Modulation of Paracetamol and Nefopam Antinociception by Serotonin 5-HT₃ Receptor Antagonists in Mice

Abstract

Background/Aims: Post-operative nausea and vomiting are common adverse events that require administration of anti-emetic compounds, such as the serotonin 5-HT₃ receptor antagonists, but these drugs can also reduce the analgesic efficacy of some analgesics (paracetamol, tramadol). Methods: The present study was designed to explore the effect of 3 serotonin 5-HT₃ receptor antagonists on the antinociceptive efficacy of another frequently used post-operative analgesic, nefopam, in the mouse writhing and formalin tests. Results: Pre-treatment with tropisetron, ondansetron or MDL72222 did not significantly modify nefopam antinociception in both tests. However, paracetamol antinociception was blocked by ondansetron in the formalin test. Conclusion: These results provide a rationale for the clinical use of nefopam with anti-emetics during surgery.

Efficacy of intravenous paracetamol compared to dipyrone and parecoxib for postoperative pain management after minor-to-intermediate surgery: a randomised, double-blind trial

“…8 Hence, it has become a mainstay of many multimodal postoperative analgesia regimen, 22 but the analgesic efficacy is still debated, [9][10][11][12] especially as its pharmacokinetic is affected by other drugs used in the perioperative setting. 13 Although they may have a more pronounced risk profile, other intravenous non-opioids like dipyrone or parecoxib are frequently preferred. Indeed, dipyrone is not licensed in many countries due to potential risk of serious blood dyscrasias.…”

“…When emesis required additional treatment by 5-HT(3)-receptor antagonists, which affect the action of paracetamol, these patients were excluded from the pain analysis. 13 The PCA devices and the use of VASs were explained to patients preoperatively. If a patient experienced insufficient pain relief (surgical VAS >40), rescue analgesia was provided as additional boluses of intravenous piritramide 2 mg until pain relief was satisfactory (VAS <40).…”

“…[9][10][11][12] This apparent difference might be explained, at least in part, by pharmacokinetic interactions with comedication such as 5-HT(3)-receptor antagonists that are frequently given for prophylaxis of postoperative nausea and vomiting (PONV) and might reduce its analgesic effect. 13 Although a tailored individual pain concept might be desirable, daily clinical practice requires the implementation of a straightforward standard protocol that is safe and effective, and here there is room for improvement. 14 Most protocols employ non-opioids as the basis of their multimodal perioperative pain plan, supplemented, if necessary, by opioids and regional anaesthesia.…”

The Effect of Paracetamol and Tropisetron on Pain: Experimental Studies and a Review of Published Data

“…It was, therefore, suggested that the antagonistic effect of tropisetron was mediated through a specific tropisetron-sensitive receptor [15]. In a recent study with mice, however, a high subcutaneous dose of ondansetron did attenuate the antinociceptive action of paracetamol, [16] but another study could not replicate this result [17].…”

Paracetamol: Update on its Analgesic Mechanism of Action

“…However, investigations of the involvement of 5-HT 3 receptors yielded conflicting results in both animals [36,42,43,47,49,50] and humans [51][52][53][54]. Interestingly, some of these studies showed that tropisetron, a nonspecific 5-HT 3 receptor antagonist, blocked the analgesic effect of paracetamol.…”