This quasi-experimental comparison of relatively similar heroin-dependent patients participating in varied conditions of outpatient naltrexone-maintenance treatment suggests overall that a long acting, sustained-release, depot formulation of naltrexone may be superior to oral naltrexone for the antagonist treatment of heroin dependence, although it also raises some questions about the robustness of the effect of long-acting naltrexone. When long acting injectable naltrexone conditions from the Comer et al.11
study were combined and compared to the early combined results from the Nunes et al.6
oral naltrexone maintenance study, patients receiving long acting injectable naltrexone were retained for more days in treatment. The difference in dropout rate evaluated with survival analysis was in the same direction but did not reach signficance. When missing urines were imputed as positive, the proportion of opioid negative urines was greater on injectable than oral naltrexone. The difference was not significant when only observed urines were counted, but the imputation of missing urines as positive is reasonable, because most patients who dropout can be assumed to have relapsed.
A second series of analyses compared the group that received an intensive psychosocial treatment (behavior naltrexone therapy), combining oral naltrexone with numerous and powerful psychosocial strategies, against a moderate psychosocial intervention with a full dose of long acting injectable naltrexone; this set of analyses was included because it represented the two most likely manners in which naltrexone might be used in actual clinical practice. In this comparison with relatively small numbers, injectable naltrexone with moderate treatment retained patients significantly longer than the intensive strategy intended to support oral maintenance. But, when the interaction of baseline heroin severity with treatment condition was included in the model, it was significant, indicating that patients with high baseline heroin use demonstrated better retention on oral naltrexone plus intensive psychosocial intervention, while lower severity heroin users were more successful in the condition with moderate psychosocial treatment and long acting injectable naltrexone. Differences in heroin use demonstrated a similar pattern.
The finding of an interaction effect between condition and baseline severity of use should be approached with caution. It is possible that the intensive psychosocial approaches employed in BNT are most needed amongst heavy opioid users, and that while the majority of users might be served by moderate psychosocial treatment and implants or injections, patients with high levels of opioid dependence may require more intensive psychosocial treatment. Of course, given the quasi-experimental nature of this research, these findings should be viewed cautiously and be considered as hypotheses to guide further study. Future research examining long-acting injectable naltrexone in combination with an intensive behavioral regimen similar to BNT in a randomized trial would more definitively measure the value of high-intensity psychosocial treatments.
One of the most interesting findings of this comparison was the relatively similar level of early opiate use by patients across all conditions; approximately 50% of patients used heroin in the first two weeks of treatment, regardless of the route of naltrexone treatment. In this respect, High Dose Injection (384 ng/ml) showed its promise, as 70% of early opiate users recovered from this use to go on to complete eight weeks of treatment.
It is also noteworthy that across these 111 patients, we were aware of no patient attempts to override the naltrexone blockade. This is a common concern about naltrexone, but seems to be rare and our experience bears this out. The main concern with naltrexone is overdose risk after the blockade has worn off. Injectable naltrexone may be safer in this respect because the blockade wears off more slowly.
In comparison to other quasi-experimental studies of oral and implant formulations of naltrexone13-15
, this modestly-powered study is the most rigorous comparison to date. The data were collected during the course of randomized clinical trials; consequently, numerous urine samples were collected from patients engaged in treatment, and opiate use results are available over the course of the full eight weeks of treatment, rather than having to rely on self-report or collateral report. Some groups differed significantly from each other on some key variables, such as age and number of years of regular heroin use; these variables were controlled for during analysis.
All advantages to this comparison noted, the study suffers from some significant limitations. Patients were not randomized to conditions, and significant selection biases are possible. The selection criteria for patients and background treatment patients received in both trials were very similar, although patients treated at the STARS clinic had some latitude in choosing which treatment study to participate in. (If anything, the bias in patient selection favors the oral naltrexone study and against injectable naltrexone for two reasons: patients in the oral naltrexone study were required to have a significant other willing to participate in treatment [indicating a certain level of social support and functioning], and half of the injection patients were on a lower, less powerful dose of medication.) Furthermore, these treatments were not originally intended to be compared to one another, so there may be differences that cannot be accounted for. We do not have follow-up data on patients who dropped from treatment early on, and so can only presume relapse to heroin use (the most typical course when patients have been recently detoxed and are not maintained on medication). Finally, while other opiate users were not excluded, we have only heroin users in these samples because this is how the recruitment advertising was worded; further studies with prescription opiate users are needed to assess the effectiveness of these approaches with other opioids of abuse.
Given these limitations, these results should be interpreted with caution, and viewed as exploratory, for the purposes of informing the hypotheses of future research studies, as well as to help manage practitioners expectations when working with oral and injectable naltrexone. However, despite these limitations, the differences between high-dose long acting injectable formulations and other oral maintenance strategies are intriguing. This quasi-experimental study of early outcomes in naltrexone maintenance strategies demonstrates some benefit to long acting injectable formulations, but also shows that heroin use behavior during maintenance treatment is relatively similar despite route of naltrexone administration; this is not surprising, as retention in treatment is the more important outcome in maintenance treatment. If opioid dependent patients are able to stay on naltrexone, opioid taking behavior is likely to extinguish due to the powerful blockade of opioid reinforcing effects. Furthermore, contingent on future replication, the findings of this study also indicate that despite the development of new formulations of naltrexone, the value of intensive psychosocial approaches may continue to be demonstrated for severe users. It is possible that combining monthly injections with some of the strategies which have maximized oral compliance (high-value vouchers, significant-other involvement) could further increase the effectiveness of long acting injectable naltrexone maintenance, and position this treatment as a viable alternative to agonist maintenance (buprenorphine or methadone) for some opioid dependent patients.. There is a need for continued studies that would determine the optimal strategies for combining psychosocial approaches with the new long acting injectable formulations of naltrexone to yield maximal effectiveness.