Nancy A. Melville

June 12, 2012

June 12, 2012 (Phoenix, Arizona) — Doxazosin, an alpha1-adrenergic antagonist traditionally used to treat hypertension and benign prostatic hypertrophy (BPH), may also be effective in treating cocaine dependence, new research suggests.

Investigators from Baylor College in Houston, Texas, found that the rapid titration of the drug significantly reduced cocaine use compared with slow titration of doxazosin or placebo.

In the meantime, the current study's findings are important in supporting the growing body of literature suggesting that the noradrenergic system is an important pharmacologic target in the treatment of addiction, said lead investigator Daryl Shorter, MD.

"For so long, we believed that dopamine must be the primary target if we hoped to reduce drug craving and use, [but] it has become clear that addressing other neurobiological systems is necessary if we hope to more effectively treat addiction," Dr. Shorter told Medscape Medical News.

The findings were presented here at the New Clinical Drug Evaluation Unit (NCDEU) 52nd Annual Meeting.

Surprise Finding

Previous research has shown that prozosin, an alpha1-adrenergic antagonist, reduced cocaine-induced drug-seeking behavior in rats.

Noting that doxazosin has greater specificity for the alpha1-noradrenergic system and longer duration of activity as an alpha1 blocker, the team conducted a pilot study to examine the drug's effect in comparison with placebo.

The study included 35 cocaine-dependent participants who were randomly assigned to receive either doxazosin 8 mg/day or placebo for 17 weeks.

The patients were first titrated at 1 mg/day, with the dose increased by 1 mg per week, but after it was discovered that a dose escalation was possible, a second group was created in which a faster titration was employed.

"Initially, participants were titrated according to Physicians' Desk Reference recommendations, starting at 1 mg/day and increasing by 1 mg/week," the authors note.

"After analyzing data from our human laboratory study, we found doxazosin could be increased more rapidly. Dose escalation was changed to a rate of 2 mg/week, allowing the 8 mg/day dose to be reached after 4 weeks."

All participants in the study also received weekly cognitive behavioral therapy.

Eighty-eight percent of participants were male, 66% were black, all had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of cocaine dependence, and 93% were also nicotine dependent.

Only 12% of patients in the slow titration group achieved 2 or more consecutive weeks of abstinence, compared with 55% in the fast titration group and 7% for placebo (chi-square, 7.5; df, 2; P < .023).

"We were surprised the slow titration group did not demonstrate statistically significant difference from placebo, since we presumed the medication would at least have some effect, even if it was not as robust as in the fast titration group," said Dr. Shorter.

"There is a body of literature throughout mental health that argues for rapid titration of medications since you increase the serum concentration levels and can create a more robust effect more quickly, so it's possible this sort of phenomenon is the underlying reason behind the success in the fast titration group."

Well Tolerated

Interestingly, adverse events rates were lower in the fast titration group than in either of the other groups. Among 58 distinct adverse events reported, 26 (45%) were reported in the slow titration group, 9 (16%) in the fast titration group, and 23 (45%) in the placebo group.

The most significant side effect, headache, was reported among 7.7% in the slow titration group, 22% in the high titration group, and 13% in the group receiving placebo. Dr. Shorter noted that the higher rate in the fast titration group was likely due to the fact that so many fewer overall distinct side effects were reported (9 in the fast titration group vs 26 in the slow titration group and 23 in the placebo group).

Although other potential pharmaceutical treatments for cocaine dependence have also been explored, none have yet to offer a truly effective solution, Dr. Shorter noted.

"Interestingly, stimulant dependence is like the final frontier in medication development for addictions treatment," he said.

"Currently, there are no FDA-approved medications for treatment of cocaine dependence or methamphetamine dependence, so the hunt is on for medications that will more effectively treat this illness."

Some other medications that have shown promise include disulfiram, modafanil, and medications impacting the GABAergic system (topiramate, baclofen), and Dr. Shorter's team has also recently completed work as the lead site for a multisite trial of TA-CD, a cocaine vaccine.

The Baylor researchers are currently conducting a larger clinical trial of doxazosin in cocaine-dependent individuals, aiming for a target of 100 participants.

An Important First Step

Although the findings are interesting, the study has several limitations that should be considered, said Stuart Gitlow, MD, MPH, president of the American Society of Addiction Medicine.

"Of particular interest is the significant increase in cocaine-negative findings in the fast titration group," said Dr. Gitlow, who is executive director of the Annenberg Physician Training Program in Addictive Disease and an associate clinical professor at the Mount Sinai School of Medicine, in New York City. "But this is a very short study for a lifelong illness."

"The other issue is that participants here were receiving weekly cognitive behavioral therapy as opposed to the level of medical treatment that was indicated for each individual based upon an individual medical assessment," he told Medscape Medical News.

"Perhaps if they simply received the level of medical care necessary, we would have seen an even higher degree of abstinence."

In future studies, the drug should be compared not only with placebo but also with therapy that is regarded as representative of the standard of care, Dr. Gitlow noted.

"That's not to say this is a poor study — it's a fine study — but it needs to be taken for what it is: a first step designed to determine whether this approach is worthy of further study."

The study was supported by the Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas. Funding for the study was provided to coauthor Thomas R. Kosten, MD, by National Institutes of Health/National Institute on Drug Abuse grant P50-DA12762. Dr. Shorter and Dr. Gitlow have disclosed no relevant financial relationships.


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