A medication used to treat high blood pressure may be an effective add-on therapy for cocaine-dependent patients who suffer severe withdrawal symptoms when they stop using the drug, a NIDA-funded study indicates. Patients who experienced severe anxiety and other symptoms and were treated with the medication -- propranolol -- stayed in treatment longer and used less cocaine than a comparable group of patients who were treated with a placebo, the study shows.

Cocaine-dependent patients who experience severe withdrawal symptoms generally use cocaine heavily and are more dependent on the drug than patients who have less severe withdrawal symptoms. "These patients are unable to stop using the drug for significant periods and are more likely to drop out of treatment programs," says Dr. Kyle Kampman of the University of Pennsylvania School of Medicine in Philadelphia, who conducted the study. "This is not a tiny subgroup. We've found that about 40 percent of the cocaine abusers who come into the Day Treatment Program of the Philadelphia Veterans Affairs Hospital have withdrawal severity scores that are high enough to put them at risk for doing poorly in treatment."

Dr. Kampman and his colleagues theorized that propranolol might lessen the severity of symptoms such as anxiety and craving experienced by newly abstinent cocaine treatment patients. Propranolol belongs to a class of medications called beta-adrenergic blockers that inhibit the effects of adrenaline in the central and peripheral nervous systems, where it works to arouse the body's "fight or flight" response to dangerous or stressful situations. Beta-adrenergic blockers have been used clinically to treat general anxiety and anxiety associated with alcohol withdrawal. The researchers thought propranolol's tempering of symptoms such as palpitations and sweating might also reduce cocaine craving associated with such symptoms.

In the study, the researchers used an interviewer-administered questionnaire, the cocaine selective severity assessment (CSSA), to measure cocaine withdrawal symptoms among 108 treatment-seeking cocaine-dependent men and women. The CSSA assesses the intensity of 18 symptoms including anxiety, cocaine craving, depressed mood, appetite changes, sleep disturbances, and altered heart rates that patients may experience when they stop using cocaine. In a previous study, the researchers found that patients who had high CSSA scores when they entered treatment were likely to drop out of treatment.

Following a 1-week lead-in period in which all subjects were given a placebo, researchers randomly assigned patients to receive either propranolol or a placebo daily for 8 weeks. All subjects also received cognitive-behavioral counseling twice a week. Urine tests for cocaine were conducted three times a week throughout the trial to assess cocaine use. Treatment retention, cocaine withdrawal symptoms, craving, mood, and anxiety symptoms were evaluated weekly.

Nearly 69 percent of cocaine treatment patients experiencing severe withdrawal symptoms who received propranolol completed the treatment program, compared to 29 percent of patients with similar symptoms who were treated with a placebo.

When the researchers analyzed results for all study subjects, they found that propranolol-treated subjects had less severe cocaine withdrawal symptoms during the trial, but they did not do significantly better on any other outcome measure than those treated with the placebo. However, when the researchers looked at outcomes in conjunction with the severity of cocaine withdrawal symptoms, they found that propranolol-treated individuals who had CSSA scores in the upper third of all subjects at baseline were much more likely to complete the treatment program than subjects with similar baseline CSSA scores who were treated with placebo. Among subjects with high CSSA scores, 69 percent of those who received propranolol completed treatment, compared to 29 percent of those treated with a placebo. Propranolol-treated high-CSSA subjects also had significantly lower urine levels of benzoylecognine, a cocaine metabolite, than did placebo-treated subjects, indicating they used less cocaine throughout the trial. There were no significant gender differences in any outcome measures.

Treatment and Research Implications
Although the study's findings are preliminary, they suggest that propranolol may be a useful add-on treatment for the substantial subset of cocaine-dependent patients who have severe withdrawal symptoms. However, treatment outcomes in propranolol-treated subjects were still far from optimal. Additional medication or more intense counseling may be needed to treat such patients effectively, the researchers indicate. "Clinicians can use the CSSA score to predict treatment outcomes and try to match people to appropriate levels of treatment," says Dr. Kampman. "If you put someone with a high score in once- or even twice-a-week individual counseling, they just aren't going to do well. They need more intensive treatment."

The study also has implications for researchers testing cocaine treatment medications, Dr. Kampman says. "Until now, clinical trials haven't separated out those patients who need to be detoxified," he says. "They come in with 'hot' urines [indicative of heavy, current cocaine use], have a lot of withdrawal symptoms, and have trouble getting abstinent. They are so different from people who enter treatment with cocaine-free urines and low withdrawal symptoms, that if you put the two groups together when you test a medication, you are going to miss significant treatment effects. In our studies, we are now dividing patients into two distinct populations based on initial assessment of the severity of their withdrawal symptoms. For patients who have a lot of withdrawal symptoms, we test medications that have the potential to reduce severity of these symptoms to see if it will help them get clean and stay in treatment. For patients who have few withdrawal symptoms and less difficulty achieving initial abstinence, we select a medication that might work better to prevent relapse."

Additional Medications Research
In addition to propranolol, Dr. Kampman has been testing the potential of other medications to improve treatment outcomes for cocaine-dependent patients with severe withdrawal symptoms. Results of a preliminary trial of amantadine, which may alleviate cocaine's disruption of the brain's dopamine system, were promising. Patients with severe cocaine withdrawal symptoms at the start of treatment used less cocaine during the trial than those who received a placebo.

Following up on these results, Dr. Kampman and his colleagues now are conducting a large, double-blind prospective study of the effectiveness of amantadine and propranolol individually and in combination. The study is targeted specifically at cocaine-dependent patients who score in the upper one-third of patients on the CSSA.

"We know that amantadine slightly increases the release of dopamine, which in turn might reduce the dysphoria -- the pervasive unhappiness and restlessness -- that also is associated with cocaine withdrawal," says Dr. Maria Majewska of NIDA's Division of Treatment Research and Development. "If amantadine can reduce dysphoria and propranolol can reduce the anxiety and the arousal associated with craving, maybe this will be a winning combination with this population. We are cautiously optimistic as we await the results of the trial."

Sources
Kampman, K.M., et al. Cocaine withdrawal symptoms and initial urine toxicology results predict treatment attrition in outpatient cocaine dependence treatment. Psychology of Addictive Behaviors 15(1):52-59, 2001.

Kampman, K.M., et al. Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity. Drug and Alcohol Dependence 63(1):69-78, 2001.

Kampman, K.M., et al. Amantadine in the treatment of cocaine-dependent patients with severe withdrawal symptoms. American Journal of Psychiatry 157(12):2052-2054, 2000. [Abstract]