Early clinical trials of metoclopramide at traditional doses failed to demonstrate protection against antineoplastic drug-induced vomiting, and its antiemetic potential for oncology patients was not re-examined until the unacceptable nausea and vomiting of the newly introduced cisplatin emphasised the need for improved supportive care. Repetition of the early studies with metoclopramide at usual doses (0.15 to 0.30 mg/kg) in cisplatin-induced emesis confirmed the lack of benefit for low dose therapy. However, on the basis of known pharmacodynamic data, metoclopramide was evaluated as an antiemetic in animal models, and a dose-related response was observed for cisplatin-induced emesis. After establishing safety in a phase I trial, rigorously controlled studies were conducted to assess the antiemetic potential of high dose metoclopramide in preventing cisplatin-induced emesis. Metoclopramide (2 mg/kg) was administered intravenously for a total of 5 doses during a 9-hour period beginning 30 minutes before administration of high-dose cisplatin (120 mg/m2). The results of 3 sequential trials established the superiority of metoclopramide over placebo, prochlorperazine, and tetrahydrocannabinol. Toxicity consisted of mild sedation, diarrhoea, and reversible extrapyramidal reactions. In no case was it necessary to discontinue metoclopramide because of adverse drug reactions. These encouraging results were rapidly followed by a series of pilot studies designed to extend the use of metoclopramide to other clinical situations. Intermediate dose metoclopramide (1 mg/kg for 6 doses) appeared effective particularly for emesis associated with lower doses of cisplatin (50 mg/m2 or less). The results of studies of short course metoclopramide (2 mg/kg for 3 doses) provided a promising alternative regimen for the outpatient setting. As with high dose metoclopramide, the toxicity of these two protocols was acceptable, manifesting as sedation, diarrhoea, and extrapyramidal reactions. Uncontrolled observations of continued metoclopramide treatment during subsequent courses of cisplatin suggest preservation of antiemetic efficacy, and preliminary results of studies of metoclopramide in non-cisplatin-containing regimens also suggest benefit. The combination of metoclopramide with other effective antiemetic agents may provide improved protection. These studies show how a rational approach based on preclinical observations can expand the usefulness of a drug at first thought ineffective in chemotherapy-induced emesis.
ASJC Scopus subject areas
- Pharmacology (medical)