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REGIONAL ANESTHESIA AND PAIN MEDICINE

The Analgesic Efficacy of Tramadol is Impaired by Concurrent Administration of Ondansetron

Jan L. De Witte, MD^*, Bart Schoenmaekers, MD^*, Daniel I. Sessler, MD, and Thierry Deloof, MD^*

*Department of Anesthesia and Intensive Care, OLV-Hospital, Aalst, Belgium; and the Outcomes Research^TM Institute, and Department of Anesthesiology, University of Louisville, Louisville, Kentucky

Address correspondence to Jan De Witte, MD, Department of Anesthesia and Intensive Care, OLV-Hospital, Aalst, Belgium. Addess e-mail to jan.de.witte{at}olvz-aalst.be

	Introduction

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Tramadol has weak opioid properties, and an analgesic effect that is mediated mainly by inhibition of the reuptake of norepinephrine and serotonin (5-hydroxytryptamine [5-HT]) and facilitation of 5-HT release (1,2) at the spinal cord.

Because 5-HT₃ receptors play a key role in pain transmission at the spinal level (3), the 5-HT₃ antagonist ondansetron may decrease the efficacy of tramadol, as suggested in an abstract by Maroof et al.¹

In that study, a small dose of 1 mg/kg tramadol was administered along with ondansetron 0.1 mg/kg or placebo, 15 min before the induction of anesthesia. Early postoperative pain scores differed significantly between the treatment groups. We therefore tested the hypothesis that the tramadol requirement by patient-controlled analgesia (PCA) may be increased when ondansetron is administered for antiemetic prophylaxis.

	Methods

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With ethics committee approval, written, informed consent was obtained from 40 adult patients undergoing lumbar laminectomy. Criteria for exclusion were a history of alcohol or drug abuse or seizures, age more than 70 yr, and intake of monoamine oxidase inhibitors. Patients were randomly assigned to receive 4 mg of ondansetron (Zofran®; Glaxo Wellcome, Parma, Italy) or saline 0.9%. Both solutions were given 1 min before the induction of anesthesia. Patients and investigators were blinded to the study drug.

At induction of anesthesia, remifentanil 1 µg/kg was injected, followed by an infusion of 0.25 µg/kg/min until skin closure. A Diprifusor^TM (AstraZeneca, Södertälje, Sweden) pharmacokinetic model (Fresenius Vial S. A., Brézius, France) was used for propofol infusion to a target plasma concentration of 4 µg/mL for intubation, which was adjusted thereafter to between 2 and 4 µg/mL. Atracurium was administered to facilitate endotracheal intubation. Tramadol, 2 mg/kg for 10 min, was given at discontinuation of remifentanil. A PCA pump (Pain Management Provider; Abbott Laboratories, North Chicago, IL) was programmed as follows: tramadol, 24 mg IV bolus; lockout time, 5 min; 4-h dose limit, 384 mg. The PCA system automatically recorded the doses.

Patients who required supplemental medication for analgesia could receive a single 100-mg tramadol top-up dose, or 5 mg piritramid, a synthetic opioid (Dipidolor®; Janssen Pharmaceutica, Beerse, Belgium). Simultaneous use of the PCA pump was always permitted. Nausea or vomiting was treated with alizapride 50–100 mg IV. Patients in both study groups were given 2 g IV propacetamol (Prodafalgan®; Upsamedica s.a., Brussels, Belgium) at 6-h intervals after discharge from the recovery unit. Other analgesic or sedative drugs than those mentioned above, were prohibited.

Patients were observed for 4 h in the recovery unit by study nurses. Pain was evaluated at rest with a 100-mm long visual analog scale, where 0 mm represented no pain and 100 mm represented the worst imaginable pain. The degree of sedation was rated on a 4-point scale, and the presence of postoperative nausea and vomiting (PONV) was registered. A verbal retrospective pain score (4) was obtained 24 h after discharge from the recovery unit by using a 5-point scale. Overall satisfaction with pain relief was recorded.

Differences between the two groups were compared by using two-tailed unpaired t tests, ² analysis, and Mann-Whitney ranked sum tests. The cumulative incidence of PONV was compared by using the log rank test. All results were presented as means ± SD; P < 0.05 was considered statistically significant.

	Results

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The patient groups were comparable with respect to age, weight, height, ASA physical status, and duration of surgery ( Table 1).

View larger version (21K): [in this window] [in a new window]   Figure 1. Cumulative tramadol consumption was larger in the Ondansetron than Control group during the first 24 h postoperatively. Tramadol consumption on an hourly basis did not differ significantly between the groups except during the first postoperative hour: 155 ± 83 mg in the Ondansetron group versus 86 ± 54 mg in the Control group. (*P = 0.003).

	Discussion

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Our results suggest that tramadol will usually be effective when given at a rate near 24 mg/h (i.e., the bolus dose of our PCA system given hourly). The recommended maximum 24-hour dose of 400 mg of tramadol thus seems insufficiently large for treatment of severe acute postoperative pain.

Tramadol administration is associated with a disturbingly frequent incidence of PONV, which often leads to discontinuation of PCA (7). In a recent study, ondansetron failed to reduce the nausea associated with tramadol (8). Our results indicate that ondansetron 4 mg administered at the induction of anesthesia does not reduce the incidence of this complication in the recovery unit and later on. As an alternative for ondansetron, the administration of droperidol (an antiemetic with antidopaminergic activity) might be recommended. Droperidol suppresses PONV effectively in patients who receive tramadol PCA (9).

In conclusion, ondansetron decreases the analgesic effectiveness of tramadol. A single 4-mg dose of ondansetron given at the induction of anesthesia does not reduce the 24-h incidence of PONV.

	Acknowledgments

 
Tramadol (Contramal®) was kindly provided by Searle Continental Pharma (Brussels, Belgium). The authors also thank GlaxoWellcome (Brussels, Belgium) for providing ondansetron (Zofran®).

	Footnotes

 
¹Maroof M, Moied AS, Bano S, Khan RM. Ondansetron inhibits the analgesic effect of tramadol hydrochloride [abstract]. Anesth Analg 1996;82:S296.

	References

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1. Driessen B, Reimann W. Interaction of the central analgesic tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. Br J Pharmacol 1992; 105: 147–51.[ISI][Medline]
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3. Alhaider AA, Lei SZ, Wilcox GL. Spinal 5-HT3-mediated antinociception: possible release of GABA. J Neurosci 1991; 11: 1881–8.[Abstract]
4. Lehmann KA, Kratzenberg U, Schroeder-Bark B, Horrichs-Haermeyer G. Postoperative patient-controlled analgesia with tramadol: analgesic efficacy and minimum effective concentrations. Clin J Pain 1990; 6: 212–20.[ISI][Medline]
5. Jellinek H, Haumer H, Grusshofer G, et al. Tramadol zur postoperativen schmerztherapie: patientenkontrollierte analgesie. Anaesthesist 1990; 39: 513–20.[ISI][Medline]
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7. Silvasti M, Svartling N, Pitkänen M, Rosenberg PH. Comparison of intravenous patient-controlled analgesia with tramadol versus morphine after microvascular breast reconstruction. Eur J Anaesthesiol 2000; 17: 448–55.[ISI][Medline]
8. Broome IJ, Robb HM, Raj N, et al. The use of tramadol following day-case oral surgery. Anaesthesia 1999; 54: 266–96.[ISI][Medline]
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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (37) Citing Articles via Google Scholar Google Scholar Articles by De Witte, J. L. Articles by Deloof, T. Search for Related Content PubMed PubMed Citation Articles by De Witte, J. L. Articles by Deloof, T. Related Collections Pain Pharmacology

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999