An assessment of the effects of neurokinin 1 receptor antagonism against nausea and vomiting: Relative efficacy, sites of action and lessons for future drug development.

A 'broad-spectrum' anti-vomiting effect of neurokinin 1 receptor antagonists (NK 1 RA), shown in preclinical animal studies, has been supported by a more limited range of clinical studies in different indications. However, this review suggests that compared with vomiting, the self-reported sensation of nausea is less affected or possibly unaffected (depending on the stimulus) by NK 1 receptor antagonism, a common finding for 'anti-emetics'. The stimulus-independent effects of NK 1 RAs against vomiting are explicable by actions within the central pattern generator (CPG; ventral brainstem) and the nucleus tractus solitarius (NTS; dorsal brainstem), with additional effects on vagal afferent activity for certain stimuli (e.g., highly emetogenic chemotherapy). The CPG and NTS neurones are multifunctional so the notable lack of obvious effects of NK 1 RAs on other reflexes mediated by the same neurones suggests that their anti-vomiting action is dependent on the activation state of the pathway leading to vomiting. Nausea requires activation of cerebral pathways by projection of information from the NTS. Although NK 1 receptors are present in cerebral nuclei implicated in nausea, and imaging studies show very high receptor occupancy at clinically used doses, the variable or limited ability of NK 1 RAs to inhibit nausea emphasises (a) our inadequate understanding of the mechanisms of nausea and (b) that classification of a drug as an "anti-emetic" may give a false impression of efficacy against nausea versus vomiting. We discuss the potential mechanisms for the differential efficacy of NK 1 RA and the implications for future development of drugs which can effectively treat nausea, an area of unmet clinical need.