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 lapsesTime to lapse and relapse were examined with Cox regressions; longest period of abstinence was examined with a t test, and ecological momentary assessment data was 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 alleviation 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.

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

“…For example, blockade of mineralocorticoid receptors markedly attenuates EEP and ptosis (Navarro-Zaragoza et al, 2014), and inhibition of endocannabinoid catabolic enzymes attenuates wet dog shakes (Ramesh et al, 2013). Overall, our data support links between norepinephrine overflow and TC/SM as well as global withdrawal score, and provide mechanistic insight for adrenergic receptor therapy in treating human addicts (Kowalczyk et al, 2015). Moreover, the norepinephrine release during withdrawal uncovered here is the likely origin of adrenergic receptor plasticity in the vBNST (McElligott et al, 2013).…”

“…Suppression of noradrenergic signaling blocks stressinduced reinstatement (Erb et al, 2000;Leri et al, 2002;Shaham et al, 2000), and treatment with the adrenergic agonist clonidine promotes heroin-abstinence in human addicts (Kowalczyk et al, 2015). Although few studies emphasize the noradrenergic component of drug use, norepinephrine in the bed nucleus of the stria terminalis (BNST) has been clearly implicated in drug withdrawal (Aston-Jones et al, 1999).…”

Treatment of Opioid-Use Disorders

“…20 Such medically supervised withdrawal can also involve the use of nonopioid medications that help to control symptoms. 21,22 This section thus begins with the more generally available but less effective withdrawal regimen with the use of less closely controlled medications than those that are available in specialty clinics.…”

“…Once patients express interest in discontinuing or diminishing drug use, the core of care depends on the same kinds of cognitive behavioral approaches that are used for other chronic, relaps- 21 and Gowing et al 22 ‡ Doses are approximate. § Clonidine is used on an off-label basis for opioid withdrawal.…”

Clonidine Increases the Likelihood That Abstinence Can Withstand Unstructured Time in Buprenorphine-maintained Outpatients

“…In a recently published clinical trial, we tested clonidine as an adjuvant medication for opioid relapse prevention during buprenorphine treatment, and we found that participants randomized to clonidine took longer to lapse and achieved greater durations of opioid abstinence (Kowalczyk et al 2015). Using ecological momentary assessment (EMA) data from the same participants, we showed that clonidine helped to reduce the impact of stress on heroin craving.…”