These data show dose-dependent effects on respiration at relatively low concentrations of propofol and remifentanil. When combined, their effect on respiration is strikingly synergistic, resulting in severe respiratory depression.

Background: Low-dose ketamine behaves as an analgesic in the treatment of acute and chronic pain. To further understand ketamine's therapeutic profile, the authors performed a population pharmacokinetic-pharmacodynamic analysis of the S(؉)-ketamine analgesic and nonanalgesic effects in healthy volunteers. Methods: Ten men and ten women received a 2-h S(؉)ketamine infusion. The infusion was increased at 40 ng/ml per 15 min to reach a maximum of 320 ng/ml. The following measurements were made: arterial plasma S(؉)-ketamine and S(؉)norketamine concentrations, heat pain intensity, electrical pain tolerance, drug high, and cardiac output. The data were modeled by using sigmoid Emax models of S(؉)-ketamine concentration versus effect and S(؉)-ketamine ؉ S(؉)-norketamine concentrations versus effect. Results: Sex differences observed were restricted to pharmacokinetic model parameters, with a 20% greater elimination clearance of S(؉)-ketamine and S(؉)-norketamine in women resulting in higher drug plasma concentrations in men. S(؉)ketamine produced profound drug high and analgesia with six times greater potency in the heat pain than the electrical pain test. After ketamine-infusion, analgesia rapidly dissipated; in the heat pain test but not the electrical pain test, analgesia was followed by a period of hyperalgesia. Over the dose range tested, ketamine produced a 40-50% increase in cardiac output. A significant consistent contribution of S(؉)-norketamine to overall effect was detected for none of the outcome parameters. Conclusions: S(؉)-ketamine displays clinically relevant sex differences in its pharmacokinetics. It is a potent analgesic at already low plasma concentrations, but it is associated with intense side effects. KETAMINE is a phenylcyclidine derivative introduced in the early 1960s as an intravenous anesthetic agent. Ketamine acts as a noncompetitive antagonist of the ionotropic glutamate N-methyl-D-aspartate (NMDA) recep-* Doctoral Student,

The data indicate that while ketamine's effect on acute experimental pain is driven by pharmacokinetics, its effect on CRPS pain persisted beyond the infusion period when drug concentrations were below the analgesia threshold for acute pain. This indicates a disease modulatory role for ketamine in CRPS-1 pain, possibly via desensitization of NMDAR in the spinal cord or restoration of inhibitory sensory control in the brain.

To assess the analgesic efficacy of the N-methyl-D-aspartate receptor antagonist S(+)-ketamine on fibromyalgia pain, the authors performed a randomized double blind, active placebo-controlled trial. Twenty-four fibromyalgia patients were randomized to receive a 30-min intravenous infusion with S(+)-ketamine (total dose 0.5mg/kg, n=12) or the active placebo, midazolam (5mg, n=12). Visual Analogue Pain Scores (VAS) and ketamine plasma samples were obtained for 2.5-h following termination of treatment; pain scores derived from the fibromyalgia impact questionnaire (FIQ) were collected weekly during an 8-week follow-up. Fifteen min after termination of infusion the number of patients showing a reduction in pain scores >50% was 8 vs. 3 (P<0.05), at t=180min 6 vs. 2 (ns), at the end of week-1 2 vs. 0 (ns) and at end of week-8 2 vs. 2 in the ketamine and midazolam groups, respectively. Ketamine effect on VAS closely followed ketamine plasma concentrations. For VAS and FIQ scores no significant differences in treatment effects were observed in the 2.5-h following infusion or during the 8-week follow-up. Side effects as measured by the Bowdle questionnaire (which scores for 13 separate psychedelic symptoms) were mild to moderate in both study groups and declined rapidly, indicating adequate blinding of treatments. Efficacy of ketamine was limited and restricted in duration to its pharmacokinetics. The authors argue that a short-term infusion of ketamine is insufficient to induce long-term analgesic effects in fibromyalgia patients.