A prospective double-blind, randomised, phase 3 study of the efficacy of ketamine for oral and pharyngeal mucositis pain: KARM study (ketamine analgesia for refractory mucositis pain).

296 Background: Pain from oral and pharyngeal mucositis is distressing and can be severe and opioid refractory. This phase 3 randomised, placebo-controlled study evaluated the efficacy of ketamine versus active placebo in treating cancer treatment–related oral and pharyngeal mucositis pain. It also examined associations between steady-state plasma concentrations (Css) of ketamine and its metabolites and analgesic response, and explored how ketamine plasma clearance (CLss) and CYP2B6 polymorphisms influenced metabolism and adverse effects. Methods: Patients with mucositis and an average pain score ≥ 4/10 (Brief Pain Inventory) received subcutaneous infusions of either ketamine plus 5 mg midazolam or 5 mg midazolam alone for 3–5 days. Ketamine was titrated from 100 to 300 mg/24 h in 100 mg increments. A total of 18 participants (9 per group) were planned to provide 80% power to detect a between-group difference at a two-sided alpha of 0.05. A clinically significant response was defined as a ≥ 2-point reduction in average pain with ≤ 4 breakthrough doses in 24 h. Linear mixed models (LMM) and Fisher’s exact test were used for analysis. Css and CLss of ketamine and metabolites were measured, and pharmacogenetic testing was performed in nine patients receiving ketamine. Results: Among 16 patients, 77.8% (7/9) in the ketamine group achieved clinically significant pain reduction versus 14.3% (1/7) in the placebo group (p = 0.04). LMM showed ketamine significantly lowered average pain scores (−5.40 vs −0.72; p < 0.01), worst pain (−5.82 vs −1.1; p = 0.027) and verbal rating scale (VRS) (−5.12 vs −0.41; p < 0.01) compared to placebo. Post-hoc LMM with Dunnett’s test confirmed significant pain reductions from baseline through day 5 (average pain score, worst pain score and VRS) for the ketamine group relative to baseline. The mean daily opioid requirement was significantly lower in the ketamine group throughout the study period (−1.29 mg vs +64.63 mg) ( p = 0.028). The most common adverse effects were psychomimetic. All adverse effects were mild, with no group differences. CYP2B6 genotyping identified *1 and *6 alleles at 66.7% and 33.3% frequencies. Among ketamine-treated patients, 4 had *1/*1 (wild-type) and 5 had *1/*6 genotypes. No significant differences in Css or CLss were observed between genotype groups based on general LMM analysis. Plasma concentrations of ketamine and its metabolites were not predictive of pain response or adverse effects. Conclusions: Low-dose continuous subcutaneous ketamine is effective for opioid-refractory oral and pharyngeal mucositis pain. Further research is needed to define optimal dosing and duration. Exploring the impact of CYP2B6 *6 on ketamine clearance and plasma levels may enhance understanding of variability in response and support individualized treatment strategies. Clinical trial information: 12619000108112 .