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

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)_0–24 of 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 (t_max) or paired t-tests on log-transformed variables (other variables).

RESULTS:

While the AUC_0–24 was similar between the 2 phases, S-ketamine reduced the AUC_0–1.5 of oral morphine by 69% (ratio to control, 0.31; 90% confidence interval [CI], 0.15–0.65; P = .0171) and increased its t_max from 0.5 (range, 0.50–1.5) to 1.0 hour (range, 0.50–4.0; P = .010). The AUC_0–1.5 of morphine-6-glucuronide (M6G) was reduced by 84% (0.16; 90% CI, 0.07–0.37; P = .0025) and maximum plasma concentration (C_max) by 43% (0.57; 90% CI, 0.40–0.81; P = .0155), while its t_max was 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 AUC_0–1.5 of morphine-3-glucuronide (M3G) was reduced by 85% (0.15; 90% CI, 0.05–0.43; P = .0083), and t_max increased 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.