The design of the POATS trial has a number of unique characteristics and strengths that will help to answer important questions regarding the treatment of individuals with prescription opioid dependence. The two-phase adaptive treatment research design provides an innovative approach to examining the efficacy of different lengths of bup/nx treatment, paired with different intensities of accompanying counseling. Because there is evidence that prescription drug abusers may have a better prognosis than those with heroin dependence [10
], POATS will help to determine the frequency with which a short-term taper (as in Phase 1) with bup/nx could be beneficial to this population, with or without individual counseling. The POATS design is strengthened by the selection of sites from rural, urban, and suburban sites throughout the country, enhancing the generalizability of the study’s results.
The two-phase design that is intended to approximate real-world practice (i.e., start with a relatively non-intensive approach, and then institute more intensive treatment if the first treatment fails) provides ecological validity to the study. However, designing and instituting a two-phase study also poses specific challenges. First, of course, is the choice of the two study phases. We chose a 4-week detoxification period after consulting multiple physicians and CTN community treatment program directors around the country with experience using bup/nx in opioid dependence treatment. When the study was being designed in 2006, detoxification was the most common initial treatment for this population. This design choice was also supported by findings from a study by Gandhi et al. [40
], who reported reduced frequency and intensity of drug use at 1-month and 3-month follow-up in a relatively young population (ages 18–25) of heroin addicts after a very brief (3-day) detoxification with buprenorphine. While some practitioners used a rapid taper schedule (as little as several days) at the time of the study design, a 4-week taper was most frequently utilized, and was therefore chosen for POATS. Moore et al. [11
] found that participants in their opioid dependence treatment study who were dependent on prescription opioids were significantly younger and had significantly fewer years of opioid use than heroin-dependent individuals; thus, one might expect better outcomes following detoxification in this population than in traditional heroin-dependent populations. In fact, Moore et al. [11
] did report substantially better outcomes for those dependent on prescription opioids than for participants dependent on heroin (63% vs. 31% of participants achieving 6 consecutive weeks of opioid-negative urines in a 24-week bup/nx trial); this finding provided additional support for our hypothesis that a substantial minority of individuals dependent on prescription opioids would succeed in Phase 1 of our study.
When considering which options to study in participants who relapsed to opioids during Phase 1, a longer period (12 weeks) of bup/nx stabilization was chosen for Phase 2 to study the impact of additional counseling (i.e., EMM vs. SMM) during both bup/nx detoxification and longer-term bup/nx treatment.
Many of the participants entering this study have received opioids by prescription from a physician; a key question for physicians treating these individuals is thus whether their drug dependence can be managed in a medical office setting (as exemplified by SMM) or whether they should instead be referred to a specialty drug abuse treatment program, a model of care more consistent with EMM. Although SMM and EMM in this study occur in the same setting, the contrast between these two models of care should help to answer the question of the optimal treatment setting for this population. Moreover, since many such patients may resist referral to a drug abuse treatment program, studying the efficacy of SMM could help determine whether treatment in an office setting, without additional specialized counseling, is a reasonable approach for this population.
Another challenge in designing and implementing an adaptive treatment research design of this type involved masking from participants the eligibility criteria that would trigger entry into Phase 2. If these criteria were revealed, then some participants who wanted additional bup/nx treatment could falsify their self-report data (i.e., by reporting more ongoing opioid use than actually occurred) in order to be classified as Phase 1 failures. We managed this situation by emphasizing during initial training and booster sessions with study staff the importance of not disclosing Phase 1 failure criteria to participants; we also engaged in role playing scenarios with staff illustrating ways to respond when study participants asked about criteria for entry into Phase 2.
Another challenge involved powering the study when we were uncertain about how many participants from the Phase 1 population would be eligible for and interested in Phase 2. We were, in essence, working backwards in conducting our power analysis; we knew that we needed 324 participants in Phase 2, but had to estimate the number of Phase 1 participants needed to produce this Phase 2 sample size. We addressed this by making conservative assumptions that approximately 50% of subjects randomized to Phase 1 would meet treatment failure criteria and agree to be randomized in Phase 2.
POATS presents a unique opportunity to evaluate a treatment strategy, rather than a discrete treatment intervention for prescription opioid dependence. This is the largest study yet conducted with this population, and also represents one of the first adaptive treatment research designs to be instituted in a large-scale addiction treatment study. This type of study design with drug dependent patients presents both advantages and challenges, as described above; a clinical trial of this scope should generate important results regarding the delivery of treatment for this important population.