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.
Keywords: Cancer pain; breakthrough pain; sublingual ketamine.
What uncertainties existed regarding the feasibility? It was uncertain whether the use of sublingual ketamine for treatment of breakthrough pain in patients with advanced cancer would have an appreciable benefit and would be tolerable with an acceptable safety profile. In addition, it was unclear if a large study with a repeated cross-over design to assess the efficacy of ketamine for breakthrough cancer pain would be practical. In particular, it was unclear whether the pre-specified recruitment rate would be achievable, if the length of the study period was appropriate, and if the outcome parameters chosen would yield meaningful clinical results for analysis.What are the key feasibility findings? Using the current study design will not be feasible for a definitive study since the pre-determined recruitment rate was not reached, and most patients were unable to discriminate between placebo and active medicine.What are the implications of the feasibility findings for the design of the main study? Modification of the target study population to those with more stable disease should be considered to increase recruitment. A larger dose of study medicine is also potentially required. Refinement of the outcome measurements may be required to reduce patients burden.