Sublingual Ketamine as Breakthrough Analgesia in Patients with Advanced Cancer—A Feasibility Randomised Controlled Repeated Cross-over Trial

This pilot study aimed to determine feasibility of a larger definitive study evaluating sublingual ketamine efficacy as first-line breakthrough analgesia for moderate-to-severe pain in advanced cancer. This prospective, double-blind, randomized, placebo-controlled, repeated cross-over trial included patients (≥18 years) with moderate-to-severe pain from advanced cancer requiring opioid analgesia, randomized to weekly-alternating treatment sequences (APAPAP, APAPPA, APPAAP, APPAPA, PAAPAP, PAAPPA, PAPAAP, PAPAPA; A = sublingual ketamine, P = placebo). The primary outcome was attrition rate, measured by completion of two treatment cycles over 12-months. Of 64 patients referred, 29 were randomized, 11 received intervention. The pre-determined criterion of 24 patients completing 2-cycles over 12-months was not met. Most patients perceived receiving active drugs in placebo (0.71) and active (0.67) periods. Ketamine scored higher than placebo for pain reduction, perceived to be more efficacious than usual breakthrough analgesia, and increased quality-of-life scores. This study design will be infeasible for a larger trial due to a high attrition rate. The patients' inability to discriminate between the placebo versus active medication and the minimal adverse effects suggested that the chosen dose was possibly too low. The potential issue of disease progression over the study period suggests that further target population refinement should be considered.