Timing of administration of dolasetron affects dose necessary to prevent post-operative nausea and vomiting (PONV)

Abstract

Administration of a 5-HT3 receptor antagonist before induction of anaesthesia is based on the hypothesis that blocking the receptors is necessary prior to the emetogenic stimuli of anaesthesia and surgery. To test this hypothesis, we pooled eight clinical trials of oral or i.v. dolestron mesilate (DM) administered at four different intervals, pre- and post-surgery. DM is a new 5-HT3 receptor antagonist, shown to prevent and treat PONV [1,2]. The eight pooled trials were designed identically (double-blind, placebo-controlled, randomized), had similar enrolment criteria (ASA physical status 1–3 patients), and used general balanced anaesthesia. Six trials (four i.v. and two oral) studied doses of DM for prevention of PONV. (One of the i.v. prevention trials used ondansetron (OND) as an active comparator.) Two trials assessed doses of DM for the treatment of established PONV in patients with moderate to severe nausea lasting >5 min and/or vomiting, within 2 h of awakening. The table lists number of trials, doses studied, and timing of DM or OND administration. Complete response (CR: no vomiting/retching and no rescue medication over a 24 h study period) was the primary endpoint. When administered before or at induction of anaesthesia, the 50 mg dose was significantly more effective in preventing PONV than placebo and equivalent to OND (4 mg). The 25 mg DM dose was ineffective compared with placebo. When administered near the end of anaesthesia, the 12.5 mg DM dose produced significantly higher CR rates than placebo. CR rates with the higher doses were equivalent to the 12.5 mg dose. For treatment of established PONV, DM 12.5 mg was statistically superior to placebo for CR. Again, no increases in efficacy were recorded with higher DM doses (Table 10).Table 10: abstract 32).We conclude that blocking 5-HT3 receptors prior to the emetogenic stimuli of anaesthesia and surgery is not required to prevent PONV. When dosed near the end of anaesthesia, a lower dose of dolasetron (12.5 mg) was as efficacious as 50 mg DM administered at or before induction of anaesthesia. The significant efficacy of DM 12.5 mg in treating established PONV further corroborate this finding. All doses were safely administered and well tolerated across the eight trials.