Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity
Introduction
Early treatment failure continues to be a major problem in the treatment of cocaine dependence. Significant treatment attrition and failure to attain significant periods of abstinence is common. At the Day Treatment Program of the Philadelphia Veterans Affairs Hospital, the dropout rate is 50% in the first 4 weeks (Alterman et al., 1994). A figure similar to that has been reported in at least four other studies (Gawin and Kleber, 1984, Gawin et al., 1989, Agosti et al., 1991, Kleinman et al., 1992). Even subjects who remain in treatment often find it difficult to maintain abstinence. Most studies show that only a small minority of cocaine dependent patients are able to attain 3–4 weeks of continuous abstinence from cocaine in the first 8–12 weeks of treatment (Gawin et al., 1989, Kosten et al., 1992, Higgins et al., 1993, Caroll et al., 1994, Nunes et al., 1995, Silverman et al., 1996).
The high rate of attrition and inability to attain abstinence during early treatment may be related to symptoms of anxiety caused by cocaine-induced dysregulation of noradrenergic neurons. Several studies have demonstrated an association of anxiety symptoms with early cocaine abstinence (Aronson and Craig, 1986, Price and Giannini, 1987, Bystritsky et al., 1991, Harris and Aston-Jones, 1993). In one model, these symptoms were reversed by beta-adrenergic blockade (Harris and Aston-Jones, 1993). More specific evidence of noradrenergic dysfunction comes from a study by McDougle and colleagues (McDougle et al., 1994). In this study, cocaine dependent subjects were significantly more likely to respond to a yohimbine challenge with a panic attack after 3 days of cocaine abstinence compared to after 15 days of cocaine abstinence. The precise mechanism by which cocaine induces this noradrenergic dysregulation is not known but it may represent a compensatory response of presynaptic noradrenergic neurons to an acute deficiency of synaptic norepinephrine (McDougle et al., 1994).
As a beta-blocker, propranolol can directly attenuate the increased responsivity of noradrenergic neurons, which may relieve the anxiety associated with early abstinence from cocaine. Propranolol has been shown to reduce anxiety associated with cocaine withdrawal in rats (Harris and Aston-Jones, 1993). Beta-blockers are used clinically to treat anxiety associated with drug withdrawal syndromes including alcohol and benzodiazepine withdrawal (Bailly et al., 1992, Naranjo and Sellers, 1986). In addition, beta-blockers are a well established treatment for a number of other anxiety states including generalized anxiety disorder, panic disorder and social phobia (Kathol et al., 1980, Liebowitz et al., 1988).
Propranolol may be uniquely suited to decrease cocaine craving during early abstinence based on its ability to block central and peripheral noradrenergic receptors (Hoffman and Lefkowitz, 1996). Cocaine dependent patients report symptoms of autonomic arousal in association with cocaine craving (Childress et al., 1992). Conversely, these same symptoms of autonomic arousal (for example, palpitations and sweating) may themselves act as cues of cocaine use and prompt cocaine craving. Thus, by blocking the autonomic arousal associated with cocaine craving with an agent such as propranolol, it may be possible to reduce both the incidence and intensity of cocaine craving.
Propranolol may also diminish cocaine craving due to its effect on beta-adrenergic associated augmentation of memory. Animal studies suggest that activation of the beta adrenergic stress hormone systems results in enhanced memory of emotionally arousing events (McGaugh, 1989, McGaugh et al., 1990). Recently, Cahill and colleagues demonstrated that propranolol was able to selectively block the improvement in memory associated with emotional arousal in humans (Cahill et al., 1994). The clinical observation that conditioned cues of cocaine use trigger emotionally arousing memories of prior cocaine use, and thereby tend to initiate relapse, has been supported by studies in our cue reactivity laboratory (Childress et al., 1992, Ehrman et al., 1992). Pet imaging studies have also demonstrated increased blood flow in the temporal lobe and amygdala during cue exposure suggesting that regions of the brain associated with emotionally arousing memories are being activated during these sessions (Childress et al., 1999). Thus, propranolol may reduce cocaine craving by blocking the beta-adrenergic augmentation of pleasurable memories related to prior cocaine use.
Propranolol was recently evaluated in a rapid screening protocol (Kampman et al., 1999). In that trial, propranolol was found to be significantly better than nefazodone, the combination of phentermine and fenfluramine, and a multivitamin in promoting treatment retention (73% retention for propranolol vs. 53% for nefazodone, 50% for phen/fen and 47% for the multivitamin group). Propranolol was also found to be especially useful in patients with concurrent alcohol dependence.
Based on these encouraging results the current double-blind, placebo-controlled, trial of propranolol was undertaken. In addition to the main analysis, a secondary, exploratory analysis was conducted. In order to account for the differences in cocaine withdrawal symptom severity and the effect that this might have on treatment outcome, the efficacy of propranolol was compared to placebo in subjects who presented to treatment with more severe cocaine withdrawal symptoms.
Section snippets
Subjects
The subjects were 108 DSM-IV cocaine dependent men and women between the ages of 18 and 60. All the subjects had used cocaine recently as evidenced by a urine toxicology screen positive for benzoylecgonine in the 30 days prior to entry into the trial.
Psychiatric diagnoses were obtained by master's level clinicians using the Structured Clinical Interview for DSM-IV. Medical screening included a complete medical history and physical examination conducted by a certified nurse practitioner.
Subject characteristics
Three hundred and forty-eight potential subjects were screened by telephone and 267 came for an initial visit. Out of the group of cocaine dependent individuals who attended an initial screening visit, 44 did not meet inclusion/exclusion criteria for this trial and 57 others either dropped out or were assigned to other studies at the center. The remaining 166 signed informed consent. Fifty-eight of these subjects failed to complete the compliance evaluation period, leaving 108 subjects who were
Discussion
In the sample as a whole propranolol was not superior to placebo in promoting abstinence from cocaine. Likewise, propranolol was not superior to placebo in reducing symptoms of anxiety or cocaine craving. In fact, the only outcome measure that showed a significant difference between propranolol and placebo was cocaine withdrawal symptoms. Propranolol was superior to placebo in reducing cocaine withdrawal symptoms measured by scores on the CSSA. Thus, it appears that for cocaine dependent
Acknowledgements
This work was supported by grants from the National Institute on Drug Abuse K20 DA00238 to Kyle M. Kampman, Y01 DA30012 to Charles P. O'Brien, and a Department of Veterans Affairs Medical Service Center Grant.
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2021, Neurobiology of StressCitation Excerpt :Propranolol reduced relapse rates in people with severe cocaine withdrawal symptoms, but there was no difference from placebo in those with mild or moderate symptoms (Kampman et al., 2001). Propranolol also had no effect on anxiety or cocaine craving, even when stratifying by withdrawal symptom severity (Kampman et al., 2001). The effect of propranolol on abstinence was then lost in a larger trial of only people with severe cocaine withdrawal, and was not rescued by additional amantadine treatment (Kampman et al., 2006).
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