Low dose ketamine : analgesia and side-effects in patients and volunteers

Abstract

There is a need for novel approaches in the pharmacological treatment of pain. In many pain states the present treatment options are insufficient. Altered processing in sensory pathways often underlies such intractable pain. There is now ample evidence from animal and human experimental pain research, as well as clinical studies, suggesting a role for ketamine as an analgesic in these situations. The clinical usefulness of ketamine is, however, not clear due to prominent side-effects, mainly of a psychotropic nature. Defining the role of ketamine in clinical pain-treatment practice requires the clarification of several issues: the concentration-effect relationships for analgesia and side-effects, the influence of adjuvant drugs, and the differences in effect profiles between the enantiomers. The present thesis investigates these issues.

Study I: A case report concerning a previously healthy young girl with an intractable pain state from a persistent suppurating wound after an appendectomy. There was a mechanical allodynia and considerable aberrations in thermal sensitivity. During the dressing procedures, racemic ketamine in a bolus dose of 0.2-0.5 mg/kg BW gave a better analgesia than morphine 30 mg, with less subjective side-effects. After treatment with ketamine once or twice daily for a total of three months there was a marked reduction of the allodynia and sensory aberrations despite the unchanged character of the wound.

Study II: Five healthy volunteers received S-ketamine mixed with tracer amounts of 11C S-ketamine as randomised bolus doses. The magnitude of specific binding of (S)-ketamine was measured with Positron Emission Tomography (PET). The analgesic effects were evaluated by an experimental ischaemic pain model, and by thermal pain threshold testing. S-ketamine had a marginal and inconsistent effect on heat and cold pain thresholds, but the subjects were able to withstand ischaemic pain better. Side-effects and relief of ischaemic pain were related to dose and brain concentrations.

Study III: Eight patients with rest pain in the lower extremity due to arteriosclerosis obliterans were given doses of 0.15, 0.30, or 0.45 mg.kg-1 racemic ketamine and morphine 10 mg as a five minute infusion in random order. Ketamine 0. 15 mg.kg-1 gave a pain relief equivalent to morphine 10 mg. Ketamine 0.30 mg/kg gave 7/8 patients, and Ketamine 0.45 mg/kg 8/8 patients a total pain relief at the end of the five-minute infusion. Side effects, mainly disturbed cognition and perception, were pronounced and dose-dependent.

Study IV: Alfentanil was infused to a target plasma concentration of 50 ng mL-1 in 8 healthy volunteers. An escalating racemic ketamine infusion (target concentration 50, 100 and 200 ng mL-1) was then added to the alfentanil infusion. The alfentanil infusion induced hypoventilation by decreasing respiratory rate while tidal volume and respiratory drive were unaffected. This hypoventilation was antagonised by ketamine in a concentration-dependent manner mainly through an increase in respiratory rate. There were no significant differences in any of the variables related to respiratory drive. The C02 response was not affected by alfentanil or ketamine.

Study V: R- and S-ketamine were infused in 10 healthy volunteers, 4 of whom were poor metabolisers (2 for the CYP2D6, 2 for the CYP2C19 pathways). Arteriovenous differences in plasma concentrations were significant and caused a difference between volumes of distributions but not between clearances calculated for arterial and venous data, respectively. Clearance was smaller for R- than for S-ketamine. Subjective side-effects were mild but more pronounced for S- than for R-ketamine.

Study VI: R- and S-ketamine, together with midazolam (target concentration 10 ng mL-1), were administered to nine patients with longstanding, intractable postherpetic neuralgia using computer controlled infusions. The target levels for R-ketamine (60, 120 and 240 ng mL-1), were threefold higher than for S-ketamine. There were moderate analgesic effects of ketamine in the patients as a group. Spontaneous pain and pain evoked by a vibrating mechanical brush were significantly relieved, whereas pain evoked by light stroking with a brush was not. Some patients did not respond at all, some experienced complete relief In plasma-concentration ratios of 3:1 R- and S-ketamine were equianalgesic. At these equianalgesic concentrations S-ketamine caused more inebriation and drowsiness than R-ketamine.

Conclusion: There are potent analgesic effects of ketamine in clinical and experimental ischaemic pain. The effect in postherpetic neuralgia is variable, some patients receive complete pain relief, some no relief. Specific binding of S-ketamine in the brain, measured with positron emission tomography, is related to analgesia and psychotropic side effects. Ketamine antagonises the resting hypoventilation induced by alfentanil. Side-effects, mainly affecting memory imprinting, cognition and perception, are prominent at ketamine plasma-concentrations required for acute analgesia. Alfentanil and midazolam do not eliminate the side-effects.