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Letters to the Editor: Letters & Announcements

The Combination of Tramadol and Morphine May Be Recommended for Postoperative Analgesia

Benhamou, Dan, MD; Mazoit, Jean-Xavier, MD, PhD; Marcou, Aurore, MD

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In Response:

We agree with Webb and Leong that the last sentence of our abstract should have been more in line with what we found, i.e., that tramadol and morphine have an infra-additive interaction. However, within the limits of our study, i.e., the measurement of ED50 of morphine and tramadol alone and in combination immediately after moderately painful surgery, only a suboptimal morphine sparing effect was obtained because the combination was infra-additive. In another study recently published by our group, we found a similar result (1). Indeed, nefopam and morphine interact as an infra-additive combination although clinical studies have shown a benefit when using this combination in the clinical setting (2,3). A major difference exists, however, between these studies and the drugs that were combined with morphine; nefopam mechanism of action involves inhibition on serotonergic and norepinephrine descending pathways by inhibiting the synaptosomal uptake of dopamine, norepinephrine, and serotonin but is unlikely to involve an opioidergic component. By contrast, the mechanism by which tramadol analgesic produces analgesia clearly involves an opioid component and this probably explains why infra-additivity was observed.

These findings are interesting because they demonstrate that a morphine-sparing effect may uncover different interactions, some being more interesting (synergism) than others (i.e., infra-additivity). Although we cannot recommend firmly avoiding the use of tramadol in morphine-recipient patients (and vice versa) from our data, this combination is in our view likely suboptimal because it is illogical to combine two drugs that share a similar mechanism of action. There is no reason to believe that a tramadol-morphine combination should be a first-line choice in major surgical procedures as proposed by Webb and Leong, as other potent analgesic drugs such as nonsteroidal antiinflammatory drugs and paracetamol are available. They can be combined with either morphine or tramadol and have been found to produce both opioid sparing effect (4,5) and synergism (6).

Dan Benhamou, MD

Jean-Xavier Mazoit, MD, PhD

Aurore Marcou, MD

Department of Anesthesia and Intensive Care

Hôpital de Bicêtre

Bicêtre, France


1. Beloeil H, Delage N, Negre I, et al. The median effective dose of nefopam and morphine administered intravenously for postoperative pain after minor surgery: a prospective randomized double-blinded isobolographic study of their analgesic action. Anesth Analg 2004;98:395–400.
2. McLintock TT, Kenny GN, Howie JC, et al. Assessment of the analgesic efficacy of nefopam hydrochloride after upper abdominal surgery: a study using patient controlled analgesia. Br J Surg 1988;75:779–81.
3. Mimoz O, Incagnoli P, Josse C, et al. Analgesic efficacy and safety of nefopam vs. propacetamol following hepatic resection. Anaesthesia 2001;56:520–5.
4. Romsing J, Moiniche S, Dahl JB. Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia. Br J Anaesth 2002;88:215–26.
5. Tuncer S, Pirbudak L, Balat O, Capar M. Adding ketoprofen to intravenous patient-controlled analgesia with tramadol after major gynecological cancer surgery: a double-blinded, randomized, placebo-controlled clinical trial. Eur J Gynaecol Oncol 2003;24:181–4.
6. Zelcer S, Kolesnikov Y, Kovalyshyn I, et al. Selective potentiation of opioid analgesia by nonsteroidal anti-inflammatory drugs. Brain Res 2005;1040:151–6.
© 2005 International Anesthesia Research Society