This paper examined the relationship between medication adherence and drinking outcomes at 16 weeks, the time period between treatment entry and treatment completion. More specifically, we addressed whether there were differences in medication adherence rates across 8 medication/behavioral treatment combinations. We also investigated whether there were differences in medication adherence between the two behavioral treatment modalities (i.e., combined behavior intervention (CBI) + medical management (MM) vs. MM only). Additionally, we examined whether differences in medication adherence rates across the 8 combinations were associated with differences in drinking outcomes. Answers to these questions were expected to further our understanding of the interrelationship between medication adherence and treatment outcome
Data revealed significant differences in pill taking adherence rates between the combination medications (naltrexone + acamprosate) and the double placebo conditions. Similarly, significant differences in pill taking adherence rates were found between acamprosate + naltrexone placebo and the double placebo conditions but not between the naltrexone + acamprosate placebo and the double placebo conditions. Also, significant differences in pill taking adherence rates were revealed between the combination medications (naltrexone + acamprosate) and the naltrexone + acamprosate placebo conditions. These findings were consistent across behavioral treatments.
Individuals that received acamprosate only exhibited prominent side effects and lower adherence rates than the double placebo group. Consequently, it would seem that adding acamprosate to naltrexone lowered the adherence rates of patients assigned to this combination medication condition. The higher number of reported side effects in the combination conditions could account for these differences. For example, nausea was present in 42.4% of the combination group (acamprosate and naltrexone) in contrast to 21.2% in the placebo conditions (p = 0.05) (Ciraulo, 2007
). Similar findings were observed with regard to other adverse effects such as vomiting and diarrhea (p = 0.05) (Ciraulo, 2007
). These findings are comparable with other drug trials where pill adherence rates are typically higher for patients in the placebo than in the active medication groups (Osterberg and Blaschke, 2005
Moreover, those patients who failed to take their medication regularly were also more likely to stop their medication completely. This is important to note since those who stopped taking their medication were also more likely to resume drinking than those who continued taking the medication until the end of treatment; the average PDA for medication withdrawers was 65.9% in contrast to 80.7% among nonwithdrawers (p<0.0001). These findings are in agreement with Rohsenhow and her colleagues (2000) who found that a higher severity of side effects such as nausea and vomiting predicted nonadherence among naltrexone-treated patients and might also contribute to poorer drinking outcomes in an alcohol-dependent population.
Concerning the relationship between medication adherence and behavioral treatments, the more intensive, specialty treatment CBI, did not perform better than the less intensive, primary care type MM approach. There were no significant differences in both adherence and medication discontinuance rates between MM alone or in combination with CBI. Such findings are consistent with other alcohol medication trials involving naltrexone (Baros et al., 2007
; Oslin et al., in press
). Baros et al., (2007)
found no significant differences in medication adherence rates between the more intensive cognitive behavioral therapy (CBT) and the less intensive motivational enhancement therapy (MET). Similarly, Oslin et al., (in press)
in testing the effects of naltrexone among alcohol patients assigned to behavioral interventions of varying intensities (e.g., compliance enhancement (CE), doctor only and cognitive behavioral therapy, found no significant differences between the three contrasting behavioral approaches in facilitating medication adherence.
As expected, high medication adherence fared better than low medication adherence with regard to PDA and time to first heavy drinking day. With regard to PDA, we found a significant interaction between naltrexone and CBI with the naltrexone/MM only group having the highest PDA and the placebo/MM only having the lowest PDA. These results are comparable to the COMBINE Study primary intent-to-treat outcome findings (Anton et al., 2006
). As in the current paper, the results of the main outcome paper show PDA highest in the naltrexone/no CBI (i.e., MM only) group (80.6%) and the lowest for the placebo/no CBI group (75%, p = 0.0009). In short, drinking outcomes (i.e., PDA) of the COMBINE study did not change when pill taking adherence status was introduced into the analysis, thereby strengthening the conclusions drawn from the main outcome paper.
With respect to first heavy drinking day, a significant three-way interaction was found between medication adherence, CBI and naltrexone. Lower relapse rates appeared to be dependent upon whether the patient was adherent to medication and received naltrexone or CBI. Within the placebo group, CBI seems to have had a beneficial impact on decreasing the odds of returning to drinking among patients nonadherent to pill taking. In the presence of CBI, the recovery (non-relapse) period for patients who were nonadherent to placebo was extended. CBI may have provided these nonadherent patients with an increased level of support that resulted in a reduction in heavy drinking. Other components of CBI such as increasing coping skills to deal with cravings or drink refusal strategies, providing optimism for change and enhancing self-efficacy might have been useful in extending the recovery period.
In contrast, among naltrexone-treated patients, CBI demonstrated no significant additional benefit beyond what was produced by exposure to the active medication in the context of medical management. Unlike the placebo group, ongoing adherence to the study medication may have helped to reduce the likelihood of relapse with CBI providing minimal additional benefit. The findings on the three-way interaction indicate that effects of medication on outcomes are moderated by both medication and CBI, such that CBI provides a buffer for nonadherence in the placebo but not in the medication condition.
In interpreting the results on the three-way interaction, consideration should be given to why CBI did not have a noticeable impact on naltrexone-treated patients. MM was primarily designed to maximize and support pill taking adherence. Consequently, maximum dose medication adherence rates were relatively high across MM treatment combinations. Thus, it is conceivable that since MM had a strong focus on adherence, it may have caused a “ceiling effect” on this outcome variable such that any additional work on adherence via CBI may be less potent or observable. It is also conceivable that CBI inadvertently helped these naltrexone-treated patients to be less concerned about not taking or stopping the medication. CBI emphasizes decision-making responsibilities and promotes self-efficacy on the part of patients. Such an approach may have indirectly empowered or allowed patients to stop taking the medication if they felt it was not working (i.e., experiencing side effects).
It is not clear which components of CBI have benefited or not benefited nonadherent patients. A process analysis aimed at examining mechanisms of action associated with CBI and medication adherence might provide further understanding of how this treatment modality impacts on alcohol patients (Stout, 2007
In summary, high medication adherents fared better than low medication adherents across all combinations. CBI seemed to have a beneficial impact on nonadherents in the placebo condition raising the issue of whether CBI may serve as a cushion or have a protective function for nonadherent, placebo patients. On the other hand, adherence to naltrexone provided a significant increase in time to relapse. However, CBI did not add any such advantage to naltrexone-treated patients.
The current study adds to the growing literature (see e.g., O’Malley et al., 2003
; Garbutt et al., 2005
) supporting the use of a primary care approach as a behavioral platform for pharmacotherapy with alcohol dependent patients. It confirms the findings of the primary COMBINE Study report (Anton et al. 2006
) which showed MM to be beneficial for a sizeable proportion of patients regularly taking naltrexone. However, the MM approach was utilized in a clinical trial. Consequently, other factors, unrelated to the treatment approach (e.g., conducting an extensive assessment battery, repeated contact with research staff, and follow-up visits) could account for the positive findings (Clifford et al., 2007
). Thus, MM will need to be adapted to “real world” medical settings like primary care clinics, to determine the feasibility and utility of the approach.
In conclusion, there are several new treatment strategies for alcohol dependent patients, involving pharmacotherapies, behavioral interventions, or the combination. The success of these treatments is strongly tied to good patient medication adherence and visit attendance at behavioral interventions. In studies like the COMBINE study, where medication adherence rates and session attendance rates are high, treatment outcomes reported for the total study group in an intent to treat analysis, as previously reported, were not substantially altered by a retrospective analyses that considered medication adherence. However, in clinical practice these issues must be considered.