Significantly more in-patients assigned to bup-nx (77%) were present on days 13/14 and provided urine samples free of metabolites of illicit opioids compared to those in-patients assigned to clonidine (8/36 or 22%; χ12 = 30.1, P < 0.0001; odds ratio = 11.9; ). Significantly more out-patients assigned to bup-nx (46/157 or 29%) were present on days 13/14 and provided urine samples free of metabolites of illicit opioids compared to out-patients assigned to the clonidine (5%; χ12 = 16.9, odds ratio = 7.7, P < 0.0001).
Percentages (n) of participants who provided urine samples free of metabolites of illicit opioids by study, treatment group and treatment day.
Subjective ratings of withdrawal
Comparison of the summary COWS measure (computed for each subject as mean of COWS scores across available observations) for the in-patient groups indicates that the bup-nx group had significantly fewer withdrawal symptoms documented by the COWS (M = 3.8, SD = 2.2) compared to the clonidine group (M = 7.4, SD = 3.6; F1110 = 48.8, P < 0. 001; η2 = 0.31). Comparing groups of treatment completers, both bup-nx (M = 3.5, SD = 1.8) and clonidine groups (M = 3.7, SD = 1.9) produced similar COWS summary scores (NS; η2 = 0.001). The summary ARSW scores for patients was 23.6 (SD = 14.2) for bup-nx and 48.9 (SD = 29.8) for the clonidine group, a statistically significant difference (F1106 = 53.6, P < 0. 001; η2 = 0.34). Comparison between groups of treatment completers showed significant differences between bup-nx and clonidine groups on the ARSW summary scores (M = 22.5, SD = 11.5 versus M = 30.5, SD = 11.2, respectively; F1,69 = 4.1, P = 0. 05; η2 = 0.06).
A similar pattern of results was observed in out-patients for the subjective reports of withdrawal and craving. Comparisons of the summary COWS measure shows that the bup-nx group had significantly fewer withdrawal symptoms (M = 4.0, SD = 3.0) compared to the clonidine group (M = 5.1, SD = 3.2, F1,227 = 9.3, P < 0.01, η2 = 0.04). For the completer sample, the bup-nx group reported significantly fewer withdrawal symptoms(M = 3.1, SD= 2.2) than the clonidine conditions (M = 4.2, SD = 2.8; F1,107 = 4.7, P < 0.05, η2 = 0.04). The summary ARSW score was significantly lower for the bup-nx condition (M = 29.7, SD = 24.8) compared to the clonidine condition (M = 41.6, SD = 33.7, F1,218 = 20.1, P < 0.001, η2 = 0.08). Analysis of the completer sample also showed significantly lower ARSW withdrawal scores for the bup-nx condition (M = 23.2, SD = 17.9) than the clonidine condition (M = 36.2, SD = 24.2, F1.104 = 8.7, P < 0.01, η2 = 0.08).
Analysis of craving scores in the in-patient study using the VAS showed statistically significant differences for the groups in the in-patient study with the bup-nx group producing lower mean craving ratings (M = 29.1, SD = 19.1) than the clonidine group (M = 51.5, SD = 28.4, F1109 = 25.1, P < 0.001; η2 = 0.19). No statistically significant differences were found between mean craving ratings for the bup-nx and clonidine completer groups (M = 24.5, SD = 15.3 versus 23.4, SD = 13.0, respectively; η2 = 0.001).
Analysis of the VAS craving scores for the out-patient group showed that ratings for the bup-nx condition were significantly lower (M = 37.7, SD = 20.8) compared to the clonidine condition (M = 57.1, SD = 23.3, F1,224 = 46.7, P < 0.0001, η2 = 0.17). Analysis of the completer sample showed similarly lower mean craving ratings for bup-nx (M = 30.3, SD = 17.1) compared to clonidine (M = 49.6, SD = 19.9, F1,106) =15.4, P < 0.0001, η2 = 0.13).
shows the proportion of patients retained at each of the evaluation points for both studies. Both bup-nx groups had significantly better retention than the clonidine groups over the entire study period (in-patient: Wilcoxon (1) = 29.7, P < 0.0001; out-patient: Wilcoxon (1) = 32.8, P < 0.0001). Participants in the in-patient protocol assigned to the bup-nx condition averaged 12.6 days (SD = 3.2) compared to 6.7 days (SD = 4.8) for participants in the clonidine condition (t111 = 7.7, P < 0.0001, η2 = 0.35). Similarly, participants in the out-patient protocol assigned to the bup-nx condition averaged 11.3 days (SD = 4.2) compared to 7.1 days (SD = 5.3) for the clonidine condition (t229 = 6.4, P < 0.0001, η2 = 0.15).
Proportion of patients retained over time for the in-patient (diamond symbols) and out-patient (square symbols) protocols as a function of assignment to bup-nx (closed symbols) or clonidine (open symbols)
When possible, patients were surveyed to ascertain why they were dropped from the study or voluntarily terminated treatment. In the in-patient study, six patients were administratively withdrawn, 10 transferred to another treatment program, one was hospitalized, one moved from the area, one was in a controlled environment, four could no longer attend clinic, 17 no longer attended clinic for reasons not specified, one developed a sensitivity to the study medication and one patient died. In the out-patient study, 35 patients were administratively withdrawn, two were hospitalized for a medical condition, 38 transferred to other treatment programs, three moved from the treatment area, one was in a controlled environment, eight could no longer attend clinic and 104 no longer attended clinic for reasons not specified. The reasons provided were not mutually exclusive.
Use of ancillary medications
Comparison of the number of symptoms for which medications were prescribed in the in-patient study showed similar levels of medication usage for the bup-nx (M 2.7 doses, SD = 1.2) and clonidine groups (M = 2.9 doses, SD = 1.3). Of those who completed treatment, those assigned to the bup-nx group averaged similar doses (M = 2.8 doses, SD = 1.2) of ancillary medications, as did those in the clonidine group (M = 2.6 doses, SD = 1.2, NS). For the out-patient protocol, no significant differences were found between the number of symptoms for which medications were prescribed for the bup-nx (M = 2.0, SD = 1.9) and clonidine conditions (M = 2.3, SD = 2.0). Significant differences were observed between conditions in the analysis of the completer sample, with 1.7 (SD = 1.8) reported for the bup-nx condition and 3.2 (SD = 2.0) for the clonidine condition (t109 = −3.1, P < 0.01).
For the in-patient protocol, the mean number of reported adverse events per participant per day was significantly different across conditions, with an average of 1.5 (SD = 0.8) adverse events for the bup-nx condition and 2.4 (SD = 1.6) for the clonidine condition (t111 = −3.9, P < 0.0001). Analyses of the completer sample for the in-patients showed no significant differences between the bup-nx and clonidine conditions (M = 1.6, SD = 0.8; M = 2.0, SD = 1.3, respectively). In the out-patient study, the mean number of adverse events per participant per day was significantly different across conditions, with an average of 0.7 (SD = 0.8) for the bup-nx condition and 1.2 for the clonidine group (SD = 1.6, t224 = −3.0, P < 0.001). In the analysis of the completer sample, the bup-nx condition averaged 0.6 events (SD = 0.6) compared to 1.1 events for the clonidine group (SD = 0.8, t109 = −3.7, P < 0.0001).
Serious adverse events
Few serious adverse events occurred in either protocol. In the in-patient study, four serious adverse events occurred in each condition, including a death in each condition. Respiratory failure was the cause of death for a participant in the bup-nx condition, whereas bacterial endocarditis was the cause of death for a participant in the clonidine condition. Neither death was attributed to study medication. The three other adverse events reported in the bup-nx group include suicidal behavior for two participants and severe vomiting in one. The three additional adverse events reported in the clonidine group include severe vomiting in one participant, a motor vehicle accident in another and cellulitis in yet another. In the out-patient sites, 18 serious adverse events occurred, with 14 occurring in the bup-nx group and four in the clonidine group. No deaths occurred in either of the out-patient groups. The adverse events reported in the bup-nx group include 10 cases of continued substance abuse/overdose, two cases of depression, one case of severe vomiting and case of spine surgery. The adverse events reported in the clonidine group include one participant each reporting continued substance abuse, nausea/vomiting, kidney stones and pneumonia.