Morphine tolerance, physical dependence, and synthesis of brain 5-hydroxytryptamine.

Tolerance and physical dependence development to morphine in mice can be prevented by concomitant administration of cycloheximide. The fact that the rate of synthesis of brain 5-hydroxytryptamine (5HT) increases with tolerance to morphine suggests that the protein involved may be associated with 5HT synthesis. Inhibition of this synthesis with p-chlorophenylalanine markedly decreases tolerance and physical dependence development to morphine.

The long-acting phenothiazines.

Injected intramuscularly, the enanthane and decanoate esters of the phenothiazine fluphenazine are an effective treatment of the disordered behavior and thinking of schizophrenia. The decanoate preparation is not only slightly longer-acting but also has a smaller incidence of side-effects that the enanthate. The major adverse effect of these medications is the high frequency of extrapyramidal system disturbance. Since the 50% rate of failure of schizophrenic outpatients to take prescribed oral medications decreases treatment failure to about 20% with the use of long-acting injectable phenothiazines, this route of administration offers an advantage in patient management particularly applicable to community mental health systems. Moreover, parenteral administration of long-acting fluphenazine may be useful for patients who do not attain effective serum levels with medication taken orally because of metabolic or absorption difficulties.

Extrapyramidal reactions with metoclopramide.

The epidemiology of extrapyramidal reactions to metoclopramide was studied by examining reports in the Adverse Reactions Register of the Committee on the Safety of Medicines and comparing these with prescribing figures by general practitioners in the United Kingdom for metoclopramide (Maxolon). In the period 1967-82 there were an estimated 15.9 million prescriptions and 479 reports of extrapyramidal reactions (455 of dystonia-dyskinesia, 20 of parkinsonism, and four of tardive dyskinesia). When corrected for prescribing rates the relative risk of dystonia and dyskinesia was 1.8 in female compared with male patients (95% confidence interval 1.4-2.2). The overall reporting rate for dystonia and dyskinesia was 28.6/million prescriptions but was significantly more common in young adults (p less than 0.0001) and especially girls and women aged 12-19 (190.7 reports/million prescriptions). By contrast parkinsonian reactions were significantly more common in the elderly (p less than 0.0001).

Development of extrapyramidal symptoms in hypertensive patients treated with diazoxide.

Extrapyramidal symptoms developed a variable time after the start of treatment with oral diazoxide in 15% of a series of 100 severely hypertensive patients. Six illustrative cases are described. Treatment with diazoxide could be continued in four of these. The symptoms are usually controllable either by dosage adjustment or by the use of diazepam or procyclidine. There was no evidence of irreversibility of the extrapyramidal syndromes observed.