again, these results indicate that pharmacotherapy with buprenorphine is effective as shown in reductions in drug use and treatment retention. Whether behavioral treatment is beneficial or even necessary may be predicated on the needs of individual patients.
Limitations
We selected a treatment length similar to real-world settings, but better outcomes are associated with longer treatment periods. Different outcomes by group may have occurred had the treatment duration been longer. A related issue is that the MM in this study may not be representative of that offered in private practice or clinic settings. Few clinicians see patients twice-weekly for 18 weeks. Although this may be an issue when comparing our protocol with treatment plans in other settings, all participants received the same level of MM in this study.
Another limitation is generalizability of findings. Study eligibility criteria eliminated individuals with health issues so participants may be healthier, stable individuals with better resources. Comparisons between randomized participants (n=202) and a combined group of those who were not randomized (n=164) shows the non-randomized group reported more mean days of heroin use (15.3 (13.6) vs. 22.5 (11.5); 4.96, p<0.0001), and had a higher percentage of opioid-positive UA test results (90.7% vs. 80.2%; p=0.009).
Recommendations
Future research should study how private practice physicians provide behavioral treatment with buprenorphine to collect information about how buprenorphine treatment requirements are being interpreted. A related investigation could examine how the MM plan is developed and implemented in treatment settings as compared to MM plans utilized in research.
These findings also suggest that buprenorphine-prescribing physicians need to take care in developing appropriate MM plans. We have found no study that has examined MM as a treatment component. Our MM included regularly scheduled appointments, which may contribute to improved outcomes, particularly when provided at the beginning of treatment.
Acknowledgments
We are grateful to the National Institute on Drug Abuse for funding this project (DA020210). The authors thank the research team at the UCLA Outpatient Clinical Research Center for their assistance: Sandy MacNicoll, Susan Reed, Christie Thomas, Al Hasson, Geetha Doraimani, Michele Smith, Elizabeth Schaper, Brittany Thornton, Larissa Mooney, Karen Miotto, Dan Dickerson, Matt Torrington, David Chim, Claire Mannah, Linda Wilhelm, Catherine Cannamar, Laura McGraw, Lupe Ettinger, Mark Oyama, Scott Baker, Wendy Medina, Xochitl Cordova, Jasmin Hernandez, Mary Olear, Claudia Gonzales, Jeff Annon, Katie Morrison, Brian Perrochet, and Shannon Schroeder.
Footnotes
Ethical Statement: The material in this paper has not been published in whole or part elsewhere; the paper is not currently being considered for publication elsewhere; all authors have been personally and actively involved in substantive work leading to the report and will hold themselves jointly and individually responsible for its content; all relevant ethical safeguards have been met in relation to patient or subject protection including clinical review by an appropriate ethical review committee and written informed patient consent. This research complies with the World Medical Association Declaration of Helsinki.
Declaration of Interest: Funding for this study was provided by the National Institute on Drug Abuse (DA020210). Study medications were provided by Reckitt Benckiser Pharmaceuticals. Walter Ling has received funding from Reckett Benckiser for consultant activities. All other authors report no financial or other possible conflicts of interest.
References
- 1.Amass L, Kamien JB, Mikulich SK. Efficacy of daily and alternate-day dosing regimens with the combination buprenorphine-naloxone tablet. Drug Alcohol Depend. 2000;58:143–52. doi: 10.1016/s0376-8716(99)00074-5. [DOI] [PubMed] [Google Scholar]
- 2.Fiellin DA, Rosenheck RA, Kosten TR. Office-based treatment for opioid dependence: Reaching new patient populations. Am J Psychiatry. 2001;158:1200–04. doi: 10.1176/appi.ajp.158.8.1200. [DOI] [PubMed] [Google Scholar]
- 3.Fudala PJ, Bridge TP, Herbert S, Chiang CN, Leiderman DB the Buprenorphine/Naloxone Collaborative Study Group. NIDA Research Monograph. US. Vol. 179. Rockville: DHHS/NIH/NIDA; 1998. A multisite efficacy evaluation of a buprenorphine/naloxone product for opioid dependence treatment; p. 105. [Google Scholar]
- 4.Ling W, Wesson DR, Charuvastra C, Klett CJ. A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch Gen Psychiatry. 1996;53:401–7. doi: 10.1001/archpsyc.1996.01830050035005. [DOI] [PubMed] [Google Scholar]
- 5.Ling W, Charuvastra VC, Collins JF, Batki S, Brown LS, Jr, Kintaudi P, et al. Buprenorphine maintenance treatment of opioid dependence: A multicenter randomized clinical trial. Addiction. 1998;93:475–86. doi: 10.1046/j.1360-0443.1998.9344753.x. [DOI] [PubMed] [Google Scholar]
- 6.Ling W, Wesson DR. Clinical efficacy of buprenorphine: Comparisons to methadone and placebo. Drug Alcohol Depend. 2003;70(2 Suppl):S49–57. doi: 10.1016/s0376-8716(03)00059-0. [DOI] [PubMed] [Google Scholar]
- 7.Amass L, Ling W, Freese TE, Reiber C, Annon JJ, Cohen AJ, et al. Bringing buprenorphine-naloxone detoxification to community treatment providers: The NIDA Clinical Trials Network field experience. Am J Addict. 2004;13(1):42–66. doi: 10.1080/10550490490440807. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Compton PA, Wesson DR, Charuvastra VC, Ling W. Buprenorphine as a pharmacotherapy for opioid addiction. What dose provides a therapeutic response? Am J Addict. 1996;5:220–2. [Google Scholar]
- 9.Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN, Jones K, et al. Office-based treatment of opioid addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med. 2003;349:949–58. doi: 10.1056/NEJMoa022164. [DOI] [PubMed] [Google Scholar]
- 10.Ling W, Amass L, Shoptaw S, Annon JJ, Hillhouse M, Babcock D, et al. and the Buprenorphine Study Protocol Group A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: Findings from the National Institute on Drug Abuse Clinical Trials Network. Addiction. 2005;100:1090–100. doi: 10.1111/j.1360-0443.2005.01154.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Substance Abuse and Mental Health Services Administration (SAMHSA) [Accessed January 7, 2013];Html Drug Abuse Treatment Act Drug Addiction Treatment Act of 2000, Amendment to Controlled Substance Act. http://buprenorphine.samhsa.gov/data.html.
- 12.Carroll KM, Ball SA, Nich C, O'Connor PG, Eagan DA, Frankforter TL, et al. Targeting behavioral therapies to enhance naltrexone treatment of opioid dependence. Arch Gen Psychiatry. 2001;58:755–61. doi: 10.1001/archpsyc.58.8.755. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Sees KS, Delucchi KL, Masson C, Rosen A, Clark HW, Robillard H, et al. Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: A randomized controlled trial. JAMA. 2000;283:1303–10. doi: 10.1001/jama.283.10.1303. [DOI] [PubMed] [Google Scholar]
- 14.Stitzer M, Bigelow G, Leibson I. Reducing drug use among methadone maintenance clients: Contingent reinforcement for morphine-free urine urines. Addict Beh. 1980;4:245–52. doi: 10.1016/0306-4603(80)90007-6. [DOI] [PubMed] [Google Scholar]
- 15.Woody GE, Luborsky L, McLellan AT, et al. (1983). Psychotherapy for opiate addicts: Does it help? Arch Gen Psychiatry. 1983;40:639–45. doi: 10.1001/archpsyc.1983.04390010049006. [DOI] [PubMed] [Google Scholar]
- 16.Carroll KM, Rounsaville BJ, Gawin FH. (1991). A comparative trial of psychotherapies for ambulatory cocaine abusers: Relapse prevention and interpersonal psychotherapy. Am J Drug Alcohol Abuse. 1991;17:229–47. doi: 10.3109/00952999109027549. [DOI] [PubMed] [Google Scholar]
- 17.Carroll KM, Rounsaville BJ, Gordon LT, Nich C, Jatlow PM, Bisighini RM, et al. Psychotherapy and pharmacotherapy for ambulatory cocaine abusers. Arch Gen Psychiatry. 1994a;51:177–97. doi: 10.1001/archpsyc.1994.03950030013002. [DOI] [PubMed] [Google Scholar]
- 18.Carroll KM, Nich C, Ball SA, McCance-Katz E, Rounsaville BJ. Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction. 1998;93:713–28. doi: 10.1046/j.1360-0443.1998.9357137.x. [DOI] [PubMed] [Google Scholar]
- 19.Carroll KM, Nich C, Ball SA, McCance-Katz EF, Frankforter TF, Rounsaville BJ. (2000). One year follow-up of disulfiram and psychotherapy for cocaine-alcohol abusers: Sustained effects of treatment. Addiction. 2000;95:1335–49. doi: 10.1046/j.1360-0443.2000.95913355.x. [DOI] [PubMed] [Google Scholar]
- 20.Rawson R, Huber A, McCann MJ, Shoptaw S, Farabee D, Reiber C, et al. A comparison of contingency management and cognitive-behavioral approaches during methadone maintenance for cocaine dependence. Arch Gen Psychiatry. 2002;59:817–24. doi: 10.1001/archpsyc.59.9.817. [DOI] [PubMed] [Google Scholar]
- 21.Shoptaw S, Reback CJ, Peck JA, Yang X, Rotheram-Fuller E, Larkins S. Behavioral treatment approaches for methamphetamine dependence and HIV-related sexual risk behaviors among urban gay and bisexual men. Drug Alcohol Depend. 2005;78:125–34. doi: 10.1016/j.drugalcdep.2004.10.004. [DOI] [PubMed] [Google Scholar]
- 22.Carroll KM, Rounsaville BJ, Nich C, Gordon LT, Wirtz PW, Gawin FH. One year follow-up of psychotherapy and pharmacotherapy for cocaine dependence: Delayed emergence of psychotherapy effects. Arch Gen Psychiatry. 1994b;51:989–97. doi: 10.1001/archpsyc.1994.03950120061010. [DOI] [PubMed] [Google Scholar]
- 23.Bigelow G, Silverman K. Theoretical and empirical foundations of contingency management treatments for drug abuse. In: Higgins ST, Silverman K, editors. Motivating behavior change among illicit-drug abusers: Research on contingency management interventions. Washington, DC: American Psychological Association; 1999. [Google Scholar]
- 24.Higgins ST. The influence of alternative reinforcers on cocaine use and abuse: A brief review. Pharmacol Biochem Behav. 1997;57:419–27. doi: 10.1016/s0091-3057(96)00446-7. [DOI] [PubMed] [Google Scholar]
- 25.Skinner BF. Intermittent reinforcement. Psychol Rev. 1950;57:193–216. doi: 10.1037/h0054367. [DOI] [PubMed] [Google Scholar]
- 26.Carroll ME, Lac ST, Nygaard SL. (1989). A concurrently available nondrug reinforcer prevents the acquisition or decreases the maintenance of cocaine-reinforced behavior. Psychopharmacology (Berl) 1989;97:23–29. doi: 10.1007/BF00443407. [DOI] [PubMed] [Google Scholar]
- 27.Higgins ST, Bickel WK, Hughes JR. Influence of an alternative reinforcer on human cocaine self-administration. Life Sci. 1994a;55:179–87. doi: 10.1016/0024-3205(94)00878-7. [DOI] [PubMed] [Google Scholar]
- 28.Nader MA, Woolverton WL. Effects of increasing the magnitude of an alternative reinforcer on drug choice in a discrete-trials choice procedure. Psychopharmacology (Berl) 1991;105:169–74. doi: 10.1007/BF02244304. [DOI] [PubMed] [Google Scholar]
- 29.Roll JM, Higgins ST. A within-subject comparison of three different schedules of reinforcement of drug abstinence using cigarette smoking as an exemplar. Drug Alcohol Depend. 2000;58:103–9. doi: 10.1016/s0376-8716(99)00073-3. [DOI] [PubMed] [Google Scholar]
- 30.Higgins ST, Alessi SM, Dantona RL. Voucher-based incentives A substance abuse treatment innovation. Addict Beh. 2002;27:887–910. doi: 10.1016/s0306-4603(02)00297-6. [DOI] [PubMed] [Google Scholar]
- 31.Higgins ST, Silverman K. Research on contingency management interventions. Washington, DC: American Psychological Association; 1999. Motivating behavior change among illicit-drug abusers. [Google Scholar]
- 32.Higgins ST, Badger GJ, Budney AJ. Initial abstinence and success in achieving longer term cocaine abstinence. Ex Clin Psychopharmacol. 2000;8:377–86. doi: 10.1037//1064-1297.8.3.377. [DOI] [PubMed] [Google Scholar]
- 33.Higgins ST, Budney AJ, Bickel WK, Badger GJ, Foerg FE, Ogden D. Outpatient behavioral treatment for cocaine dependence: One-year outcome. Ex Clin Psychopharmacol. 1995;3:205–12. [Google Scholar]
- 34.Silverman K, Higgins ST, Brooner RK, Montoya ID, Cohen EJ, Schuster CR. Sustained cocaine abstinence in methadone maintained patients through voucher based reinforcement therapy. Arch Gen Psychiatry. 1996;53:409–15. doi: 10.1001/archpsyc.1996.01830050045007. [DOI] [PubMed] [Google Scholar]
- 35.Petry NM, Martin B. Low-cost contingency management for treating cocaine- and opioid abusing methadone patients. J Consult Clin Psychol. 2002;70:398–405. doi: 10.1037//0022-006x.70.2.398. [DOI] [PubMed] [Google Scholar]
- 36.Bickel WK, Amass L, Higgins ST, Badger GJ, Esch RA. Effects of adding behavioral treatment to opioid detoxification with buprenorphine. J Consult Clin Psychol. 1997;65:803–810. doi: 10.1037//0022-006x.65.5.803. [DOI] [PubMed] [Google Scholar]
- 37.Downey KK, Helmus TC, Schuster CR. Treatment of heroin-dependent poly-drug abusers with contingency management and buprenorphine maintenance. Exp Clin Psychopharmacol. 2000;8:176–84. doi: 10.1037//1064-1297.8.2.176. [DOI] [PubMed] [Google Scholar]
- 38.Fiellin DA, Pantalon MV, Chawarski MC, Moore BA, Sullivan LE, O'Connor PG, et al. Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence. N Engl J Med. 2006;355:365–74. doi: 10.1056/NEJMoa055255. [DOI] [PubMed] [Google Scholar]
- 39.Fiellin DA, Barry DT, Sullivan LE, Cutter CJ, Moore BA, O'Connor PG, et al. A randomized trial of cognitive behavioral therapy in primary care-based buprenorphine. Am J Med. 2013;126:74.e11–74.e17. doi: 10.1016/j.amjmed.2012.07.005. http://dx.doi.org/10.1016/j.amjmed.2012.07.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Rawson RA, Shoptaw SJ, Obert JL, McCann MJ, Hasson AL, Marinelli-Casey, et al. An intensive outpatient approach for cocaine abuse treatment: The Matrix Model. J Subst Abuse Treat. 1995;12:117–27. doi: 10.1016/0740-5472(94)00080-b. [DOI] [PubMed] [Google Scholar]
- 41.Hillhouse MP, Thomas C, Jenkins J, Fahey J, Thornton B, Schaper E, et al. Comparison of contingency management reinforcement schedules provided with buprenoprhine for the treatment of opioid dependence. Presented at the 2012 meeting of the College on Problems of Drug Dependence; June, 2012; Palms Springs, California. [Google Scholar]
- 42.McLellan AT, Kushner H, Metzger D, Peters R, Smith I, Grissom G, et al. The fifth edition of the Addiction Severity Index. J Subst Abuse Treat. 1992;9:199–213. doi: 10.1016/0740-5472(92)90062-s. [DOI] [PubMed] [Google Scholar]
- 43.Childress AR, McLellan AT, O'Brien CP. Conditioned responses in a methadone population: A comparison of laboratory, clinic, and natural settings. J Subst Abuse Treat. 1986;3:173–9. doi: 10.1016/0740-5472(86)90018-8. [DOI] [PubMed] [Google Scholar]
- 44.Kaplan RF, Cooney NL, Baker LH, Gillespie RA, Meyer RE, Pomerlau OF. Reactivity to alcohol-related cues: Physiological and subjective responses in alcoholics and non-problem drinkers. J Stud Alcohol. 1985;46:267–72. doi: 10.15288/jsa.1985.46.267. [DOI] [PubMed] [Google Scholar]
- 45.Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS) J Psychoactive Drugs. 2003;35:253–9. doi: 10.1080/02791072.2003.10400007. [DOI] [PubMed] [Google Scholar]
- 46.Wesson D, Ling W, Jara G. Buprenorphine in pharmacotherapy of opioid addiction: implementation in office-based medical practice. Translating the experience of clinical trials into clinical practice. Newsletter of the California Society of Addiction Medicine. 1999;25(3) [Google Scholar]
- 47.Lavori PW. WClinical trials in psychiatry: Should protocol deviation censor patient data? Neuropsychopharmacology. 1992;6(1):39–48. [PubMed] [Google Scholar]
- 48.Ling W, Shoptaw S, Wesson D, Rawson RA, Compton M, Klett CJ. Treatment effectiveness score as an outcome measure in clinical trials. NIDA Monographs. 1997;175:208–220. [PubMed] [Google Scholar]
- 49.Amato L, Minozzi S, Davoli M, Vecchi S. The Cochrane Collaboration. Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence. John Wiley and Sons Publishers; 2011. [DOI] [PubMed] [Google Scholar]