Ketamine Analgesia for Refractory Mucositis Pain (KARM): A prospective, double-blind, randomised, phase 2 study of ketamine for oral and pharyngeal mucositis pain.

Abstract

Oral and pharyngeal mucositis (OM) pain is often severe, distressing, and effective analgesic management remains challenging, particularly when pain is inadequately controlled with opioids. Ketamine, a potent NMDA-receptor antagonist, has shown promise in open-label studies. This study evaluated the efficacy of ketamine versus an active placebo for treatment-related OM pain, alongside examining its pharmacokinetics, adverse effects, and the influence of CYP2B6 polymorphisms. Adults with OM and an average Brief Pain Inventory pain score ≥4/10 were randomised to receive either ketamine plus 5 mg midazolam or an active placebo consisting of midazolam 5 mg to maintain blinding administered as a 24-hour continuous subcutaneous infusion for 3-5 days. Ketamine doses were escalated from 100 to 300 mg/day. The primary endpoint was average pain severity, and that between-group comparisons were performed using a repeated-measures analysis evaluating the treatment-by-time interaction. Linear mixed method analysis of 16 patients revealed a significant, clinically meaningful pain reduction in 77.8% of the ketamine group compared to 14.3% in the placebo group (p=0.04). Compared to the placebo, ketamine significantly reduced average pain score (-5.40 vs. -0.72; p<0.01), worst pain score (-5.82 vs. -1.1; p=0.027), and verbal rating scale scores over time (-5.12 vs. -0.41; p<0.01). Post-hoc analysis confirmed these findings from Day 1 to 5 relative to baseline. Mean daily opioid requirements were significantly lower in the ketamine group compared to baseline (-1.29mg vs. +64.63mg; p=0.028). Adverse effects were mild and typically psychomimetic, with no between-group differences. CYP2B6 *1 and *6 variants were identified (66.7% and 33.3% allelic frequencies, respectively), but genotypes showed no significant differences in ketamine metabolism, analgesic response, or adverse effects. Low-dose continuous subcutaneous ketamine infusion appears effective and well-tolerated for opioid-refractory moderate to severe OM pain.