title: 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.
  
  
  METHODS
  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.
authors.affiliation: From the Clinical Pharmacology and Therapeutics Research Branch, NIDA, Baltimore; the Clinical Trials Operations and Biostatistics Branch, NIMH, Rockville, Md.; the Center for Clinical Trials Network, NIDA, Bethesda, Md.; and Advanced Heart Failure Program, Spectrum Health System, Grand Rapids, Mich.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kowalczyk
authors.affiliation: From the Clinical Pharmacology and Therapeutics Research Branch, NIDA, Baltimore; the Clinical Trials Operations and Biostatistics Branch, NIMH, Rockville, Md.; the Center for Clinical Trials Network, NIDA, Bethesda, Md.; and Advanced Heart Failure Program, Spectrum Health System, Grand Rapids, Mich.
authors.forename: Karran A
authors.initials: KA
authors.lastname: Phillips
authors.affiliation: From the Clinical Pharmacology and Therapeutics Research Branch, NIDA, Baltimore; the Clinical Trials Operations and Biostatistics Branch, NIMH, Rockville, Md.; the Center for Clinical Trials Network, NIDA, Bethesda, Md.; and Advanced Heart Failure Program, Spectrum Health System, Grand Rapids, Mich.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Jobes
authors.affiliation: From the Clinical Pharmacology and Therapeutics Research Branch, NIDA, Baltimore; the Clinical Trials Operations and Biostatistics Branch, NIMH, Rockville, Md.; the Center for Clinical Trials Network, NIDA, Bethesda, Md.; and Advanced Heart Failure Program, Spectrum Health System, Grand Rapids, Mich.
authors.forename: Ashley P
authors.initials: AP
authors.lastname: Kennedy
authors.affiliation: From the Clinical Pharmacology and Therapeutics Research Branch, NIDA, Baltimore; the Clinical Trials Operations and Biostatistics Branch, NIMH, Rockville, Md.; the Center for Clinical Trials Network, NIDA, Bethesda, Md.; and Advanced Heart Failure Program, Spectrum Health System, Grand Rapids, Mich.
authors.forename: Udi E
authors.initials: UE
authors.lastname: Ghitza
authors.affiliation: From the Clinical Pharmacology and Therapeutics Research Branch, NIDA, Baltimore; the Clinical Trials Operations and Biostatistics Branch, NIMH, Rockville, Md.; the Center for Clinical Trials Network, NIDA, Bethesda, Md.; and Advanced Heart Failure Program, Spectrum Health System, Grand Rapids, Mich.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Agage
authors.affiliation: From the Clinical Pharmacology and Therapeutics Research Branch, NIDA, Baltimore; the Clinical Trials Operations and Biostatistics Branch, NIMH, Rockville, Md.; the Center for Clinical Trials Network, NIDA, Bethesda, Md.; and Advanced Heart Failure Program, Spectrum Health System, Grand Rapids, Mich.
authors.forename: John P
authors.initials: JP
authors.lastname: Schmittner
authors.affiliation: From the Clinical Pharmacology and Therapeutics Research Branch, NIDA, Baltimore; the Clinical Trials Operations and Biostatistics Branch, NIMH, Rockville, Md.; the Center for Clinical Trials Network, NIDA, Bethesda, Md.; and Advanced Heart Failure Program, Spectrum Health System, Grand Rapids, Mich.
authors.forename: David H
authors.initials: DH
authors.lastname: Epstein
authors.affiliation: From the Clinical Pharmacology and Therapeutics Research Branch, NIDA, Baltimore; the Clinical Trials Operations and Biostatistics Branch, NIMH, Rockville, Md.; the Center for Clinical Trials Network, NIDA, Bethesda, Md.; and Advanced Heart Failure Program, Spectrum Health System, Grand Rapids, Mich.
authors.forename: Kenzie L
authors.initials: KL
authors.lastname: Preston
mesh_terms: D000328:Adult; D000700:Analgesics / Q000627:therapeutic use*; D002047:Buprenorphine / Q000627:therapeutic use*; D003000:Clonidine / Q000627:therapeutic use*; D066249:Craving; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders / Q000188:drug therapy*; D016016:Proportional Hazards Models; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; D009292:Narcotic Antagonists; D002047:Buprenorphine; D003000:Clonidine