Alcoholism and Drug Addiction

PHT has been found useful in alcohol and drug withdrawal, not only for seizure control, but also for mood and behavioral problems.

Problems of the nervous system are frequent causes of drug and alcohol addiction. For this reason PHT’s use as a preventive should be considered. In addition to its regulatory effect on the nervous system it has the advantage of being nonaddictive.

Wilhoit, Journal of the Florida Medical Association (1965),383 reported that one of the most important steps taken in the treatment of acute alcoholism and delirium tremens is the prophylactic use of PHT. With PHT patients tended to have a much easier and quicker recovery from acute alcoholism. The author also noted that with PHT treatment, by the fourth to the seventh day, there was a marked improvement in sense of well-being, sleep pattern, appetite and motivation.

383. Wilhoit, W. M. C., The broader treatment of acute alcoholism and delirium tremens, J. Florida Med. Assn., 52: 254-255, 1965.

Fox, Modern Treatment (1966),105 recommended PHT (100 mg four times a day) for five to ten days for prevention of convulsions due to alcohol withdrawal. The author stated that frequently convulsions due to withdrawal from alcohol are mistaken for epilepsy and the patient is sent home on PHT and phenobarbital. PHT offers no problem, but, in the case of phenobarbital, the danger exists that the patient may gradually increase it to the point of addiction.

105. Fox, V., Treatment of the non-neurologic complications of alcoholism, Mod. Treatm., 3: 502-508, 1966.

Ramirez, Personal Communication (1967),290 described the effective use of PHT during withdrawal of patients with various forms of addiction including heroin. During a three-year period of clinical study it was found that after physical detoxification most patients went through a stormy period of behavioral difficulties which lasted from seven to ten days on the average. Patients were irritable, intolerant, and frequently showed temper tantrums. In addition, they were insomniac and depressed. On PHT there was a rapid change in the overall behavior patterns of the patients. Acting out behavior was much less frequent. Sleeplessness, which is a very difficult problem with addicts, was also modified favorably. After a preliminary study with thirty patients, the author used PHT routinely, 100 mg three times a day.

290. Ramirez, E., The use of diphenylhydantoin in the modification of acting-out behavior of post-detoxification addict patients, Personal communication. 1967.

Chafetz, Journal of the American Medical Association (1967),571 stated that PHT is most effective in the treatment and prevention of convulsions associated with alcoholic withdrawal. He pointed out that PHT is a desirable medication because it lacks the hypotensive effect sometimes found with the phenothiazines.

571. Chafetz, M. E., Alcohol withdrawal and seizures, JAMA, 200: 195-196, 1967.

Thurlow and Girvin, Canadian Medical Association Journal (1971),1616 reported the successful treatment with PHT of two cases of flashbacks (recurrent visual hallucinations after LSD). In one of the cases the patient had been suffering from flashbacks five months after the discontinuance of all hallucinogenic drugs. She was given chlorpromazine, 25 mg t.i.d., with moderate diminution in the intensity, frequency and affective component of her flashbacks. Hallucinations continued to occur, but were less terrifying. Chlorpromazine was discontinued and the previous level of flashbacks returned within twenty-four hours. PHT was instituted, 100 mg t.i.d. Within forty-eight hours she noted a very marked reduction in all types of flashbacks. In the other case, 100 mg of PHT intravenously terminated a flashback while in progress. Before injecting PHT, saline solution was injected, as a control, with no effect. (See also Ref. 1988.)

1616. Thurlow, H. J. and Girvin, J. P., Use of anti-epileptic medication in treating “flashbacks” from hallucinogenic drugs, Canad. Med. Assoc. J., 105: 947-948, 1971.
1988. Mohan, K. J., Salo, M. W. and Nagaswami, S., A case of limbic system dysfunction with hypersexuality and fugue state, Dis. Nerv. Syst., 36: 621-4, 1975.

Adams, Journal of the American Medical Association (1971),2141 states: “In more than 500 cases of acute alcohol withdrawal, I have yet to see a patient suffer delirium tremens or convulsions when PHT, 100 mg orally four times daily, is given . . .”

2141. Adams, H.P., Diphenylhydantoin in the treatment of alcohol withdrawal, JAMA, 218(4): 598, 1971.

Finer, Journal of the American Medical Association (1971),2182 reporting on the experience in a 1400-bed hospital, states that it is their belief that the tremors, apprehension and psychomotor excitation experienced in withdrawing alcohol should not be subdued by another depressant drug. The author states that it is their practice to give PHT orally, 100 mg four times a day. Out of 735 admissions and 565 readmissions over a three-year period, no seizures occurred in alcoholic patients who received PHT.

2182. Finer, M.J., Diphenylhydantoin for treatment of alcohol withdrawal syndromes, JAMA, 215(1): 119, 1971.

Fisher and Dimino, British Journal of Addiction (1975),1033 in discussing their clinical experience, report that they found PHT to be useful in their over-all therapeutic approach to withdrawal from addictive agents, including heroin, amphetamines, and alcohol.

1033. Fisher, D. and DiMino, J. M., Case presentation of an alternative therapeutic approach for the borderline psychotic heroin addict: diphenylhydantoin, Br. J. Addict., 70: 51-55, 1975.

Ifabumayi and Jeffries, Canadian Psychiatric Association Journal (1976),1904 describe the successful use of PHT in treating several cases of drug-induced psychosis and detail three cases which had previously been unsuccessfully treated with major tranquilizers. All patients had taken hallucinogenic drugs for over five years. PHT, 100 mg two or three times a day, resulted in prompt improvement in symptoms of psychotic behavior, bizarre visual, auditory and tactile hallucinations, feelings of derealization, fragmented thinking, and lack of concentration. The authors state that PHT was dramatically effective in treating these refractory cases.

1904. Ifabumuyi, O. I. and Jeffries, J. J., Treatment of drug induced psychosis with diphenylhydantoin, Can. Psychiatr. Assoc. J., 21: 565-9, 1976.

De Sousa, De Sousa and Sinorawala, Journal of Community Psychiatry (1988), 3139 compared the treatment of 43 alcoholics with phenytoin (300 mg/kg) with that of 41 treated with placebo. Both groups of patients were hospitalized and received a nutritious diet, adequate fluids and vitamins. Over a 10-day withdrawal period, the signs and symptoms of the patients were recorded and compared. Tremors, anxiety, depressed mood, irritability, headache, restless sleep, nightmares, and hallucinations were much less frequent in the PHT-treated group. For example, on day 3, 28 patients complained of anxiety in the placebo group vs. only 4 in the phenytoin group. On the same day 17 patients were irritable with placebo and only 2 with phenytoin. The authors conclude that phenytoin is a very useful drug in the management of alcohol withdrawal.

3139. De Sousa, A., De Sousa, D.A., and Sinorawala, A.K., Diphenylhydantoin in alcohol withdrawal states, J. Commun. Psychiatry, 11: 19-21, 1988.

De Sousa and De Sousa, Journal of Community Psychiatry (1988), 3140 conducted a study of 77 heroin addicts randomly assigned to two treatment groups, both receiving vitamins and tranquilizers. In addition, one group received phenytoin 300 mg/day in divided doses and the other group received placebo for ten days. Using a standard checklist of heroin withdrawal symptoms, the authors found that signs and symptoms of heroin withdrawal including restlessness, insomnia, argumentativeness, fault-finding, goose flesh, twitching, tachycardia, aches and pains, memory disturbances, and hallucinations were much less frequent in the phenytoin-treated group. They recommend more trials of phenytoin in heroin withdrawal.

3140. De Sousa, A. and De Sousa, D.A., Diphenylhydantoin in heroin withdrawal, J. Commun. Psychiatry, 11: 3-4, 1988.

Alldredge, Lowenstein and Simon, American Journal of Medicine (1989), 3141 carried out a prospective, randomized, placebo-controlled study of phenytoin's effectiveness in the short-term treatment/prevention of alcohol withdrawal seizures. Forty-five patients received PHT (1000 mg IV) and 45 patients received placebo. Six in each group had at least one recurrent seizure. Equivalent PHT levels were found in those with and without seizures. The authors conclude that phenytoin showed no benefit over placebo in the prevention of alcohol withdrawal seizures.

3141. Alldredge, B.K., Lowenstein, D.H., and Simon, R.P., Placebo-controlled trial of intravenous diphenylhydantoin for short-term treatment of alcohol withdrawal seizures, Am. J. Med., 87: 645-48, 1989.

Shah and Ratner, New York State Journal of Medicine (1992), 3142 reported that phenytoin therapy was associated with a lower prevalence and lower intensity of smoking in a group of psychiatric patients. Of 22 patients on neuroleptic agents, who were also receiving oral phenytoin (100 - 500 mg per day), there were eight non-smokers. While in the control group of 22 age- and sex-matched patients on neuroleptics but not taking phenytoin, only 3 of 22 were non-smokers. Nearly two-thirds of the patients taking phenytoin were either non-smokers or nominal smokers (1 - 5 cgs/day). Two-thirds of the control patients were either moderate (6 - 20 cgs/day) or severe (more than 20 cgs/day) smokers. These results were significant at p < 0.05.

3142. Shah, B.S. and Ratner, H., Phenytoin and smoking, NY State J. Med., 92(2): 71-72,1992.

Shah and Ratner, New York State Journal of Medicine (1993), 3143 hypothesize that some anticonvulsant drugs have a calming effect that may be useful for reducing cigarette smoking. To test this, they conducted a cross-sectional study of all one hundred psychiatric in-service patients receiving various anticonvulsant drugs. A group of one hundred other patients receiving medications other than anticonvulsants, and matched for their age and sex, served as controls. Intensity of daily cigarette smoking and body weights were recorded. Of the twenty-two patients on phenytoin, eight were non-smokers, as compared to three in the control group. Of the group of phenytoin-treated patients, fourteen were either non-smokers or nominal smokers (one to five cigarettes/day). Patients taking phenytoin weighed less than the controls (mean weight, 149 lbs vs. 163 lbs). The odds ratio for a patient on phenytoin being a moderate or heavy smoker was 0.125, which was much lower than that for valproic acid, clonazepam or carbamazepine. In contrast, of the 178 patients not taking phenytoin (the total number of control patients and those receiving other anticonvulsants), 118 were either moderate (6-20 cigarettes/day) or heavy smokers (21 or more cigarettes/day). Valproic acid therapy was associated with a significantly higher body weight and with more smoking (odds ratio 2.75). Clonazepam's effect was similar to that of valproic acid, although its odds ratio was 2.00. For carbamazepine (odds ratio, >1.00), there was no relationship either with smoking or with body weight.

The authors conclude that therapy with phenytoin is associated with a lower prevalence and intensity of cigarette smoking, together with lower body weights in a psychiatric in-patient population. They suggest further trials of PHT's usefulness in reducing cigarette smoking.

3143. Shah, B.S., Ratner, H., Anti-convulsant drugs, smoking, and body weights in psychiatric in-patients, N.Y. State J. Med., 93(1): 16-17, 1993.

Ilyuchina and Nikitina, Alcohol (1995), 3144 evaluated the effects of phenytoin (PHT) on both the acute withdrawal syndrome (AWS) and the asthenic-autonomic syndrome associated with chronic alcoholism in a single-blind, controlled, clinical, and comprehensive multiparameter psychophysiological and neurophysiological study. Twenty-four patients were treated with PHT (100 mg, PO, tid) and the authors' standard detoxification therapy (intravenous fluids and vitamins as an antihistamine and a vasodilator; cognitive psychotherapy; and occupational therapy) and their progress was compared to that of 12 patients receiving only the standard detoxification therapy. The use of PHT and standard detoxification therapy resulted in an amelioration or cessation of the main symptoms of acute alcohol withdrawal within a mean of 3 +/- 1 day. Vital fear, psychomotor excitation, sense of shortness of breath, pronounced chill-like state, and pronounced perspiration disappeared within 3 days. In the control group, the same improvements were found in a mean of 11 ± 3 days. After the acute withdrawal period, PHT (50 - 100 mg, bid-tid) was continued in all 24 patients of the PHT group to evaluate its effects on the asthenic-autonomic syndrome. PHT's most marked therapeutic effects (improvements in mood, aggression, ability to react appropriately to surroundings, attention, active vigilance, and autonomic parameters) were seen in eight patients with the sympathetic-adrenal type of autonomic disorders. Dynamic EEG and infraslow physiological processes showed confirmatory improvement. A reduction in alcohol craving and longer alcohol-free remission times were also seen. Although there were some benefits in the 16 patients with the parasympathetic type of autonomic disorders, they were smaller and less stable. There were no beneficial effects of PHT or standard therapy in a group of five young patients with a malignant, rapidly progressive form of alcoholism.

The authors conclude that PHT is useful in acute alcohol withdrawal and in the treatment of the asthenic-autonomic syndrome (during the rehabilitative phase) in patients with sympathetic type of autonomic disorder. In the authors' opinion, further clinical evaluation and use of PHT in alcohol withdrawal and rehabilitation are indicated.

3144. Ilyuchina, V.A. and Nikitina, L.I., Clinical physiologic study of the therapeutic effects of phenytoin in acute alcohol withdrawal and the asthenic-autonomic syndrome in patients with chronic alcoholism, Alcohol, 12(6):511-17, 1995.

Rao and Suneetha, Personal Communication (1995), 3145 conducted a prospective randomized, double-blind, controlled study to compare the efficacy and safety of phenytoin and chlordiazepoxide in ameliorating the symptoms of acute alcohol withdrawal. The drugs were administered for 21 days to 60 patients who met the criteria of alcohol dependence as defined by DSM III R. Initially, thirty patients received, in three divided doses, either phenytoin (400 mg) or chlordiazepoxide (100 mg). After ten days this dosage was reduced to 200 mg and 50 mg respectively. Efficacy was measured daily throughout the study period using a standard alcohol withdrawal symptom checklist including vital signs and assessment of sleep duration and quality. The Speilberger State-trait Anxiety Scale, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, Brief Psychiatry Rating Scale and cognitive screening test were administered at regular intervals. Phenytoin was found to be as efficient as chlordiazepoxide in reducing the intensity of symptoms of acute withdrawal, improving sleep and alleviating anxiety progressively. Based on their study, the authors recommend phenytoin as an alternative drug to chlordiazepoxide in treating acute alcohol withdrawal symptoms.

3145. Rao, A. and Suneetha, V.T., A controlled trial of phenytoin and chlordiazepoxide (Librium) during the acute alcohol withdrawal period, Personal Communication, 1-20, 1994.

Crosby, Pearson, Eller, Winegarden and Graves, Clinical Pharmacology and Therapeutics (1996), 3146 conducted a twelve-week, double-blind, placebo-controlled outpatient study of phenytoin in the treatment of cocaine abuse. Sixty cocaine-using subjects were randomly assigned to a daily fixed dose of 300 mg phenytoin or placebo. Forty-four subjects initiated treatment and returned for weekly visits. Twelve patients completed the entire twelve-week protocol (six each for PHT and placebo). Primary measures of outcome included weekly quantitative and qualitative cocaine urinalysis, self-reported cocaine use, global functioning and improvement, craving intensity and subject retention.

Cocaine use, as measured by both weekly urinalysis and self-report, was significantly lower in the PHT-treated group. Sixteen of twenty PHT-treated patients had at least one cocaine-free week during the trial, as compared to 45% of those on placebo, and the longest cocaine-free period for the PHT group was double that of patients on placebo. The phenytoin group was also rated as significantly less impaired and more improved than the placebo group. Craving intensity was lower in the phenytoin group, but the difference was not statistically significant. Serum PHT levels above 6.0 µg/ml were associated with lower rates of positive cocaine urine specimens and longer cocaine-free periods. Based on their findings, the authors suggest that phenytoin may be useful in the treatment of cocaine abuse and urge further studies.

3146. Crosby, R.D., Pearson, V.L., Eller, C., Winegarden, T., Graves, N.L., Phenytoin in the treatment of cocaine abuse: a double-blind study, Clin. Pharmacol. Ther., 59: 458-468, 1996.

Alexandrova, Kirov and Douchlensky, Personal Communication (2001), 3147report on the usefulness of PHT in the management of heroin withdrawal symptoms. In a study of forty patients undergoing heroin withdraw at an addiction treatment center in Pleven, Bulgaria, twenty patients were administered 300 mg/day PHT and another twenty patients were given 600 mg/day carbamazepine (CBZ). Heroin withdrawal symptoms including restlessness, insomnia, argumentativeness, memory disturbances, twitching and hallucinations, were markedly decreased in the group undergoing PHT treatment, compared to those in the group treated with carbamazepine. In addition, the duration of withdrawal symptoms was forty-eight hours shorter in the PHT-treated group.

3147. Alexandrova, M., Kirov, D., Douchlensky, I., Diphenylhydantoin (phenytoin) in the treatment of heroin withdrawal, Personal Communication, 2001.

See also Ref.

3148. Sofuoglu, M., Pentel, P.R., Bliss, R.L., Goldman, A.I., and Hatsukami, D.K., Effects of phenytoin on cocaine self-administration in humans, Drug Alcohol Depend., 53: 273-75, 1999.

3149. Jaffe, J.H., Pharmacological agents in the treatment of drug dependence, Psychopharmacology: The Third Generation of Progress, 1605-16, Meltzer, H.Y., Ed., Raven Press, NY, 1987.

3150. De Sousa, A. and De Sousa, D.A., The management of heroin dependence, CME: IPS, 6: 39-48, 1986.

3151. Huang, M. and Li, J., The detoxificated effect of phenytoin on heroin addicts, Presented at the National Workshop of Clinical Use of Phenytoin, Chengdu, China, 1995.

3152. Kasser, C., ASAM Clinical Practice Guideline: The Role of Phenytoin in the Management of alcohol Withdrawal Syndrome, Amer. Soc. Addiction Med. (ASAM), 1997.

3153. Mayo-Smith, M.F., Cushman, P., Hill, A.J., Jara, G., Kasser, C., Kraus, M., Nauts, D., Saitz, R., Smith, J.W., Sullivan, J. et al., Pharmacological management of alcohol withdrawal, JAMA, 278(2):, 1997.

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