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Chemical Dependency Research Working Group |
Richard N. Rosenthal, M.D. is Associate Chairman of the Department of Psychiatry, Beth Israel Medical Center, New York, NY.
There are several pharmacologic strategies which can be pursued with respect to treating cocaine abuse. The most direct would be to use either a receptor antagonist to block the effects of cocaine or a neuromodulatory drug which could reduce cocaine's reinforcing properties. Another approach is to cause an aversive reaction when the individual uses cocaine, much as one sees with an alcoholic who drinks alcohol while medicated with disulfuram (Antabuse). Other indirect approaches are to treat the craving states which predict relapse or to treat the comorbid disorders which contribute negatively to the outcome of cocaine treatment. With respect to the aversive approach, there are no drugs we know of which have an appropriate effect for cocaine use.
For an understanding of the direct approach, an overview of the behavioral neuropharmacology of cocaine is useful. A central role for the CNS dopamine (DA) system has been hypothesized for the mechanism of reward from all substances of abuse, from specifically dopaminergic drugs such as amphetamines and cocaine, to drugs with more indirect dopaminergic effects such as opiates, nicotine, and alcohol. The basic and clinical literature support the idea that substances of abuse augment brain stimulation reinforcement or lower thresholds to reinforcement via the ascending mesolimbic DA system. The addictive and euphorogenic effects of cocaine are thought to result primarily from inhibition of dopamine reuptake (Rothman, 1990). The more rapid institution of cocaine dependence due to use of lipid-soluble cocaine freebase as compared to water-soluble cocaine intranasal administration, supports a model for the onset of addictive behavior seen with increased dopamine activity from Nucleus Accumbens.
Self-reward is differentially reduced by dopamine receptor antagonists in animal models, and recent research has supported some utility of dopamine antagonists in the management of cocaine abuse. Gawin and colleagues (1993), in a controlled trial in 90 crack cocaine users, facilitated treatment engagement using the neuroleptic flupenthixol versus placebo, but the results for cocaine abstinence were less dramatic.
The potency of cocaine-like drugs as inhibitors of DA reuptake is highly correlated with their potency as reinforcers in animals, but several potent DA reuptake blockers such as mazindol and bupropion do not appear to produce addiction or euphoria in humans (Rothman, 1990). With the indirect approach, one research strategy has been to attempt to preferentially reduce craving for cocaine in patients with psychoactive substance use disorders by administering dopaminergic agonists such as amantadine, bromocriptine, and the antidepressants which have dopaminergic activity through reuptake inhibition. In a controlled trial of the dopamine agonist amantadine, men in substance abuse day treatment receiving 100mg BID showed significant differences in clean urines at 2 (93% vs. 60%; p=.04) and 4 weeks (83% vs. 53%; p=.049) as compared with a group receiving placebo (Alterman et al, 1992). Whereas pretreatment with the dopamine agonists bromocriptine or mazindol does not seem to affect the subjective or physiologic effects of cocaine, including cocaine-induced craving (Preston, Sullivan, Strain et al,1992; Preston, Sullivan, Bigelow et al, 1992), in a small open study (Wang et al, 1992) bromocriptine 2.5 mg BID to QID reduced cocaine craving, but caused frequent side effects such as headache, nausea, vertigo. Although results are not robust, there are enough effects to pursue this line of research in controlled trials.
Antidepressants have been used as a strategy both to reduce cocaine craving and to treat comorbid depression which may contribute to relapse. With tricyclic antidepressants, Triffleman and colleagues (1993) found in a controlled trial of 200mg/day desipramine in 82 crack abusing men, no differences in craving, abstinence, or withdrawal symptoms at 3 or 8 weeks. There was however, a strong correlation between the desepramine plasma level and treatment retention. Gawin and colleagues (1993) as well, found only significant retention effects at visits 2 and 3 for desipramine versus placebo in a controlled trial. With imipramine, Nunes (1994) in a randomized, double-blind trial in 69 methadone-maintained subjects with a history of primary or chronic depression, found that 53% had a good response (75% reduction in drug use) versus 6% in the group receiving placebo. In cocaine users with comorbid mood disorders, treating the mood disorder might have effects upon the use of cocaine.
With the non-tricyclic antidepressant bupropion, Margolin and colleaagues (1992) found in an 8 week study of 19 cocaine addicts given100mg TID that 10/19 achieved abstinence (no positive urines) in the last 4 weeks of the study and a significant decline in post-treatment craving induced by drug cues. Kosten (1993) also reported up to 70% abstinence rates seen in preliminary studies of bupropion, but controlled studies have not supported the open study findings.
There is a growing basic and clinical literature supporting the idea that the CNS serotonin (5HT) system is generally involved in consummatory behavior and satiety thereof, and may be more specifically involved in reward pathways related to certain substances of abuse. Brain 5HT systems likely have an important neuromodulatory role on psychostimulant reinforcement, and both in vitro and behavioral data suggest that the dopamine system is essential for these reinforcing effects (Roberts, 1992). Low activity at or chemical ablation of serotonin terminals enhances the reinforcing effect. Thus, another indirect strategy is to increase 5HT activity which might, as treatment of cocaine dependence, attenuate the reinforcing effect of cocaine.
Several different types of agents with direct or indirect capacity to increase serotonergic activity have been tried as treatments of cocaine dependence. The selective serotonin reuptake inhibitors fluoxetine and sertraline, 5HT1a partial agonists like gepirone, 5HT3 receptor antagonists like ondansetron, mazindol, lithium, imipramine and carbamazepine have all been used with not generally positive results. A preliminary report by Batki et al (1991) suggested that an open trial of fluoxetine 45mg /day avg. with group therapy was highly effective at reducing cocaine craving, subjective use and objective cocaine use over nine weeks, in methadone-maintained cocaine abusers. However, Batki and colleagues (1993) in a 12-week double-blind trial of fluoxetine 20-60mg in 41 methadone-maintained cocaine abusers, demonstrated no effects upon drug use. Another 12-week double-blind trial of 20, 40, and 60 mg/day of fluoxetine in pure cocaine abusers has not demonstrated significant reductions in drug use. Although Kosten et al (1992) have reported reductions in cocaine intake using sertraline, these data have not been replicated.
Given the role of serotonin in appetitive behaviors, the strategy of using a drug which could cause autoreceptor down-regulation to enhance serotonergic transmission would be expected to decrease craving and to increase satiety. In addition, the indirect dopamine-enhancing effects of 5HT1a drug like gepirone could be expected to ameliorate cocaine-induced dopamine depletion and resulting dysphoria. However, Jenkins et al (1992) reported on a 12-week randomized, double-blind placebo-controlled trial of gepirone in 60 adult patients with DSM-III-R cocaine dependence and found no difference from placebo on measures of global psychiatric severity, cocaine craving, depression and anxiety. The most important reinforcing effects of cocaine are likely due to more direct central dopaminergic stimulation, such that the serotonergic pathways, although having input, may have less effect upon intake and satiety.
5HT3 receptor antagonists inhibit DA release in the nucleus accumbens (Costall et al, 1987), release of which is hypothesized to be associated with the reinforcing effects of cocaine. Although the 5HT3 receptor antagonist ondansetron has no acute psychoactive effects (Jasinski, 1991), pretreatment of human subjects with 2mg IV significantly altered the subjective state induced by 25 mg IV cocaine 30 min. later, including the "rush", "feeling the drug", jitteriness, and difficulty concentrating (Sullivan et al, 1992).
Consummatory or appetitive behavior is differentially reduced by serotonin selective reuptake inhibitors (SSRI) and recent research has supported the utility of SSRI's in the management of appetitive dyscontrol, effects which may be independent of antidepressant actions. Whereas SSRIs such as fluoxetine and sertraline have small (9-17%) but significant effects in reducing alcohol consumption (Sellers et al, 1992; Naranjo et al, 1990,1992), the same has not been demonstrated for cocaine.
Thus far, there are no robust data from the studies of many different medications that have passed the test of randomized clinical trials and replication of effectiveness upon cocaine dependence. No "magic bullet" for cocaine dependence has been described, although certain medications may be useful as adjunctive to other forms of treatment.
Alterman, A.I.; Droba, M.; Antelo, R.E.; Cornish, J.W.; Sweeney, K.K.; Parikh, G.A.; O'Brien, C.P. Amantadine may facilitate detoxification of cocaine addicts. Drug and Alcohol Dependence 1992 31: 19-29.
Batki, A.S.L.; Manfredi, L.B.; Sorenson, J.L.; Jacob, P.; Dumontet, R.; Jones R.T. Fluoxetine for cocaine abuse in methadone patients: Preliminary findings. In: Harris, L.S. (ed), Problems of Drug Dependence 1990. NIDA Research Monograph Series105, 516-517. Rockville: National Institute on Drug Abuse, 1991.
Batki, S.L.; Manfredi, L.B.; Jacob, P.; Delucchi, K.; Murphy, J.; Washburn, A.; Goldberger; Jones, R.T. Double-blind fluoxetine treatment of cocaine dependence in methadone maintenance treatment patients: Interim analysis. In: Harris, L.S. (ed), Problems of Drug Dependence 1992. NIDA Research Monograph Series 132, 102. Rockville: National Institute on Drug Abuse, 1993.
Costall, B.; Domeney, A.M.; Naylor, R.J. et al. Effect of the 5HT3 receptor antagonist GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain. British Journal of Pharmacology 1987 92: 881-884.
Gawin, F.H.; Khalsa, M.E.; Brown, J.; Jatlow, P. Flupenthixol treatment of crack users: Initial double-blind results. In: Harris, LS (ed), Problems of Drug Dependence 1992. NIDA Research Monograph Series 132, 319. Rockville: National Institute on Drug Abuse, 1993.
Jasinski, D.R.; Preston, K.L.; Testa, M.; Sullivan, J.T. Evaluation of the 5HT3 antagonist ondansetron for cocaine-like activity and abuse potential. In: Harris, L.S. (ed), Problems of Drug Dependence 1990. NIDA Research Monograph Series105, 515. Rockville: National Institute on Drug Abuse, 1991.
Jenkins, S.W.; Warfield, NA.; Blaine, J.D.; Cornish, J.; Ling, W.; Rosen, M.I; Urschel, H.; Wesson, H.; Ziedonis, D. A pilot trial of Gepirone vs. placebo in the treatment of cocaine dependency. Psychopharmacology Bulletin 1992 28: 21-26.
Kosten, T.R. Pharmacotherapy of substance abuse with serotonergic drugs. In: Harris, L.S. (ed), Problems of Drug Dependence 1991. NIDA Research Monograph Series 119, 466. Rockville: National Institute on Drug Abuse, 1992.
Kosten, T.R. Behavioral and pharmacological treatments for cocaine dependence. In: Harris, LS (ed), Problems of Drug Dependence 1992. NIDA Research Monograph Series 132, 85. Rockville: National Institute on Drug Abuse, 1993.
Margolin, A.; Avants, S.K.; Ziedonis, D.; Petrakis, I.; Kosten, T.R. Pre- and post-treatment cue-reactivity in cocaine addicts treated with bupropion. In: Harris, L.S. (ed), Problems of Drug Dependence 1991. NIDA Research Monograph Series 119, 463. Rockville: National Institute on Drug Abuse, 1992.
Naranjo, C.A.; Kadlec, K.E.; Sanhueza, P.; Woodley-Remus, D.; Sellers, E.M.. Fluoxetine differentially alters alcohol intake and other consummatory behaviors in problem drinkers. Clinical Pharmacology and Therapeutics 1990 47: 490-498.
Naranjo, C.A.; Poulos, C.X.; Bremner, K.E.; Lanctôt, K.L. Citalopram decreases desirability, liking, and consumption of alcohol in alcohol-dependent drinkers. Clinical Pharmacology and Therapeutics 1992 :729-739.
Nunes, E. Personal communication, 1994.
Preston, K.L.; Sullivan, J.T.; Strain, E.C.; Bigelow, G.E. Effects of cocaine alone and in combination with bromocriptine in human cocaine abusers. Journal of Pharmacology and Experimental Therapeutics 1992 262: 279-291.
Preston, K.L.; Sullivan, J.T.; Bigelow, G.E.; Berger, P.; Vocci, F.J. Effects of cocaine alone and in combination with mazindol in human cocaine abusers. In: Harris, L.S. (ed), Problems of Drug Dependence 1991. NIDA Research Monograph Series 119, 465. Rockville: National Institute on Drug Abuse, 1992.
Roberts, D.S. Self-administration of stimulants and serotonergic systems. In: Harris, L.S. (ed), Problems of Drug Dependence 1991. NIDA Research Monograph Series 119, 136-140. Rockville: National Institute on Drug Abuse, 1992.
Rothman, R.B. High affinity dopamine reuptake inhibitors as potential cocaine antagonists: A strategy for drug development. Life Sciences 1990 46(20): PL17-21.
Sellers, E.M.; Higgins, G.A.; Tompkins, D.M.; Romach, M.K. Serotonin and alcohol drinking. In: Harris, L.S. (ed), Problems of Drug Dependence 1991. NIDA Research Monograph Series 119, 141-145. Rockville: National Institute on Drug Abuse, 1992.
Sullivan, J.T.; Jasinski, D.R.; Preston, K.L.; Testa, M.; Bell, J.M. Cocaine blocking effects of ondansetron. In: Harris, L.S. (ed), Problems of Drug Dependence 1991. NIDA Research Monograph Series 119, 466. Rockville: National Institute on Drug Abuse, 1992.
Triffleman, E.; Delucchi, K.; Tunis, S.; Banys, P.; Hall, S. Desipramine in the treatment of "crack" cocaine dependence: Preliminary results. In: Harris, L.S. (ed), Problems of Drug Dependence 1992. NIDA Research Monograph Series 132, 317.. Rockville: National Institute on Drug Abuse, 1993.
Wang, R.I.H.; Cho, J-K.; Salstorm, D. Bromocriptine: Anti-craving and other effects in patients abusing cocaine. In: Harris, L.S. (ed), Problems of Drug Dependence 1991. NIDA Research Monograph Series 119, 464. Rockville: National Institute on Drug Abuse, 1992.
Richard Foltin, Ph.D. is a Professor at the College of Physicians and Surgeons of Columbia University, New York, NY.
Treatment of cocaine use over the past decade has increasingly used pharmacological adjuncts to behavioral interventions. In laboratory studies evaluating potential pharmacotherapies for cocaine use it is possible to obtain data on many factors under controlled conditions which provide information about potential behavioral mechanisms of action. For example, does a drug attenuate the subjective effects of cocaine? Does it attenuate cocaine craving? Does it block cocaine self-administration? (Figures 1-3).
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Figure 1
Utility of Controlled Laboratory Studies Of Potential Pharmacotherapies for Cocaine Abuse |
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| Behavioral Mechanisms of Action |
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| Toxicity |
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| Acute vs. Repeated Dose Effects | |
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Figure 2
Controlled Laboratory Studies: Methods | |
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| Subjective Effects |
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| Craving |
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| Toxicity |
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Figure 3 Assessment of Potential Therapeutic Medications: Methods | |
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| Cocaine Choice Sessions Before Therapeutic Drug Maintenance | |
| Initiate Therapeutic Drug Maintenance | |
| Outpatient Therapeutic Drug Maintenance |
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| Cocaine Choice Sessions During Therapeutic Drug Maintenance | |
Normal healthy volunteers with histories of cocaine and other drug use participated in daily experimental sessions. Subjects resided on a hospital Clinical Research Center for the duration of their 2-3 week studies.
Study 1. In this study, subjects were given a choice between active doses of intravenous cocaine and placebo before and during a period of maintenance on desipramine. Desipramine maintenance had no effect on cocaine vs. placebo choice, cocaine craving, and the subjective effects of self-administered cocaine. Also, no effects were found on the ratings of cocaine dose, and by elevated baseline vital signs indicating possible toxicity. However, the absence of a shift in cocaine choice during desipramine maintenance, paired with the verbal reports of decreased cocaine craving suggested that if a non-drug option had been available, perhaps subjects would have chosen less cocaine. (Figure 4).
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Figure 4 Summary of Study 1 | |
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| Desipramine Maintenance |
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| Fluoxetine Maintenance |
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Study 2. The next study used a procedure involving three choices: two different doses of cocaine, and a non-drug option (tokens for the purchase of items). Buprenorphine, an opioid mixed agonist-antagonist, decreased high-dose cocaine choice, increased choice of the non-drug option (tokens), and had no effect on cocaine craving, or on ratings of cocaine dose, and produced no unexpected cardiovascular effects. However, when buprenorphine and cocaine were administered in combination the subjects exhibited subjective effects similar to those produced by the mixture of cocaine and heroin, known as a "speedball." A troublesome finding were the increased ratings of liking for buprenorphine which may portend the drugs street value on the illicit market. This later finding suggests that buprenorphine has abuse potential in a population of opiate users who are not opiate dependent. (Figure 5).
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Figure 5 Summary of Study 2 | |
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| Buprenorphine |
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In conclusion, it is only by evaluating the most prominent measure of drug abuse, drug taking behavior, within a behavioral context, that we can fully understand and predict the likelihood that a potential treatment drug will be effective in reducing cocaine-taking behavior. In addition, by combining choice procedures with other behavioral measures, including subjective and cardiovascular effects, it is possible to characterize the behavioral mechanisms of action of potential pharmacotherapies for cocaine use.
Donald Landry, M.D., Ph.D. is a Professor at the College of Physicians and Surgeons of Columbia University, New York, NY.
Since 1980 cocaine has been used by over 30,000,000 Americans with over 1,700,000 estimated compulsive users. The medical and social consequences of this stimulant are well documented and range from acute psychoses to cardiac failure, from violent behavior to crack-addicted newborns. Cocaine-induced disinhibition produces an increased propensity for high risk behavior, and now pose an additional menace with the advent of the acquired immunodeficiency syndrome. The highly reinforcing nature of cocaine makes this form of drug use especially pernicious and difficult to treat despite a variety of pharmacologic and non-pharmacologic approaches. However, no modality has been adequately successful. The reinforcing potential of cocaine is related to the peak serum concentration, and the rate of rise to the peak. The highly addictive nature of crack, a smokeable form of cocaine, most likely corresponds in part to its rapid delivery across the lung with an efficiency approaching that of an intravenous injection. Pharmacokinetics may also explain the propensity for binge use associated with crack smoking. A pharmacotherapy that reduced the 'velocity to' and 'magnitude of' peak serum levels would permit this hypothesis to be tested as well as have major therapeutic potential.
The neuropharmacological approach to drug treatment has focused on receptor systems, such as the dopaminergic pathways that mediate the effects of cocaine. A direct cocaine antagonist has not been found, but agents such as desipramine show some promise for helping users to maintain abstinence. However, there is a period of several weeks before these pharmacotherapies exert their action and effects with the expected result of relapse during this induction period. A pharmacotherapy that would be effective even for just this period could have important clinical applications, but at present no such drug exists. An alternative to receptor based approaches would be to interfere with the delivery of cocaine to the central nervous system (CNS) so that a dose of cocaine no longer had the reinforcing behavioral effect. Since there is no prospect for a pharmacotherapy that excludes cocaine from the circulation, this approach would require that the proposed drug bind in the blood stream.
A novel pharmaceutical, an artificial enzyme that has the potential to break down cocaine or crack in the blood and thus reduce the drug's addictive effects is presently being investigated. Because the enzyme inactivates cocaine and crack, it holds promise as a pharmacotherapy by preventing relapse to cocaine for users in treatment. However, years of animal studies and clinical trials will be necessary before this artificial enzyme, called a catalytic monoclonal antibody (MAb), can be used in the treatment of cocaine. If the follow-up research is successful, the pharmacotherapy will supplement the limited treatment options available for compulsive cocaine and crack use. Furthermore, the artificial enzyme will be one of the first medical applications for catalytic MAbs.
A MAb is an antibody engineered in vitro to uniquely recognize and bind to a specific antigen, in this case cocaine. The immune system of the mouse is used to produce these highly specific antibodies. Some MAbs approved by the Food and Drug Administration are currently used clinically to treat septic shock and transplant rejection. Other MAbs are in various phases of clinical trials for use in treating other human ailments ranging from cancer to arthritis.
The MAb for cocaine not only recognizes the drug but will degrade it into two inert byproducts. Since the antibodies are not used up and are free to bind additional cocaine molecules, the antibodies are true catalysts. By destroying cocaine in the bloodstream, the MAb is expected to prevent the drug's addictive action in the brain. The addictive potential of cocaine, as previously mentioned, is related to not only how much, but also how fast it gets to the brain, and these parameters are determined by the rise and the rate of the rise of its serum concentration. The faster and higher cocaine rises in the bloodstream, the faster and higher it raises in the brain and the more addictive it becomes. The less cocaine there is and the slower it goes to the brain, then the less addictive it is.
Direct antagonists, or blocking agents to cocaine do not currently exist, but certain agents such as desipramine which work indirectly show promise in helping users maintain abstinence. However, desipramine takes a few weeks before it works and the majority of patients relapse to cocaine use before the drug has had a chance to work. Passive immunization with an anti-cocaine catalytic MAb would provide a window of appropriate psychosocial and relapse prevention interventions. The MAb may also be useful in treating cocaine overdose and will soon be evaluated for its application there.
Notes
Landry, D.W.; Zhao, K.; Yang, G. X.-Q.; Glickman, M.; Georgiadis, T.M. Antibody-catalyzed degradation of cocaine. Science 1993 (March 26) 259: 1899-1901.
Leary, W.E. Scientists create an enzyme that may curb addiction to cocaine. The New York Times 1993 (March 26) National Section.
Morell, V. Enzyme may blunt cocaine's action [Addiction Research]. Science 1993 (March 26) 259: 1828.
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Last Update: March 15, 2001 |
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