TREATMENT FOR COCAINE ADDICTION

Abstract: Toxic effects of cocaine can be blocked by chronic administration of carbamazepine in amount sufficient to achieve a 4-12 mu g/ml blood concentration. In addition, the dosing with carbamazepine blocks the reinforcing effects of the cocaine, thus decreasing the likelihood of development of addiction to cocaine.

Description: TREATMENT FOR COCAINE ADDICTION This invention provides a means of treating cocaine addiction by chronic oral administration of carbamazepine. While it had previously been reported that administration of carbamazepine would prevent epi¬ leptic and lidocaine-induced seizures, the use of this medication to overcome toxic and habituating action of cocaine had not previously been known. BACKGROUND OF THE INVENTION Cocaine abuse has become a major public health problem in recent years as more reinforcing forms of the drug have become available. Acute intoxication from cocaine is marked by convulsions and cardiac arrhythmias, and chronic cocaine use can be associated with increasing behavioral pathology and toxicity. The mechanisms under- lyng the reinforcing and toxic effects of cocaine are not fully understood, particularly since cocaine has dual actions as a potentiator of catecholaminergic systems; in particular, the dopamine system, and as a local anesthetic. Although dopaminergic antagonists have shown some success in blocking the reinforcing effects of cocaine in experimental animals, there is, at present, no pharmacological treatment that is efficacious and acceptable to patients. Carbamazepine is a major anti- epileptic drug that has also been shown to be effective in the treatment of manic-depressive disorder. Recent studies in the Biological Psychiatry Branch have shown that chronic carbamazepine is extremely effective in preventing cocaine-induced seizures and deaths in rats. Carbamazopine is an iminostilbene derivative that is used clinically to treat seizure disorders, tri- geminal neuralgia, and, most recently, manic-depressive illness. Carbamazepine is very effective as an anti- convulsant in several experimental seizure paradigms including amygdala kindling, alcohol withdrawal, and maximal electroconvulsive shock, but is less effective on seizures induced by pentylenetetrazole and high-dose picrotoxin. The effectiveness of anticonvulsants has been shown to depend upon the stage of evolution of the seizure process. For example, carbamazepine suppresses completed amygdala-kindled seizures in rats, but is ineffective in preventing their development. While diazepam inhibits the early development and fully-kindled phases of amygdala kindling, it is not effective in the later phase of kindling when seizures occur spontaneous¬ ly. Conversely, ^phenytoin shows the opposite profile on amygdala-kindled seizures — it is ineffective in early stages, but blocks spontaneous seizures. Lidocaine is a local anesthetic that can be used to kindle seizures when given repeatedly in large, but initially subconvulsant, doses. This process has been called pharmacological kindling. Local anesthetic seizures resemble those produced by electrical kindling of the amygdala in that there is a prominent facial component, clonic jerking of the forepaws, and electro- encephalographic evidence of seizure activity in the amygdala. In addition, " the lidocaine seizures have been shown to increase glucose utilization in the amygdala, hippocampus, and perirhinal cortex. Cocaine is equi- potent to lidocaine as a local anesthetic, but addi¬ tionally has psychomotor stimulant properties 'that are thought to result from its ability to block catecholamine reuptake. Repeated administration of low to moderate doses of cocaine induces increased motor activation and stereotypy, a process called behavioral sensitization or reverse tolerance. This aspect of cocaine's effect appears closely related to its psychomotor stimulant properties, as similar behavioral changes are not seen with repeated lidocaine administration, but are observed with other psycho-motor stimulants; e.g., amphetamine. Repeated administration of high doses of cocaine results in the progressive development of seizures which follow a time course akin to kindling. In a study at the National Institute of Mental Health, it was found that chronic oral treatment with carbamazepine inhibited the development of lidocaine- and cocaine-kindled seizures in the rat. The carbamazepine diet produces combined blood levels of carbamazepine and its 10,11-epoxide that are similar to those achieved in humans treated with carbamazepine for affective, pain, or seizure disorders. DESCRIPTION OF THE INVENTION It is the purpose of this invention to provide a method for treating cocaine addiction by chronic administration of carbamazepine to block reinforcing effects of cocaine. It is, furthermore, a purpose of this invention to provide a method of blocking toxic effects of inter¬ mittent administration of cocaine by chronic administra- tion of carbamazepine. It has now been determined that, in addition to its use as an anticonvulsant for prevention of seizures, the chronic use of carbamazepine is an appropriate method for treatment of habituation by blocking reinforcing properties of cocaine and for relief of toxic responses to cocaine such as panic attacks. To effect the desired result, the carbamazepine must be administered chronical¬ ly to maintain a relatively constant blood level. Doses ranging from 200-2000 g/day will usually result in a blood level of 4-12 tg/ml. The drug must be given when the patient is relatively drug free. This is because the use of carbamazepine appears at times to worsen seizures and increase lethal effects of cocaine when given acutely near the time cocaine is administered. While the preferred method of treatment is by oral administration, any method which would result in a relatively constant blood level of the compound would be acceptable. The pharmaceutical compositions for admini¬ stration may contain therein the usual fillers known in the pharmaceutical art. Since the reinforcing effects of cocaine are so powerful, the cocaine user becomes addicted rapidly. The addition is persistent, and even the user who is aware of ■ the often lethal results of cocaine dosing Jπay be unable to resist the reinforcing effects of cocaine. The chronic oral administration of carbamazepine provides a useful adjuct to other means of treating the cocaine addict.

Claims: WHAT IS CLAIMED IS; 1. A method of blocking toxic effects of cocaine comprising the chronic administration of carbama¬ zepine to achieve a 4-12 μg/ml blood concentration of carbamazepine. 2. A method of claim 1, wherein the carbama¬ zepine is given orally. 3. A method of claim 2, wherein the dosage of carbamazepine given is 200-2000 mg/day. 4. A method of blocking the reinforcing effects of cocaine by administering to a susceptable host a reinforcing-blocking effective amount of carbamazepine. 5. A method of claim 4, wherein the carbama¬ zepine is given by oral route in a pharmaceutically acceptable carrier. 6. A method of claim 5, wherein the dosage of carbamazepine administered is 200-2000 mg/day.

Inventors: AIGNER THOMAS G, POST ROBERT M, WEISS SUSAN R B, AIGNER, THOMAS, G., POST, ROBERT, M., WEISS, SUSAN, R., B.
Applicants: US COMMERCE, THE UNITED STATES OF AMERICA, REPRESENTED BY THE S
Application year: 1990
Main classification: A61K31
IPC codes: A61K31, A61P25, C07D223