Drug Addiction and Withdrawal

Fertziger, Lynch and Stein, Brain Research (1974),1026 reported that PHT (15-30 mg/kg, twice daily) decreased the naloxone-induced withdrawal syndrome in morphine-dependent rats. The authors state that abrupt withdrawal of morphine is known to increase neuronal excitability in animals as well as man. The PHT-treated animals contrasted sharply with controls in some aspects of the abstinence syndrome. Hyperexcitability was remarkably reduced and significantly fewer "wet dog" or body shakes occurred in the PHT-treated groups.

1026. Fertziger, A. P., Lynch, J. J., and Stein, E. A., Modification of the morphine withdrawal syndrome in rats, Brain Res., 78:331-334, 1974.

Fertziger, Stein and Lynch, Psychopharmacologia (1974),1027 investigated the effects of pretreatment with PHT on the morphine-induced mania response in cats. The authors note that in the cat, morphine is known to produce a species specific excitant or manic response. This response includes extreme excitation and agitation, with explosive impulsivity, abrupt jumping and intermittent vocalizing. Pretreatment with PHT (15 mg/kg, twice daily for four to six days) prevented these hypermanic responses to morphine. The authors suggest that PHT may prove useful in reducing some of the withdrawal symptoms commonly seen in human addicts.

1027. Fertziger, A. P., Stein, E. A., and Lynch, J. J., Suppression of morphine-induced mania in cats, Psychopharmacologia, 36: 185-187, 1974.

Sprague and Craigmill, Research Communications in Chemical Pathology and Pharmacology (1976), 2977 showed that PHT (10-20 mg/kg) not only reduced the severity of handling-induced convulsions, but also elevated the threshold of the startle reflex, used as a measure of central nervous system excitability, during ethanol withdrawal in mice.

2977. Sprague, G. L., Craigmill, A. L., Control of ethanol withdrawal symptoms in mice by phenytoin, Res. Commun. Chem. Pathol. Pharmacol., 15: 721-31, 1976.

Saad, Osman, Mustafa and Hussein, IRCS Medical Science (1977),2062 found that PHT reduced naloxone-induced withdrawal symptoms in morphine-dependent rats.

2062. Saad, S. F., Osman, 0. H., Mustafa, A. and Hussein, K. E., Possible involvement of gamma-aminobutyric acid in morphine abstinence in rats, IRCS Med. Sci., 5(7): 317, 1977.

Cookson and Mann, Neuroscience Abstracts (1978),1781 reported that intravenous PHT (35 mg/kg) reversed the morphine induced catalepsy in rats within fifteen minutes. PHT also prevented the appearance of catalepsy when given prior to morphine. The authors suggest that PHT may correct excessive morphine-induced calcium dependent neurotransmitter release, which causes the cataleptic response.

1781. Cookson, S. L. and Mann, J. D., Reversal and prevention of acute morphine induced catalepsy by phenytoin in naive rats, Neurosci. Absir., 4: 488, 1978.

Tsai, Smith, Robinson, Olubadewo and Ochillo, FASEB Journal (1993),3641 used an in vitro experimental model to investigate the pharmacodynamic basis for the usefulness of phenytoin in the therapeutic management of alcohol withdrawal syndrome. A dose-response curve (DRC) for acetylcholine (ACh) was constructed for a longitudinal muscle segment of guinea-pig isolated ileum. This preparation was exposed to an ethanol solution for 60 minutes. Washing off the ethanol simulated alcohol withdrawal conditions, which facilitated a significant leftward shift in the DRC of ACh. The presence of phenytoin (8.0 x 10-5) antagonized the leftward shift of the alcohol withdrawal-induced hypersensitivity which is thought to be a feature of the alcohol withdrawal syndrome. The authors suggest that this in vitro evidence provides further rationale for the usefulness of phenytoin in alcohol withdrawal.

3641. Tsai, C.S., Smith, M.O., Robinson, T.J, Olubadewo, J.O., and Ochillo, R.F., Pharmacodynamic basis of the therapeutic use of phenytoin to manage alcohol withdrawal syndrome, Faseb J., 7(3):A255,1474, 1993.