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

Van Elstraete, A. C.; Lebrun, T.

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European Journal of Anaesthesiology: March 2004 - Volume 21 - Issue 3 - p 237


We read with great interest the article of Ünlügenç and colleagues about the effect of adding magnesium or ketamine to intravenous (i.v.) patient-controlled morphine for postoperative pain management [1]. The patients were first given a loading dose of the mixture and were then allowed to use bolus doses of the same mixture via a patient-controlled analgesia (PCA) device. Addition of magnesium or ketamine to morphine for i.v. PCA led to a significantly lower consumption of morphine after 12 and 24 h. The authors concluded that these differences were unlikely to be of any clinical relevance. We would like to make some comments about ketamine administration.

First, given the intermittent bolus dose of ketamine allowed in the study and the lockout interval of 20 min, the maximum dose that might therefore be administered to the patient is 1.56 μg kg−1 min−1. Ketamine plasma concentration of 60 ng mL−1 is the smallest concentration known to counteract hyperalgesia while producing minimal side-effects [2]. An initial bolus dose of ketamine 0.5 mg kg−1 followed by a continuous infusion of 2 μg kg−1 min−1 allows a plasma concentration of close to 60 ng mL−1 to be achieved without side-effects [3,4]. On the other hand, the initial loading dose of ketamine given in the study is 0.125 mg kg−1. We can therefore wonder whether effective plasma concentration of ketamine is likely to be achieved whatever the bolus doses of the mixture given to the patient?

Second, the concept of administering bolus doses of ketamine based on i.v. patient-controlled morphine is questionable. When ketamine is combined with morphine for PCA, 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 inter-individual variability.

Third, Stubhaug and colleagues [4] conducted a study where a loading dose of i.v. ketamine 0.5 mg kg−1 followed by a continuous infusion of 2 μg kg−1 min−1 was given to kidney donors. PCA morphine consumption was significantly reduced only during the first hours after surgery. However, central sensitization leading to 'wind-up pain' was significantly reduced 1, 3 and 7 days after the operation. Therefore, we think that perioperative low-dose i.v. infusion of ketamine can be of clinical interest.

Finally, we believe that concomitant continuous infusion of low-dose i.v. ketamine with PCA morphine is the optimal technique allowing opioid-sparing effect and reduced central sensitization.

A. C. Van Elstraete

T. Lebrun

Clinique Saint Paul; Martinique, French West Indies


1. Ünlügenç H, Özalevli M, Güler T, Işik G. Postoperative pain management with intravenous patient-controlled morphine: comparison of the effect of adding magnesium or ketamine. Eur J Anaesthesiol 2003; 20: 416-421.
2. Leung A, Wallace M, Ridgeway B, Yaksh T. Concentration-effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory threshold, allodynia and hyperalgesia of neuropathic pain. Pain 2001; 91: 177-187.
3. 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: 111-125.
4. Stubhaug A, Breivik H, Eide PK, Kreunen M, 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 Anaesth Scand 1997; 41: 1124-1132.
© 2004 European Society of Anaesthesiology