Clonidine Maintenance Prolongs Opioid Abstinence and Decouples Stress From Craving in Daily Life: A Randomized Controlled Trial With Ecological Momentary Assessment

Abstract

Objective: The authors tested whether clonidine blocks stress-induced seeking of heroin and cocaine. The study was also intended to confirm translational findings from a rat model of drug relapse by using ecological momentary assessment of patients' stress to test hypotheses about clonidine's behavioral mechanism of action.

Method: The authors conducted a randomized double-blind placebo-controlled clinical trial with 208 opioid-dependent patients at an outpatient buprenorphine clinic. The 118 participants (57%) who maintained abstinence during weeks 5-6 were continued on buprenorphine and randomly assigned to receive clonidine (N=61) or placebo (N=57) for 14 weeks. Urine was tested thrice weekly. Lapse was defined as any opioid-positive or missed urine test, and relapse as two or more consecutive lapses. Time to lapse and relapse were examined with Cox regressions; longest period of abstinence was examined with a t test, and ecological momentary assessment data were examined with generalized linear mixed models.

Results: In an intent-to-treat analysis, clonidine produced the longest duration (in consecutive days) of abstinence from opioids during the intervention phase (34.8 days [SD=3.7] compared with 25.5 days [SD=2.7]; Cohen's d=0.38). There was no group difference in time to relapse, but the clonidine group took longer to lapse (hazard ratio=0.67, 95% CI=0.45-1.00). Ecological momentary assessment showed that daily-life stress was partly decoupled from opioid craving in the clonidine group, supporting the authors' hypothesized mechanism for clonidine's benefits.

Conclusions: Clonidine, a readily available medication, is useful in opioid dependence not just for reduction of withdrawal signs, but also as an adjunctive maintenance treatment that increases duration of abstinence. Even in the absence of physical withdrawal, it decouples stress from craving in everyday life.

Trial registration: ClinicalTrials.gov NCT00295308.

FIGURE 1.

Longest Period of Consecutive Opioid Abstinence in the Intervention Phase Among Patients Who Received Placebo or Clonidine in Addition to Buprenorphine^{a a} Each circle represents a single participant’s longest period of abstinence during the intervention phase (weeks 9–20, following a 2-week induction phase; the induction phase followed a 6-week baseline period of buprenorphine treatment alone). Horizontal bars show the group means. The clonidine group maintained continuous abstinence longer than the placebo group (p≤0.05).

FIGURE 2.

Survival Curve for Time Until Lapse to Opioid Use Among Patients Who Received Placebo or Clonidine in Addition to Buprenorphine^{a a} Participants in the clonidine group tended to maintain abstinence longer before an initial lapse (p=0.07); controlling for the effect of cocaine use during the 6-week baseline period., the effect was statistically significant (p≤0.05). We had included this control term expecting it to eliminate, not strengthen, the effect of group.

FIGURE 3.

Association of Stress and Cues With Likelihood of Reporting Heroin Craving Among Patients Who Received Placebo or Clonidine in Addition to Buprenorphine^{a a} The left panel shows the interaction of stress and group (F=8.8, df=3, 257, p≤0.001) on likelihood of reporting craving: at the moderate (though not the highest) level of stress, there was a decoupling of stress from craving with clonidine treatment. The right panel shows that there was no such interaction for exposure to heroin cues. Error bars represent 95% confidence intervals.