Adding clonidine to buprenorphine as maintenance therapy extends the duration of abstinence in heroin- or opioid-dependent adults participating in outpatient drug treatment, according to a report published in American Journal of Psychiatry.

“Although a new standard of care cannot be derived from the findings of just one clinical trial, we think our results provide support for a potential new off-label use for an old medication, expanding the addiction treatment armamentarium of opioid-agonist clinics, and perhaps also of psychiatrists and internists who are not prescribing opioid agonists,” said William J. Kowalczyk, Ph.D., of the Clinical Pharmacology and Therapeutics Research Branch, National Institute on Drug Abuse, Baltimore, and his associates.

Animal and laboratory studies have suggested that alpha-2 adrenoceptor agonists like clonidine might block stress-related drug-seeking behavior, independently of their action as adjunctive medications during opioid detoxification. To investigate this possibility, the researchers performed a double-blind randomized trial at a single Baltimore clinic in 118 patients aged 18-60 years.

After abstaining from opioids for 6 weeks, the study participants were randomly assigned to receive daily clonidine (61 patients) or matching placebo capsules (57 patients) in addition to sublingual buprenorphine as maintenance therapy for 8 weeks. They provided urine and breath samples under observation three times per week to test for opioids, cocaine, marijuana, amphetamines, barbiturates, benzodiazepines, and alcohol. They also used electronic diaries to report on stress, drug cravings, mood, and drug-related environmental cues at four randomly chosen times each day.

Compared with placebo, clonidine significantly increased the time to initial opioid lapse, lengthening the duration of consecutive days of abstinence to 34.8 days, compared with 25.5 days for placebo. Other studies have reported that the longer the duration of abstinence, the greater the likelihood that it will be sustained, the investigators said (Am. J. Psychiatry 2015;AiA:1-8 [ doi:10.1176/appi.ajp.2014.14081014 ]).

Moreover, clonidine blunted the increased drug cravings that accompanied daily life stressors. “Participants in the clonidine group were less likely than those in the placebo group to report heroin craving at moderately high levels of stress, reaching the same likelihood of heroin craving only at the highest levels of stress. We saw no such buffering effect in self-reported exposure to drug-associated cues, suggesting that clonidine’s protection was specific,” Dr. Kowalczyk and his associates said.

“Clonidine is especially appealing because it carries no special prescribing requirements … and is known to be well-tolerated in opioid users,” they wrote. In this study, the only symptom that occurred more frequently with clonidine than with placebo was dry mouth. Symptoms that were expected to cause more problems – sedation, hypotension, and dizziness – did not differ significantly between clonidine and placebo.

Among the limitations is that it was not possible to draw conclusions about the impact of clonidine maintenance “outside the context of buprenorphine maintenance,” the investigators said.

Still, for clinicians, the study findings identify a subpopulation of patients who would benefit most from clonidine maintenance therapy, described as “those who are susceptible to stress-induced lapses and those who have persistent though moderate stress.

“This is the sort of individualized approach to treatment that could greatly improve outcomes,” Dr. Kowalczyk and his associates added.

This study was supported by the NIDA and the National Institute of Mental Health. Dr. Kowalczyk and his associates reported having no financial relationships with commercial interests. 


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