Influence of Intravenous S-Ketamine on the Pharmacokinetics of Oral Morphine in Healthy Volunteers

Abstract

BACKGROUND:Subanesthetic ketamine may reduce perioperative consumption of opioids. We studied whether intravenous S-ketamine alters the pharmacokinetics of oral morphine in healthy volunteers.METHODS:In this paired, randomized, double-blind, crossover trial, 12 participants under a 2-hour intravenous S-ketamine (0.57 mg/kg/h) or placebo infusion received oral morphine (0.2 mg/kg) at 30 minutes. Plasma concentrations of ketamine, morphine, and their major metabolites were quantified for 24 hours. The primary end point was area under the curve (AUC)0–24of morphine. Other pharmacokinetic variables for morphine and its metabolites were studied as secondary end points. The data were analyzed as between-phase comparisons for each participant using Wilcoxon matched-pairs signed-rank tests (tmax) or pairedt-tests on log-transformed variables (other variables).RESULTS:While the AUC0–24was similar between the 2 phases, S-ketamine reduced the AUC0–1.5of oral morphine by 69% (ratio to control, 0.31; 90% confidence interval [CI], 0.15–0.65;P= .0171) and increased itstmaxfrom 0.5 (range, 0.50–1.5) to 1.0 hour (range, 0.50–4.0;P =.010). The AUC0–1.5of morphine-6-glucuronide (M6G) was reduced by 84% (0.16; 90% CI, 0.07–0.37;P =.0025) and maximum plasma concentration (Cmax) by 43% (0.57; 90% CI, 0.40–0.81;P =.0155), while itstmaxwas increased from 1.5 (range, 1.0–2.0) to 4.0 (range, 1.0–8.0;P =.0094) hours by S-ketamine. Similarly, the AUC0–1.5of morphine-3-glucuronide (M3G) was reduced by 85% (0.15; 90% CI, 0.05–0.43;P =.0083), andtmaxincreased from 1.0 (range, 0.5–1.5) to 4.0 hours (range, 1.0–8.0;P =.0063). In addition, the M6G-to-morphine and M3G-to-morphine metabolic AUC ratios were decreased by 47% (0.53; 90% CI, 0.39–0.71;P =.0033) and 52% (0.48; 90% CI, 0.27–0.85;P =.0043) during 0 to 1.5 hours and by 15% (0.85; 90% CI, 0.78–0.92;P =.0057) and 10% (0.90; 90% CI, 0.83–0.98;P =.0468) during 0 to 24 hours, respectively. One participant was excluded from the analyses due to vomiting in the S-ketamine phase.CONCLUSIONS:Intravenous S-ketamine inhibited the metabolism of oral morphine and delayed its absorption, resulting in a net reduction in the exposure to morphine during the first 1.5 hours. Intravenous S-ketamine may delay the absorption and impair the efficacy of orally administered analgesics and other drugs.