Histamine and the mechanisms of nausea and vomiting: Translating the uncertain pharmacology of cyclizine

Abstract Cyclizine is a long‐established, short‐acting drug, registered for preventing motion sickness, post‐operative nausea and vomiting (PONV) and ‘vomiting of known cause’. The latter is not defined but may include pregnancy and patients receiving palliative care, historically accepted without large, controlled trials. Cyclizine is often described as an ‘antihistamine’ and sometimes ‘anticholinergic’, without citing primary literature. Mechanisms of antiemetic activity are poorly understood. We reviewed the published pharmacology of cyclizine with the aim of understanding its mechanism of antiemetic activity. Preclinical/clinical studies were examined and findings interpreted with reference to known mechanisms of nausea and vomiting. Cyclizine antagonizes human H 1 receptors and may cause mild drowsiness. Selectivity of action is unclear; therapeutic doses only weakly antagonize muscarinic ACh receptor(s). Motion sickness is ameliorated by H 1 antagonism within the vestibular system and associated brainstem nuclei. Mechanisms by which histamine may contribute to PONV are unclear. Perhaps histamine from mast cells and basophils stimulate/sensitize abdominal vagal afferent nerves, synergising with other substances to cause vomiting. Any inhibition of vomiting by cyclizine during pregnancy is not understood; GDF15 is implicated, but relationships with histamine are unclear. Causes of nausea/vomiting during palliative care can be complex, and cyclizine is used without understanding mechanisms. For all indications, it is unclear if nausea is reduced to the same degree as vomiting. There is no consistent evidence to support using cyclizine for vomiting during gastroparesis or chemoradiotherapy. The pharmacology of cyclizine and mechanisms of its antiemetic activity are poorly understood. Testable hypotheses are suggested.