Of the 50 patients randomized (23 naltrexone, 27 placebo), 7 did not return after baseline (3 naltrexone, 4 placebo) leaving 43 evaluable patients. Of the 43 evaluable patients (20 naltrexone, 23 placebo) dropouts consisted of 3 patients after week 1 (1 naltrexone, 2 placebo), 4 patients after week 2 (2 naltrexone, 2 placebo), 1 naltrexone patient after week 3, 2 placebo patients after week 4, 1 placebo patient after week 5, 2 naltrexone patients after week 8, 1 placebo patient after week 9, 2 placebo patients after week 10, and 1 placebo patient after week 11. Thus, 26 patients completed (14 naltrexone, 12 placebo) the study. The average time in study was 6.8 weeks for the naltrexone group and 70.0% completed. For the placebo group the average time in study was 8.3 weeks and 52.2% completed. The difference between groups was not significant based on the log-rank test (chi-square=1.1, df=1, p=.2943). The average time in study was less in the naltrexone group even though the completion rate was higher because the patients who dropped out did so early in the study (all dropped out before week 8) (). The two groups did not differ significantly on any baseline characteristic examined ().
Survival analysis of naltrexone and placebo groups.
Demographic and baseline characteristics of the participants in the naltrexone and placebo groups (N=43)
Results of the random regression analysis are given in Table 2. Random regression analysis of percentage of drinking days per week (covariate: baseline percentage of drinking days) declined non-significantly more in the naltrexone group than the placebo group from baseline to week 1. The decline per log week from week 1 to week 12 was similar in each group (Table 2). Binary repeated measures analysis (covariates: baseline percent of drinking days and HRSD17 total score) showed that change in probability of having at least one drinking day between visits did not differ between groups from baseline to week 1 (f1,223=0.4, p=0.54) but a trend was observed toward greater decrease from week 1 to week 12 with naltrexone than placebo (f1,344 = 3.3, p=.07) (). At week 12, 33.1% of naltrexone participants were estimated to have had zero drinking days that week compared to 7.3% of placebo participants (effect size = 0.68). Of note, anticonvusant use and specifically valproate use were examined as possible covariates but were rejected since the did not improve the fit of the model for this and other outcome measures. They also did not significantly change the results. However, a variable was also added to the dataset with the specific name of the anticonvulsant used. A 28% or greater improvement from baseline to exit in percent of drinking days was used for response since this roughly split the sample into equal parts. A 28% improvement is about 2 days fewer drinking days per week. Only 8 out of 43 (19%) of patients had a 50% or more improvement in percent drinking days. The following table shows the percent of patients receiving anticonvulsants each week by response status. Exit responders were more likely to have used valproate during the study than exit non-responders (38.9% vs. 12.5% at week 12). Thus, valproate use was likely not an important covariate because the effect is the same in both placebo and naltrexone groups.
Probability of one or more drinking days in the naltrexone and placebo groups at each assessment.
Percentage of heavy drinking days per week (covariates: baseline percentage of heavy drinking days and ASI drug score) did not differ between groups either from baseline to week 1 or from week 1 to week 12 (Table 2). For the binary repeated measures analysis (covariates: baseline percentage of heavy drinking days, ALT, and PACS) change in probability of having at least one heavy drinking day between visits was not significantly different between groups from baseline to week 1 (f1,219=1.10, p=0.30) or from week 1 to week 12 (f1,267=0.30, p=0.86). An estimated 78.1% of the naltrexone group had zero heavy drinking days by week 12 compared with 54.4% of the placebo group (effect size = 0.51).
Analysis of the number of drinks per drinking day (covariates: number of drinks per drinking day) showed a non-significantly greater decline with naltrexone from baseline to week 1 and week 1 to week 12. At week 12 the number of drinks per drinking day was estimated to be reduced by 63.4% from baseline levels in the naltrexone group versus a 32.8% reduction in the placebo group (effect size=0.72).
Decline in PACS (covariates: baseline PACS score, ASI alcohol and drug scores, YMRS score, level of education, use of lithium, antipsychotics, antidepressants or sedative/hyponotic/anxiolytics,) from baseline to week 1 was numerically larger for naltrexone participants than placebo while decline in PACS from week 1 to week 12 showed a trend toward significance favoring naltrexone (Table 2; ). At week 12, the naltrexone group had an estimated decline in PACS total scores of 9.3 points compared with 3.4 points for the placebo group (effect size=1.0).
Change in alcohol craving as assessed by the PACS in the naltrexone and placebo groups.
Liver function measures showed greater numerical improvement in the naltrexone group than placebo group. GGT levels (n=33) assessed at weeks 0, 4, 8 and 12 (covariates: baseline GGT score, ASI drug scores, and level of education) showed no significant between-group differences in change from baseline to week 4 or from week 4 to week 12 (Table 2). From baseline to week 12 reduction in GGT was estimated to be 15.8% for naltrexone and 3.7% for placebo (effect size=0.42). AST (n=25) was assessed at week 0 and week 12 (covariates: baseline AST and lithium use). At week 12 the adjusted AST score showed a trend toward significantly lower AST in the naltrexone group (naltrexone=21.7 versus placebo=31.6, f1,21=4.20, p=.05). ALT (n=25) also assessed at week 0 and week 12 (covariates: baseline ALT and lithium use) and showed adjusted scores of 23.3 and 31.8 in the naltrexone and placebo groups, respectively, with a trend toward lower values in the naltrexone group (f1,21=3.00, p=.10).
The random regression model for HRSD17 (covariates: baseline HRSD17 score and level of education as covariates, and including a time squared term) showed no significant differences either from baseline to week 1 or from week 1 to week 12 (Table 2). Decline from baseline to week 12 was numerically larger in the naltrexone group than the placebo group (−8.3 points versus −6.4 points) (effect size=0.56). Analysis of the IDS-SR (covariates: baseline IDS-scores, gender, level of education, family history of alcoholism, sedative/hypnotic/anxiolytic use, and ASI alcohol and drug scores) showed a trend toward a significant between-group difference from baseline to week 1 but not from week 1 to week 12. At week 12, IDS-SR scores had declined by an estimated 21.9 points for naltrexone participants and 10.8 points for placebo participants (effect size=3.0) (Table 2). For the YMRS (covariates: baseline YMRS score, gender, lithium, antiseizure, antipsychotic or sedative/hypnotic/anxiolytic use, and ASI drug and alcohol scores) no significant between-group differences were observed from baseline to week 1 or from week 1 to week 12. At week 12, the decline from baseline in YMRS scores measured 9.3 points in the naltrexone group and 7.0 points in the placebo group (effect size=0.62).
The mean number of CBT sessions attended in the naltrexone and placebo groups (6.2±4.4 vs. 5.4±4.1) was similar (t48=0.7, p=.50). Outside care was uncommon and included weekly psychotherapy by a psychiatry resident and outpatient treatment at a substance abuse treatment facility (n=1 for each and both receiving placebo). Changes in concomitant medications consisted of addition of lithium (n=2 naltrexone, n=7 placebo), discontinuation of lithium (n=0 naltrexone, n=1 placebo), addition of an anticonvulsant (n=5 naltrexone, n=4 placebo), discontinuation of an anticonvulsant (n=1 naltrexone, n=0 placebo), addition of an antipsychotic (n=5 naltrexone, n=4 placebo), discontinuation of an antipsychotic n=0 naltrexone, n=3 placebo), addition of a sedative/hypnotic/anxiolytic (n=2 naltrexone, n=1 placebo) and discontinuation of a sedative/hypnotic/anxiolytic ((n=2 naltrexone, n=1 placebo). A total of 14 naltrexone patients had a medication addition and 3 a discontinuation as compared to 14 with additions and 5 with discontinuations in the placebo group. Chi squares comparisons of individual medication classes and overall additions and discontinuations showed no significant between-group differences (all p>0.05). Change in overall side-effect burden, as assessed by the PRD-III, was not significantly different between groups at week 6 (f1,26=0.02, p=.88) or week 12 (f1,25=1.10, p=.30).
Mean adherence, as measured by pill counts, for naltrexone-treated participants was 94.4% (SD=6.1), range 77.6% – 100%) and 95.3% (SD=7.4, range 69.0% – 100%) for placebo-treated participants. Including weekly adherence as a time-varying covariate in the random regression model using only the naltrexone participants produced a significantly large negative adherence coefficient for outcomes change from baseline in percent drinking days (f1,141=11.5, p=.0009), percent heavy drinking days (f1,127=11.6, p=.0009), but not drinks per drinking day (f1,103=1.1, p=.2998). For the placebo group, the random regression analyses using weekly adherence (pill counts) as a time-varying covariate produced small non-significant adherence coefficients for change from baseline in percent drinking days (f1,131<0.01, p=.9631), and percent heavy drinking days (f1,129=0.5, p=.4712), but a significant negative coefficient was found for drinks per drinking day (f 1,112=9.4, p=.0027).