Ketamine Analgesia for Refractory Mucositis Pain (KARM): A Prospective, Double-Blind, Randomized, Phase 2 Study of Ketamine for Oral and Pharyngeal Mucositis Pain

Context: 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. Objectives: 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. Methods: Adults with OM and an average Brief Pain Inventory pain score ≥ 4/10 were randomized 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 100–300 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. Results: 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 (–1.29 mg vs. +64.63 mg; 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. Conclusions: Low-dose continuous subcutaneous ketamine infusion appears effective and well-tolerated for opioid-refractory moderate to severe OM pain.