This clinical trial showed VLNTX to be safe and well-tolerated when administered with methadone. Opiate withdrawal symptoms and craving were less severe at discharge among subjects who received VLNTX during detoxification, with no significant differences between NTX regimens. Although potential symptom modifiers (ancillary medications) were allowed by the ‘real world’ design of the study, there were no significant medication group differences in proportion of subjects requesting ancillary medications, mean daily PRN-S score, or mean daily doses of ancillary medications. Thus, it is very unlikely that ancillary medications biased the observed VLNTX findings. Objective opioid withdrawal scores were not significantly reduced in VLNTX-treated subjects when alcohol use in the last month was included as a covariate. This finding requires further investigation. VLNTX may differentially affect some aspects of withdrawal in opioid-dependent subjects who use alcohol. On the other hand, the results do not suggest that recent alcohol use ‘per se’ influenced directly and significantly the manifestation of withdrawal in this sample. Subjects did not differ significantly in their use of other drugs, such as cocaine and marijuana (), so it is unlikely that non-opioid drug withdrawal influenced the findings.
The addition of VLNTX was superior to methadone taper alone in reducing withdrawal, with an effect size of 0.71. One out of every two to three subjects receiving NTX = 0.250 mg/day showed significantly less withdrawal discomfort than those treated with only methadone (NNT (number needed to treat) analysis: SOWS = 3, 95% CI 2–5; OOWS = 2, 95% CI 2–3). The methadone detoxification that was considered ‘treatment-as-usual’ in this study has been demonstrated to be more effective than non-opiate medications in controlling withdrawal severity (Amato et al. 2004
), and displays comparable efficacy to newer opiate agents such as buprenorphine (Gowing, Ali, White 2004
This is the first randomized, controlled trial to evaluate the use of VLNTX for the treatment of opioid withdrawal. The mechanisms of symptom reduction remain to be elucidated. Pre-clinical investigations suggest that VLNTX attenuates chronic opioid excitatory signaling at the mu-opioid receptor, blocking intracellular cyclic adenosine monophosphate (cAMP) up-regulation (Wang et al. 2005
). Up-regulation of the cAMP pathway is associated with development of dependence and with the expression of withdrawal (Nestler, Alreja & Aghajanian 1994
). Reduced opioid withdrawal severity by VLNTX was accompanied in opioid-dependent animal models by lower intracellular levels of enzymes of the cAMP system in brainstem noradrenergic areas that are activated during withdrawal (Mannelli et al. 2004
). The administration in this study of ancillary drugs that influence noradrenergic activity prevents direct interpretation of putative noradrenergic mechanisms of VLNTX.
Subjects in the VLNTX groups showed more pronounced clinical differences from the methadone-only group in the last few days of detoxification, a time-related treatment effect that may be reinforced by a medication dose–effect mechanism. The reduction of dependence is not immediate with VLNTX treatment. Multiple doses are required to restore opioid agonist action in animals, suggesting a slow reversal of the mechanisms that contribute to tolerance and dependence (Powell et al. 2002
). Animal studies also show that VLNTX enhances opioid analgesia and reward to a greater extent when the quantity of opioid drug is reduced, as it is at the end of methadone tapering and before discontinuation (Crain & Shen 2001
; Powell et al. 2002
The main intention of our research was to study the effects of VLNTX within an opioid agonist/antagonist administration paradigm and not to identify the best detoxification protocol for this treatment. The investigation was conducted in community hospital programs, to evaluate the feasibility of the approach in a ‘real world’ setting. Although this can be considered one strong point of the study, it is at the same time a weakness, in that major limitations to the design were necessitated to minimize the conventional requirements of a controlled clinical trial and by adopting without modifications protocols in use at the community programs. In particular, (1) considering the methadone tapering schedule, it is unclear if subjects were actually ‘detoxified’ at discharge; (2) no specific, rigid protocol existed for the administration of ancillary medications and for consistency between the two study sites. As for the first limitation, a follow-up of individuals who received VLNTX would provide useful information following methadone discontinuation. With regard to the use of ancillary drugs, subjects did not receive significantly different amounts across medications groups, nor did site-related differences in ancillary drugs influence response to treatment. Together, these potential limitations seem unlikely to bias our main findings.
This two-site study provides evidence that the administration of VLNTX is a safe and effective method to reduce withdrawal severity and treatment discomfort in opioid-dependent participants undergoing methadone detoxification.
Opioid dependence is a chronic disorder, with relapse to drug use a frequent occurrence even after multiple detoxification episodes (McLellan et al. 1996
). VLNTX adjunct showed improvement over a standard treatment for opioid-dependent patients attempting detoxification, although its utility in reducing relapse after discharge and facilitating access to long-term treatment remains to be determined. The use of VLNTX may help improve detoxification, potentially resulting in improved NTX maintenance induction or long-term, agonist substitution treatment. In particular, treatment combinations of methadone and buprenorphine with VLNTX should be tested. Finally, a number of research questions could be explored using existing animal models that have proven to be a reliable translational tool to test the properties of VLNTX in opioid dependence (Mannelli, Gottheil & Van Bockstaele 2006