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Ketamine added to intravenous patient-controlled morphine: ketamine plasma concentration is unreliable

Ünlügenç, H.; Özalevli, M.; Güler, T.; Işik, G.

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European Journal of Anaesthesiology: March 2004 - Volume 21 - Issue 3 - p 238-239

A reply


We were delighted by Van Elstraete and Lebrun's interest in our study about the management of postoperative pain with intravenous (i.v.) patient-controlled morphine and the effects of adding magnesium or ketamine [1]. They also studied the effects of ketamine added to i.v. morphine, administered using a patient-controlled device. Although some clinical reports have supported the beneficial effect of the addition of ketamine to patient-controlled analgesia (PCA) morphine [2,3], others have failed to show any useful effect [4,5].

The reason for concern between ourselves and Van Elstraete and Lebrun might be related to the prevailing conditions. These include the timing of adjuvant administrations, optimal dosage of analgesic used, and the nature and source of pain from different types of surgery. Some aspects of the use of ketamine are controversial: some workers advocate peroperative ketamine to prevent a central sensitization [6]; others consider that an activated open state of N-methyl-D-aspartate (NMDA) receptors is required for an optimal effect of ketamine [7]. In our study, ketamine was given to patients when the verbal rating score (VRS) score was ≥2.

Optimal dosage is another controversial area. Due to the differing patient opioid requirements, the amount of adjuvant delivered could range enormously. Therefore, the dose of opioid used for pain management is a crucial factor in providing effective analgesia.

The analgesic effect of ketamine given as a continuous infusion has been observed at plasma concentrations of 100-150 ng mL−1[3]. When ketamine is combined with morphine for PCA, the dose of ketamine can be reduced to achieve satisfactory analgesia. However, there is no reliable method of determining how much ketamine a patient will require as an adjunct to PCA morphine, far less how much will result in untoward side-effects. In our study, although we did not measure the plasma concentrations of ketamine, the average dose of ketamine administered was 9 mg h−1 (1.25-2.5 μg kg−1 min−1) and this dose was consistent with previous studies [4,5].

When ketamine is combined with morphine for PCA, the optimal combination of these two drugs and the optimal lockout time is not known. When the two drugs are combined at different concentrations in the PCA solution and different lockout times are investigated, many combinations of PCA regimens are possible. In our study, cumulative morphine consumption after 24 h was 4% less in the morphine + ketamine group compared to the morphine alone group. As the morphine sparing effect of adjuvants (such as ketamine) is most pronounced in the immediate postoperative period, their potential antinociceptive effect might be related with this effect. Although significant, we were clearly unable to correlate clinical outcome with the morphine sparing effect of ketamine. Furthermore, it may not be possible to demonstrate any additive effect of ketamine in a clinical setting, as painful stimuli are not confined to the immediate postoperative period, but extend from hours to days after surgery. Therefore, spinal cord wind-up or central sensitization may occur at any time when analgesia is incomplete. Finally, if effective analgesia is achieved by opioids alone for post-operative pain management, spinal cord wind-up or central sensitization may not be seen or demonstrated in a clinical setting.

H. Ünlügenç

M. Özalevli

T. Güler

G. Işik

Department of Anaesthesiology; Faculty of Medicine; Çukurova University; Adana, Turkey


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© 2004 European Society of Anaesthesiology