The combination very low-dose naltrexone-clonidine in the management of opioid withdrawal

Abstract

Background: The management of withdrawal absorbs substantial clinical efforts in opioid dependence (OD). The real challenge lies in improving current pharmacotherapies. Although widely used, clonidine causes problematic adverse effects and does not alleviate important symptoms of opioid withdrawal, alone or in combination with the opioid antagonist naltrexone. Very low-dose naltrexone (VLNTX) has been shown to attenuate withdrawal intensity and noradrenaline release following opioid agonist taper, suggesting a combination with clonidine may result in improved safety and efficacy.

Objectives: We investigated the effects of a VLNTX-clonidine combination in a secondary analysis of data from a double-blind, randomized opioid detoxification trial.

Methods: Withdrawal symptoms and treatment completion were compared following VLNTX (.125 or .25 mg/day) and clonidine (.1-.2 mg q6h) in 127 individuals with OD undergoing 6-day methadone inpatient taper at a community program.

Results: VLNTX was more effective than placebo or clonidine in reducing symptoms and signs of withdrawal. The use of VLNTX in combination with clonidine was associated with attenuated subjective withdrawal compared with each medication alone, favoring detoxification completion in comparison with clonidine or naltrexone placebo. VLNTX/clonidine was effective in reducing symptoms that are both undertreated and well controlled with clonidine treatment and was not associated with significant adverse events compared with other treatments.

Conclusions and scientific significance: Preliminary results elucidate neurobiological mechanisms of OD and support the utility of controlled studies on a novel VLNTX + low-dose clonidine combination for the management of opioid withdrawal.

Trial registration: ClinicalTrials.gov NCT00135759.

FIGURE 1

Subjective Opiate Withdrawal Scale scores of 127 opioid-dependent inpatients undergoing 6-day methadone detoxification. NTX = very low naltrexone patients, NTX/CLO = very low naltrexone plus clonidine patients, CLO = clonidine patients, and NTX-PLA = naltrexone placebo patients. Very low naltrexone use was associated with significantly attenuated withdrawal (repeated measures analysis of variance (ANOVA), change of scores, F = 7.8(3127), p = .003; for NTX vs. AM, p = .001; for NTX vs. CLO, p = .02). Patients receiving NTX + CLO reported less intense withdrawal compared with those from the NTX (p = .03) or CLO (p = .01) groups.