Pharmacodynamic Profiles of Ketamine (R)- and (S)- with 5-Day Inpatient Infusion for the Treatment of Complex Regional Pain Syndrome

Background: Ketamine might be effective in blocking central sensitization of paintransmission neurons through its effect on NMDA receptors in refractory Complex RegionalPain Syndrome (CRPS) patients. At higher doses, ketamine infusions can be associated withsignificant risks; outpatient therapy requires return visits for a 10-day period with variableefficacy and duration.Objective: This study determined the efficacy of a 5-day moderate dose, continuous racemicketamine infusion. The pharmacodynamic responses to racemic ketamine and norketaminewere examined.Design: Observational studyMethods: In this study, ketamine was titrated from 10-40 mg/hour in 16 CRPS patients, andmaintained for 5 days. Pain was assessed daily. Ketamine and norketamine concentrationswere obtained on Day 1 before starting the infusion; at 60 to 90 minutes, 120 to 150 minutes,180 to 210 minutes, and 240 to 300 minutes after the initiation of the infusion on Days 2,3, 4, and 5; and on Day 5 at 60 minutes after the conclusion of the infusion. The plasmaconcentrations of (R)-ketamine, (S)-ketamine, (R)-norketamine and (S)-norketamine weredetermined using an enantioselective liquid chromatography – mass spectrometry method.Results: Ketamine and norketamine infusion rates stabilized 5 hours after the start ofthe infusion. The subjects showed no evidence of significant tachycardia, arterial oxygendesaturation, or hallucinatory responses. Subjects generally experienced minimal pain reliefon day one followed by significant relief by day 3. Mean pain scores decreased from the 8-9to 3-5 ranges; however, the analgesic response to ketamine infusion was not uniform. On day5, there was little or no change in the pain measure assessed as the worst pain experiencedover the last 24 hours in 37% of the subjects. (R)- and (S)-ketamine concentrations peakedat 240-300 min. (R)- and (S)-norketamine concentrations were lower and peaked on Day 2of the infusion, as opposed to Day 1 for (R)- and (S)-ketamine. Significant pain relief wasachieved by the second day of infusion and correlated with the maximum plasma levels ofketamine and norketamine. Pain relief continued to significantly improve over the 5 dayinfusion at concentrations of 200-225 ng/mL for (R)- and (S)-ketamine, and 90-120 ng/mLfor(R)- and (S)-norketamine.Conclusions: A 5-day ketamine infusion for the treatment of severe CRPS providedsignificant (P <0.05) pain relief by Day 3 compared to baseline. The pain relief experienced onDay 2 of the infusion continued to improve over the 5-day infusion period and correlated withthe maximum plasma levels of ketamine and norketamine. We speculate that downstreammetabolites of ketamine and norketamine might be playing a role in its therapeutic efficacy.Key words: ketamine, norketamine, CRPS, pharmacodynamics, chronic pain, enantiomers