A total of 990 individuals agreed to participate in the study, and 894 individuals were eligible to participate based on initial screening. A total of 748 participants were inducted onto Suboxone®, although 232 participants terminated or were dropped at some point during the induction/stabilization phase due to missed visits, a desire to stay on Suboxone®, etc. Thus, 516 participants were randomized to the 7-day (n = 255) or 28-day (n = 261) taper. All analyses included data from participants who were randomized at the end of the maintenance/stabilization period (n = 516). No statistically significant demographic or drug use differences were found between the two taper groups at baseline (all comparisons P > 0.05). The mean age of participants was 35.8 and 36.0 for the 7-day and 28-day groups, and the percentage of females in both taper groups was identical at 32.9%. Ethnicity also did not differ between the groups, with 78.8% and 73.6% whites, 12.6% and 10.7% African Americans and 4.3% and 8.1% Hispanics in the 7-day and 28-day groups, respectively. The mean number of years of education in both groups was 12.8 years, and the percentage of participants unemployed in the last month was 31.0% and 39.1% for the 7-day and 28-day groups, respectively. Total life-time drug use and drug use in the 30 days before screening were not statistically different between groups. For example, both groups reported a mean of approximately 28 days of heroin use in the last 30 days [standard deviation (SD) = 5.45, 5.34] and about 8 years of life-time heroin use (SD = 8.99, 7.53). The taper groups also did not differ in self-reported or clinically assessed withdrawal symptoms, or self-reported craving at baseline or randomization (P > 0.05 for all comparisons). The two groups did not differ in opioid use (measured using the percentage of opioid-negative urine test results over the possible urine test results) during the stabilization period (t = 1.02; P = 0.3087). Further comparisons document that the two taper groups did not differ in the number of concomitant medications used for withdrawal symptoms reported as adverse events during the stabilization period (P > 0.05). χ2 and t-tests were used to compare the group of participants who remained in the study until the end of the taper with those who dropped out before the end of the taper. The two groups were not statistically different in demographic and drug use characteristics.
This was a randomized, parallel-group, open-label study in which all procedures were identical for all participants until the taper period. After completing the consent process and baseline assessments, participants were inducted onto buprenorphine (Suboxone®) according to clinical practice, and stabilized on dose during the 4-week stabilization period. After the induction/stabilization phase, participants were assigned randomly to either a 7-day or 28-day tapering regimen ().
Suboxone® taper regimen for two study taper groups.
Participants completed weekly data collection to week 8, including the 4 induction/stabilization weeks and 4 successive weeks, so that participants in both conditions had the same number of data collection visits. Participants in both groups also attended clinic once weekly for 4 weeks after starting the taper (post-randomization) to maintain equivalence in the number of clinic visits across the two taper groups. For the 7-day taper group, medication provision ended at day 7, and medication provision extended to day 28 for the longer taper group. Follow-up interviews occurred at 1 month and 3 months post-taper.
The maximum length of study participation was approximately 5 months, including screening, induction/stabilization, taper and follow-up phases. Participants were encouraged to participate in the psychosocial treatment program administered at the treatment site (treatment as usual; TAU). Because this trial was designed to reflect real-world practice, no effort was made to standardize the psychosocial services or require participation in the psychosocial component. Following the taper, participants could continue in TAU or be referred to other local treatment resources.
The primary outcome was the percentage of participants in each taper group who were present and provided urine samples free of illicit opioids at the end of the taper period, and again at 1-month and 3-month follow-up assessments. Secondary outcomes included group comparisons of use of all drugs; withdrawal scores; the number of concomitant medications used to treat withdrawal symptoms; craving scores; and treatment satisfaction scores.
Recruitment began in June 2003 and data collection was completed in November 2005. Eligible participants were at least 15 years of age, and seeking treatment for opioid dependence at one of the 11 participating treatment programs in 10 US cities in Colorado, Washington, Oregon, Connecticut, New York, Virginia and North Carolina. Methods of recruitment included word of mouth, radio announcements, newspaper advertisements and referrals from local opioid treatment and outreach programs, alcohol and drug abuse clinics, primary care providers, local mental health centers, crisis clinics and hospital emergency rooms.
Participants were excluded if they provided a urine sample testing positive for methadone or benzodiazepine, were in poor general health, had a self-reported allergy to buprenorphine or naloxone, were pregnant or nursing, or had a medical or psychiatric condition that could make participation unsafe. Participants were also excluded if they were dependent on alcohol or any drug other than opioids (per DSM-IV criteria), or had participated in an investigational drug study, or methadone or levo-alpha acetyl methadol (LAAM) maintenance or detoxification in the previous 30 days. Pending legal action and inability to remain in the area also precluded participation. Females of childbearing potential could participate if they agreed to use an acceptable form of birth control.
All ineligible individuals were referred to standard treatment services within the community treatment program (CTP) or another local treatment facility, as determined appropriate by the CTP staff. The study was approved by each of the participating Institutional Review Boards and the Human Subjects Protection Committee at the University of California, Los Angeles (UCLA), as UCLA investigators were the lead group overseeing the study. All participants provided written informed consent prior to any study procedures. Cash and grocery tokens were used as participant incentives based on site preferences or site Institutional Review Board requirements. Participants received $25 for each ‘milestone’ visit (screening, start of induction, start of taper, follow-up visits), $10 for each weekly clinic visit and $25 for completion of all post-taper visits. Generally, the maximum incentive available was $185, although one site provided up to $210.
A priori sample size calculation indicated that 240 participants in each group would provide 82% power to detect a 12% difference, assuming 20% opioid-free urine samples in one group [12
]. With 20% dropout, 72% power to detect a 12% difference would be retained.
After providing informed consent, participants completed multiple questionnaires, as well as physical examinations and medical and laboratory testing, to determine study eligibility and to provide baseline information. Eligible individuals were scheduled for induction onto the study medication. Study measures included the following:
- The Adjective Rating Scale for Withdrawal (ARSW) collected self-report information on 16 signs and symptoms of opioid withdrawal [1,7,21] (e.g. muscle cramps, nausea, etc.) rated from 0 (none) to 9 (severe) for each item, with a maximum possible score of 144 indicating the most severe withdrawal experience. The ARSW required 5 minutes to complete and was administered at each data visit.
- The Clinical Opiate Withdrawal Scale (COWS) is an 11-item questionnaire  providing a description of signs and symptoms of opiate withdrawal that are observed clinically (e.g. sweating, runny nose, etc.). A clinician completed the COWS at each data visit with a possible total score ranging from 0 (none) to 48 (severe).
- The Visual Analog Scale (VAS) is a self-report measure that assesses the extent to which the participant feels any craving for opiates, the severity of withdrawal symptoms, and the extent to which the study medication helps to ease cravings (if applicable). Three 100-point lines anchored with ‘not at all’ at one end and ‘extremely’ at the other [29,30] are included. The VAS takes about 1 minute to complete and was administered at each data visit.
- The Addiction Severity Index-Lite (ASI-Lite) is a standardized, multi-dimensional clinical interview to collect information on problem severity profiles in domains affected commonly by substance abuse . The Lite version is an abbreviated format with assessment domains including general demographic information, alcohol use, drug use, medical, psychiatric, legal, family/social and employment/support. To collect additional information not included on the ASI, such as nicotine use and a distinction of illicit and prescribed methadone use, a one-page addendum was constructed and administered as a companion to the ASI. The ASI-Lite and the additional assessment were administered at baseline and at the 1-month and 3-month follow-up visits.
- The Satisfaction Questionnaire (SQ) collected self-report information about the clinic, medication and treatment and recovery. The current nine-item version is an abbreviated version of the CSQ , using a 10-point scale ranging from 1 = not satisfied to 10 = very satisfied. The SQ was administered at the end of taper and at the 1-month and 3-month follow-up visits.
- Concomitant medications include number and types of non-study medications used by participants, including prescription and over-the-counter medications and herbal remedies. Only data documenting concomitant medications used for withdrawal symptoms were used in these analyses.
- Urine drug screens tested urine samples collected weekly at each clinic visit and tested on-site, adhering to standard testing protocol. Methods to ensure accurate results included using temperature strips and reading results during an appropriate time window. Results were coded qualitatively as positive or negative for morphine, methadone, oxycontin, amphetamines, barbiturates, benzodiazepines, cocaine, methamphetamine, phencyclidine (PCP), marijuana and tricyclic antidepressants. Jant’s Accutest MultiDrug Screen-10 or ABI’s SureStep Drug Screen Card 10A was used at each site. All sites also tested for oxycodone with ABM’s Rapid One Oxycodone single dipstick.
Suboxone® is a combination buprenorphine and nalox-one sublingual tablet at a ratio of 4: 1. Reckitt & Benckiser (Hull, UK) provided two formulations (2 mg/0.5 mg and 8 mg/2 mg buprenorphine/naloxone), supplied to the sites by the National Institute on Drug Abuse. Participants were given weekly supplies of Suboxone® and explicit dosing instructions.
Study procedures were intended to mirror those occurring in ‘real-world’ clinic settings. As such, the psychosocial treatment procedures in place at each site were provided throughout the study with no attempt to standardize or modify site-specific TAU procedures. The study protocol required that participants receive a basic platform of substance abuse education, and all sites provided self-help buprenorphine treatment booklets. No data assessed engagement in the psychosocial treatment component.
To facilitate transition onto Suboxone®, each participant was instructed not to use any heroin or other opioids for at least 6 hours prior to the time scheduled to receive their first dose of Suboxone®. Induction occurred over the first 3 days of the study. The study physician dispensed the first dose of 2 mg or 4 mg (expressed as amount of buprenorphine) to the participant, who was instructed to hold the tablet sublingually until the medication had dissolved. The initial dose was determined by each study physician based on his/her experience with this drug and the needs of the participant, although no documentation was made of the rationale for each dosing determination. Participants remained in the clinic for at least 1 hour after dosing for monitoring of adverse effects. An additional dose could be provided in the clinic at the study physician’s discretion, with a maximum dosage of 8 mg for the first day. The physician dispensed enough medication to each participant to continue dosing until the next scheduled office visit, with no more than 7 days’ dosage provided at any time. Research staff contacted the participant by telephone on day 2 to address adverse effects, withdrawal symptoms and craving. This contact was intended to confirm the participant’s wellbeing in the first days of study drug use, and no script was used. The maximum dosage for the second day of induction was 12 mg, and 16 mg was the maximum dosage for day 3. Participants attended the clinic and saw study medical staff at least one additional day during the first week for evaluation of vital signs, drug use, craving, withdrawal symptoms, over-medication, adverse events and concomitant medication use. At these visits, medication dosage could be adjusted by the study physician, in 4 mg increments, to range between 8 mg and 24 mg. The study physician prescribed concomitant medications at his/her discretion if a participant complained of withdrawal symptoms.
The 4-week induction/stabilization period included 3 weeks of flexible dosing. Prievious clinical trials suggest that individuals vary in tolerance and response to Suboxone®
]. Flexible dosing permitted physicians and participants to determine the most effective dose while considering subjective effects such as withdrawal symptoms, craving and physical status. At each scheduled weekly visit during this period, the study physician could adjust the participant’s dose in increments of 4 mg. The maximum allowable dose was 24 mg per day, and the minimum was 8 mg per day. A change in dose could be made after assessing the participant’s vital signs, evaluating illicit drug use (by self-report and urine), craving, signs and symptoms of opioid withdrawal, over-medication, adverse events, and concomitant medication taken since the last visit. During the final (fourth) week of the induction/stabilization period, all participants remained on a set daily dose of 8 mg, 16 mg or 24 mg of Suboxone®
, as prescribed by the study physician. This study design assumed that the optimal dose for each participant was identified by the final week of the induction/stabilization period. Because determining the optimal dose was often a dynamic process, we are aware that inadequate dosing may have been responsible for some dropout during the stabilization period.
Randomization to taper schedule
Upon completion of the induction/stabilization phase, participants were assigned randomly to either the 7-day or 28-day taper schedule. Randomization was stratified by maintenance dose at the end of the stabilization phase (8, 16 or 24 mg of Suboxone®), such that approximately equal numbers of participants on each dose were randomized to each taper schedule. Each treatment site had three sets of randomization cards (one set for each stabilization dose) prepared in advance. Based on stabilization dose, the top card in the appropriate stack was selected for the participant. This card listed the assigned taper schedule. On the day of randomization, the study physician gave the participant his/her medication, described the assigned taper schedule (7 or 28 days), provided explicit written instructions detailing exactly how to take the medication for the next seven days, including when and how to decrease dosage, and a clinic visit was scheduled for the next week. For each taper group, the stabilization dose determined the schedule for reducing dosage in the taper phase, designed to maximize participant comfort during the taper phase regardless of group assignment. Daily Suboxone® dosages for each taper group are shown in .
The objective of this research was to compare a short taper versus long taper following 4 weeks of Suboxone® medication stabilization. The primary study outcome was the percentage of participants in each taper condition who provided opioid-free urine specimens at the end of the taper and, as such, were considered successful in terms of withdrawal from study medication. Furthermore, data were collected at two follow-up points, enabling the tracking of participants within each taper group over time. Using a categorical variable eliminates the ability to look at reductions in opioid use, but our intent was to determine the percentage of participants who were able to avoid using opioids completely by the end of the taper schedule.
Secondary outcomes included differences in all drug use at the end of the taper, and comparisons of the groups at each follow-up time-point. Withdrawal and craving scores between groups were computed for baseline, the taper period, at the end of the taper and at both follow-up time-points. Analyses of concomitant medications addressed only those medications prescribed by a clinician to alleviate withdrawal symptoms.
Study procedures were identical across the two taper groups until the taper began, and the groups did not differ at baseline or through stabilization or at randomization in terms of demographic or drug use characteristics. Comparison of taper duration was the reason for the study, but length of taper was also seen as a potential confound. It is impossible to remove the effect of length of time when using a time-dependent variable. All efforts were made to equate study periods, study clinic visits and study follow-up time-points during the design of the study to remove any other possible confound.
One consideration was whether to present the data collected weekly during the taper period, rather than simply the end-of-taper data. This would compare results for 1 medication week and 3 non-medication weeks (for the 7-day group) to results for 4 medication weeks (for the 28-day group). Although the short taper group was instructed to return to clinic for weekly visits, the likelihood of this happening when no medication was being provided is reduced greatly compared to a group still receiving medication. Thus, comparing weekly data was deemed inappropriate. Similarly, the long taper group had medication to potentially alleviate any withdrawal symptoms that could lead to relapse, whereas the short taper group did not. While an argument could be made that the short taper group had less time to relapse and hence would appear to do better, it could also be argued that the 28-day group had a longer period in which to adjust to abstinence and an opioid-free life-style.
Statistical methods include χ2 tests to assess the differences between the taper groups for the primary outcome. Analysis of secondary outcomes, including analysis of withdrawal and craving at the start of the taper (randomization), at the end of taper, and at the 1-month and 3-month follow-ups, were conducted at discrete time-points using χ2 and t tests as appropriate. All statistical tests utilized a two-tailed alpha level of P < 0.05.