Blood Pressure Drug May Help Prevent Opioid Relapse

Nancy A. Melville

August 10, 2015

The novel adjunctive use of clonidine (multiple brands), an agent traditionally used to treat hypertension, appears to prolong abstinence in opioid-dependent patients, new research shows.

Investigators at the National Institute on Drug Abuse (NIDA) found that combining clonidine with buprenorphine (multiple brands) prolonged abstinence, particularly in patients prone to drug craving in response to stress.

"Clonidine increased the mean longest duration of abstinence from opioids and the proportion of people who stayed abstinent for the whole length of the intervention," lead author Kenzie Preston, PhD, chief of the Clinical Pharmacology and Therapeutics Research Branch, NIDA Intramural Research Program, in Baltimore, Maryland, told Medscape Medical News.

The study was published online August 1 in the American Journal of Psychiatry.

Stress-Blocking Effect

The randomized, double-blind, placebo-controlled trial included 208 treatment-seeking heroin-dependent or prescription opioid–dependent outpatient volunteers who were recruited at the NIDA center from October 2006 to August 2013.

About half of the patients (118, 57%) successfully maintained abstinence for a period of 5 to 6 weeks. Those patients were then randomly assigned in a double-blind fashion to receive three capsules per day of adjunctive clonidine (ranging from 0.1 mg per capsule for the first week to 0.3 mg per capsule after the second week; n = 61) or placebo (n = 57) for 14 weeks.

At the end of the study period, patients in the clonidine group had the longer duration of abstinence from opioids in consecutive days (34.8 days; SD, 3.7) compared with the placebo group (25.5 days; SD = 2.7; P ≤ .05).

Although the clonidine group had a longer duration before the initial opioid lapse, as determined on the basis of one positive urine test, there was no significant difference between the two groups in the time to relapse, defined as two consecutive positive urine test results.

The improvements in time of abstinence are nevertheless important, Dr Preston said.

"Our lab strongly believes in the idea that abstinence begets abstinence ― the longer someone can refrain from using, the more likely they'll be successful in the long run," she added.

"However, this is speculation, and we would need a longer controlled study to test whether clonidine has that benefit."

In further looking at clonidine's effect on response to drug relapse triggers, the study included a real-time "ecological momentary" assessment, involving the use of mobile devices in which patients were randomly prompted four times a day to self-report activities and moods. The devices used included the PalmOne Zire 21, the Palm Tungsten E2, or an HTC TyTN II smartphone.

In the random prompts, patients provided updates on issues that included stress, craving, mood, and drug-related environmental cues they had been exposed to.

The results showed a greater decoupling effect specific to daily-life stress and opioid craving in the clonidine group compared with the placebo group.

"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 level of stress," the authors said.

A similar buffering effect in relation to drug-associated cues was not observed, indicating that clonidine's protective effect was specific to stress triggers.

The findings are supported by animal studies that have shown clonidine to be helpful regarding stress cues. Long-term buprenorphine or methadone use is known to help with drug-seeking triggers, such as a priming dose of heroin or cocaine, but not with stress exposure cues, which are among the leading causes of relapse.

Clonidine was well tolerated, and although the clonidine group was more likely to report an adverse event (P ≤ .05), the only specific symptom reported was dry mouth.

The drug, best known as an antihypertension agent, is already commonly used in detoxification, the authors note.

"Clonidine is especially appealing because it carries no special prescribing requirements like those imposed on buprenorphine and methadone, and it is known to be well tolerated in opioid users because it is used regularly for short-term amelioration of withdrawal signs," they write.

Dr Preston noted that patients who would be most likely to benefit from a treatment strategy with clonidine include those most prone to be vulnerable to stress as a trigger for their drug use.

"Based on our findings, the best candidates would be recently abstinent people on opioid agonist maintenance who report stress as a reason for past resumptions of opioid misuse and who experience only moderate levels of stress, as clonidine did not block the effect of intense stress on craving," she said.

Real-Time Effect

In an accompanying editorial, Harriet deWit, PhD, of the Department of Psychiatry and Behavioral Neuroscience at the University of Chicago, in Illinois, said the study is especially intriguing for its use of ecological momentary assessment, showing, in real time, the effect of the drug treatment on stress triggers and drug craving.

"Despite an enormous scientific literature derived from controlled studies of drugs of abuse, our understanding of the natural ecology of drug use, outside of the laboratory setting, is very limited."

"This lack of knowledge of the natural course of drug use constitutes an enormous gap in our understanding of the determinants of addiction," she added.

"The gap can be addressed using innovative techniques such as that used in the study by Kowalczyk and colleagues."

Frank J Vocci, PhD, who is coeditor of American Society of Addiction Medicine's Journal of Addiction Medicine and is president of Friends Research Institute, in Baltimore, Maryland, agreed that the rigorous data collection offers extremely useful information.

"The ecological momentary assessment essentially validates what the clinician has been told by the patient," he told Medscape Medical News.

"The approach provides a granularity in which people are being queried four times a day, and this has implications from the standpoint of treatment," Dr Vocci said.

"Instead of seeing patients in the office once a week, you can have them check in with you four times a day, and that, in itself, may be therapeutic, or it may give the clinician essentially the initial red flag that something is wrong."

In terms of the findings on improvements provided by clonidine, Dr Vocci said the results make sense, considering the drug's profile.

"I wouldn't say it's a surprise ― it's essentially a natural progression of research taken to the next level," he said.

"The animal data are extremely consistent that clonidine blocks stress responses. So the question has been whether it would block stress responses in humans, and it's never really had a good test, until now."

The authors and Dr deWit have disclosed no relevant financial relationships. Dr Vocci has been a consultant for Reckitt-Benckiser Pharmaceuticals and generic manufacturers of buprenorphine products and has been an investigator and consultant for buprenorphine studies funded by Braeburn Pharmaceuticals and Titan Pharmaceuticals. All of his consulting fees go to his employer, Friends Research Institute, Inc.

Am J Psychiatry. 2015;172:760-767, 700-701. Abstract, Editorial

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