Krook and colleagues (2002) employed a 12-week, randomized, double-blind study of buprenorphine versus placebo without additional rehabilitation or support services. The study was conducted through the Centre for Medication Assisted Rehabilitation in Oslo, Norway (MARIO). Study participants were 420 patients on the waiting list for MARIO. They received a letter offering a chance to participate in the study if they met the inclusion criteria: they had to be at least 25 years old, have a history of more than 10 years of opioid dependence, and have a written plan for the rehabilitation process. In addition, participants had to have a current opioid dependence and to have already attempted drug-free treatment.
The final sample included 106 patients who were randomly assigned to a placebo group (n= 51) or a buprenorphine treatment group (n= 55). The placebo group was 67.0 percent male, with an average age of 38 years and an average drug use history of 20-year heroin addiction. The buprenorphine treatment group was 65.5 percent male, with an average age of 38 years and an average drug use history of 20-year heroin addiction. There were no significant differences between the groups in any of the demographic or baseline characteristics.
The primary outcome variables were retention and compliance. Participants were also asked to self-report drug use using a visual analog scale (VAS) from 0 to 10, where “daily heavy drug use” was recorded as 10 and “drug free” was recorded as 0. Abuse of opioids was calculated separately, while benzodiazepines, other drugs, and alcohol were calculated together. Subjective well-being was also self-reported using a VAS (where 10 meant “very bad” and 0 meant “very well”) and with the temporal satisfaction with life scale. Mental health, including anxiety and depression, was measured with the symptom checklist.
Survival analysis was used to examine study participation and attrition of patients. T–tests were used to analyze the treatment effect on the other outcome variables by comparing the change in the scores of the placebo group with the change in the scores of the buprenorphine group.
Fudala and colleagues (2003) examined the efficacy of buprenorphine in combination with naloxone in an office-based setting. There were two parts of the study that took place across multiple treatment centers. The first part was a 4-week, double-blind, placebo-controlled efficacy trial. However, the double-blind study was terminated early because buprenorphine administered in combination with naloxone and buprenorphine administered alone were found to have greater efficacy than the placebo. The second part was an open-label safety phase lasting 48 weeks (for individuals who participated in the first part of the study) or 52 weeks (for individuals who did not participate in the first part). All study visits took place in a physician’s office in a clinical research program, which provided an environment that was distinct from the clinic where methadone is usually provided.
Participants were eligible for the study if they met the diagnostic criteria of opiate dependence according to the DSM–IV, were seeking opiate-substitution pharmacotherapy, were between the ages of 18 and 59 years, and could provide informed consent and comply with study procedures. Of the 451 individuals who were screened for the double-blind study, 323 were randomly assigned to one of three study groups:
· Combination of buprenorphine and naloxone (n= 109)
· Buprenorphine alone (n= 105)
· Placebo (n= 109)
The group that received the buprenorphine and naloxone combination was 62.4 percent male and 59.5 percent white, 29.4 percent African American, 7.3 percent Hispanic, 1.8 percent Native American, and 1.8 percent Asian or Pacific Islander, with an average age of 38.1 years. The placebo group was 65.1 percent male and 64.2 percent white, 22.9 percent African American, 8.3 percent Hispanic, 1.8 percent Native American, and 2.8 percent Asian or Pacific Islander, with an average age of 38 years. There were no significant differences between the groups.
In addition to receiving medication treatment during the double-blind trial, all study participants received counseling regarding the human immunodeficiency virus (HIV) infection as well as 1 hour of individualized counseling per week. Emergency counseling (e.g., after a relapse) and referrals (e.g., to a community legal aid program) were also available to participants, but no other services were provided.
The open-label study included 461 participants (268 of whom had participated in the double-blind trial). Study participants were given buprenorphine alone for the first 2 days of treatment, after which they were given the combination of buprenorphine and naloxone. In addition to the medication, individual counseling was made available at the clinics, but participants were encouraged to obtain behavioral–treatment services outside the study.
The primary outcomes of interest in the double-blind trial were the percentage of opiate-negative urine samples and study participants’ self-reported craving for opiates. Urine samples were tested for opiates (morphine, codeine, and corresponding metabolites) as well as for other drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, and methadone). Participants’ retention in the study was also examined. The open-label phase looked at serious adverse effects and the percentage of urine samples negative for opiates, cocaine, and benzodiazepines. Urine samples were collected three times a week during the double-blind trial and two times a month during the open-label phase.
The primary comparisons were made between the treatment group that received buprenorphine in combination with naloxone and the placebo group. The group that received buprenorphine alone served as an active control. A two-factor (site and group) analysis of variance was used to analyze the percentage of urine opiate-negative urine samples. Least-square means analysis was used for each of the three pairwise combinations.