To the Editor:—

We read with much interest the article of Sveticic et al , 1who designed a study to optimize combinations of morphine and ketamine, and a lockout interval for patient-controlled analgesia, using a direct search model. Opioids may activate N -methyl-d-aspartate pain facilitatory processes, leading to hyperalgesia and enhanced postoperative pain. 2Concomitant administration of the N -methyl-d-aspartate antagonist ketamine may therefore allow reduction in the dose of morphine. The optimization procedure converged to a morphine-to-ketamine ratio of 1:1 and a lockout interval of 8 min, allowing a reduction in mean pain scores with a low incidence of side effects.

Ketamine plasma concentration of 60 ng/ml is the smallest concentration known to counteract hyperalgesia while producing minimal side effects. 3However, when ketamine is combined with morphine for patient-controlled analgesia, the dose of ketamine administered depends on the dose of morphine required. Interindividual variability in drug requirement to achieve satisfactory analgesia is well known, and there is no evidence that the dose of ketamine required to achieve optimal plasma concentration is linked to similar interindividual variability. Whether the optimal plasma concentration of ketamine has been achieved is therefore unknown.

Given that an initial bolus dose of ketamine 0.5 mg/kg followed by a continuous infusion of 2 μg/kg per min achieves a plasma concentration close to 60 ng/ml without side effects, 4,5we believe that concomitant continuous infusion of low-dose ketamine with patient-controlled analgesia morphine is the optimal technique for an opioid-sparing effect. Dosage of ketamine plasma concentration would have been of great interest in the study of Sveticic et al.  Further study would be valuable in this field.

Sveticic G, Gentilini A, Eichenberger U, Luginbühl M, Curatolo M: Combinations of morphine with ketamine for patient-controlled analgesia: A new optimization method. A nesthesiology 2003; 98: 1195–205
Celerier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, Simonnet G: Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine. A nesthesiology 2000; 92: 465–72
Leung A, Wallace M, Ridgeway, Yaksh T: Concentration-effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory threshold, allodynia and hyperalgesia of neuropathic pain. Pain 2001; 91: 177–87
Schmid R, Sandler A, Katz J: Use and efficacy of low-dose ketamine in the management of acute postoperative pain: A review of current techniques and outcomes. Pain 1999; 82: 111–25
Stubhaug A, Breivik H, Eide PK, Kreunen, Foss A: Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand 1997; 41: 1124–32