Ondansetron Inhibits the Analgesic Effects of Tramadol: A Possible 5-HT3 Spinal Receptor Involvement in Acute Pain in Humans

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Ondansetron Inhibits the Analgesic Effects of Tramadol: A Possible 5-HT3 Spinal Receptor Involvement in Acute Pain in Humans
Arcioni, Roberto MD*,; della Rocca, Marco MD*,; Romanò, Sarah MD*,; Romano, Rocco MD†,; Pietropaoli, Paolo MD*, and; Gasparetto, Alessandro MD*

Anesthesia & Analgesia: June 2002


To investigate a possible antinociceptive role of serotonin receptor subtype 3 (5-HT3), we evaluated the effects of a coadministration of ondansetron, a 5-HT3 selective antagonist, and tramadol, a central analgesic dependent on enhanced serotonergic transmission. Fifty-nine patients undergoing ear, throat, and nose surgery, using tramadol for 24-h postoperative patient-controlled analgesia (bolus = 30 mg; lockout interval = 10 min) were randomly allocated either to a group receiving ondansetron continuous infusion (1 mg · mL−1 · h−1) for postoperative nausea and vomiting (Group O) or to a control group receiving saline (Group T). Pain and vomiting scores and tramadol consumption were evaluated at 4, 8, 12, and 24 h. Pain scores were never >4, according to a 0–10 numerical rating scale, in both groups. Group O required significantly larger doses of tramadol at 4 h (213 versus 71 mg, P < 0.001), 8 h (285 versus 128 mg, P < 0.002), and 12 h (406 versus 190 mg, P < 0.002).
Vomiting scores were higher in Group O at 4 h (P < 0.05) and 8 h (P = 0.05).
We conclude that ondansetron reduced the overall analgesic effect of tramadol, probably blocking spinal 5-HT3 receptors."

"Ondansetron is a potent and selective competitive antagonist at serotonin (5-hydroxytriptamine, 5-HT) subtype 3 (5-HT3) receptors, whereas tramadol, initially considered a pure opioid, subsequently proved to be a reuptake inhibitor and a release enhancer of norepinephrine and 5-HT (3–5).
Hence, we hypothesized that this drug combination could induce mutually contrasting modifications on the 5-HT3 receptor-mediated serotonergic transmission, and particularly that ondansetron-induced receptor antagonism could enhance or weaken tramadol-induced analgesia. In fact, animal testing suggests both a pro- and an antinociceptive role for 5-HT3 neural receptors, depending on their peripheral or central expression. Given tramadol’s central action, we wanted to verify whether postoperatively administered ondansetron would increase tramadol demand during patient-controlled analgesia (PCA)."