CNS Drugs

, Volume 21, Issue 10, pp 813–833 | Cite as

Mechanisms Underlying Postoperative Nausea and Vomiting and Neurotransmitter Receptor Antagonist-Based Pharmacotherapy

  • Tong J. GanEmail author
Review Article


Postoperative nausea and vomiting (PONV) is one of the most common and distressing complications following surgery, and understanding the mechanism(s) underlying PONV is essential to providing optimal prophylaxis and/or treatment of PONV. The knowledge base of PONV physiology has significantly expanded over the past decade.

This article reviews the risk factors for the development of PONV and the mechanisms of action of pharmacological agents (including antagonists of serotonin 5-HT3, dopaminergic D2, histamine H1, muscarinic cholinergic, opioid and neurokinin NK1 receptors) for the management (i.e. prophylaxis and treatment) of PONV. NK1 receptor antagonists, with their unique mechanism of action, are a particularly promising area of research as they appear to be efficacious in preventing PONV during both the early and the late postoperative periods. A successful PONV management strategy includes: (i) identifying patients at risk; (ii) keeping the baseline risk low; and (iii) using a combination of antiemetics acting on different receptors in moderate- to high-risk patients.


Ondansetron Granisetron Droperidol Aprepitant Motion Sickness 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The preparation of this review was supported in part by the Department of Anesthesiology, Duke University Medical Center, and Roche, Inc. Dr Gan has received honoraria from Merck, Roche, Pfizer, Organon, GlaxoSmithKline, Baxter, MGI Pharma and Edwards Life Science. Grants for research support have been received from Pfizer, GlaxoSmithKline, Baxter, Merck, MGI Pharma and Roche.

The author appreciates the assistance of Nelson Erlick, DPM, MS, for his editorial assistance.


  1. 1.
    Visser K, Hassink EA, Bonsel GJ, et al. Randomized controlled trial of total intravenous anesthesia with propofol versus inhalation anesthesia with isoflurane-nitrous oxide: postoperative nausea with vomiting and economic analysis. Anesthesiology 2001; 95(3): 616–26PubMedCrossRefGoogle Scholar
  2. 2.
    Apfel CC, Laara E, Koivuranta M, et al. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology 1999; 91(3): 693–700PubMedCrossRefGoogle Scholar
  3. 3.
    Watcha MF, White PF. Postoperative nausea and vomiting: its etiology, treatment, and prevention. Anesthesiology 1992; 77(1): 162–84PubMedCrossRefGoogle Scholar
  4. 4.
    Hill RP, Lubarsky DA, Phillips-Bute B, et al. Cost-effectiveness of prophylactic antiemetic therapy with ondansetron, droperidol, or placebo. Anesthesiology 2000; 92(4): 958–67PubMedCrossRefGoogle Scholar
  5. 5.
    Schumann R, Polaner DM. Massive subcutaneous emphysema and sudden airway compromise after postoperative vomiting. Anesth Analg 1999; 89(3): 796–7PubMedGoogle Scholar
  6. 6.
    Toprak V, Keles GT, Kaygisiz Z, et al. Subcutaneous emphysema following severe vomiting after emerging from general anesthesia. Acta Anaesthesiol Scand 2004; 48(7): 917–8PubMedCrossRefGoogle Scholar
  7. 7.
    Zhang GS, Mathura JR. Images in clinical medicine: painless loss of vision after vomiting. N Engl J Med 2005; 352(17): E16PubMedCrossRefGoogle Scholar
  8. 8.
    Macario A, Weinger M, Truong P, et al. Which clinical anesthesia outcomes are both common and important to avoid? The perspective of a panel of expert anesthesiologists. Anesth nalg 1999; 88(5): 1085–91Google Scholar
  9. 9.
    Macario A, Weinger M, Carney S, et al. Which clinical anesthesia outcomes are important to avoid? The perspective of patients. Anesth Analg 1999; 89(3): 652–8PubMedGoogle Scholar
  10. 10.
    Gan T, Sloan F, Dear GL, et al. How much are patients willing to pay to avoid postoperative nausea and vomiting? Anesth Analg 2001; 92(2): 393–400PubMedCrossRefGoogle Scholar
  11. 11.
    Apfel CC, Roewer N, Korttila K. How to study postoperative nausea and vomiting. Acta Anaesthesiol Scand 2002; 46(8): 921–8PubMedCrossRefGoogle Scholar
  12. 12.
    Habib AS, Gan TJ. Pharmacotherapy of postoperative nausea and vomiting. Expert Opin Pharmacother 2003; 4(4): 457–73PubMedCrossRefGoogle Scholar
  13. 13.
    Habib AS, Gan TJ. Evidence-based management of postoperative nausea and vomiting: a review. Can J Anaesth 2004; 51(4): 326–41PubMedCrossRefGoogle Scholar
  14. 14.
    Gan TJ, Meyer T, Apfel CC, et al. Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 2003; 97(1): 62–71PubMedCrossRefGoogle Scholar
  15. 15.
    Biedler A, Wermelt J, Kunitz O, et al. A risk adapted approach reduces the overall institutional incidence of postoperative nausea and vomiting. Can J Anaesth 2004; 51(1): 13–9PubMedCrossRefGoogle Scholar
  16. 16.
    Apfel CC, Kranke P, Eberhart LH. Comparison of surgical site and patient’s history with a simplified risk score for the prediction of postoperative nausea and vomiting. Anaesthesia 2004; 59(11): 1078–82PubMedCrossRefGoogle Scholar
  17. 17.
    Pierre S, Corno G, Benais H, et al. A risk score-dependent antiemetic approach effectively reduces postoperative nausea and vomiting: a continuous quality improvement initiative. Can J Anaesth 2004; 51(4): 320–5PubMedCrossRefGoogle Scholar
  18. 18.
    Rusch D, Eberhart L, Biedler A, et al. Prospective application of a simplified risk score to prevent postoperative nausea and vomiting. Can J Anaesth 2005; 52(5): 478–84PubMedCrossRefGoogle Scholar
  19. 19.
    Eberhart LH, Morin AM, Guber D, et al. Applicability of risk scores for postoperative nausea and vomiting in adults to paediatric patients. Br J Anaesth 2004; 93(3): 386–92PubMedCrossRefGoogle Scholar
  20. 20.
    Hornby PJ. Central neurocircuitry associated with emesis. Am J Med 2001; 111Suppl. 8A: 106–2SCrossRefGoogle Scholar
  21. 21.
    Miller AD. Central mechanisms of vomiting. Dig Dis Sci 1999; 44(8 Suppl.): 39–43SGoogle Scholar
  22. 22.
    Andrews PL, Naylor RJ, Joss RA. Neuropharmacology of emesis and its relevance to anti-emetic therapy: consensus and controversies. Support Care Cancer 1998; 6(3): 197–203PubMedCrossRefGoogle Scholar
  23. 23.
    Miller AD, Nonaka S, Jakus J. Brain areas essential or non-essential for emesis. Brain Res 1994; 647(2): 255–64PubMedCrossRefGoogle Scholar
  24. 24.
    Saito R, Takano Y, Kamiya HO. Roles of substance P and NK(1) receptor in the brainstem in the development of emesis. J Pharmacol Sci 2003; 91(2): 87–94PubMedCrossRefGoogle Scholar
  25. 25.
    Kojima Y, Takahashi T, Fujina M, et al. Inhibition of cholinergic transmission by opiates in ileal myenteric plexus is mediated by kappa receptor: involvement of regulatory inhibitory G protein and calcium N-channels. J Pharmacol Exp Ther 1994; 268(2): 965–70PubMedGoogle Scholar
  26. 26.
    Tsuchida D, Fukuda H, Koda K, et al. Central effect of muopioid agonists on antral motility in conscious rats. Brain Res 2004; 1024(1–2): 244–50PubMedCrossRefGoogle Scholar
  27. 27.
    Janicki PK. Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Med Sci Monit 2005; 11(10): RA322–328PubMedGoogle Scholar
  28. 28.
    Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology 2005; 102(3): 543–9PubMedCrossRefGoogle Scholar
  29. 29.
    Arcioni R, Della RM, Romano S, et al. Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT(3) spinal receptor involvement in acute pain in humans. Anesth Analg 2002; 94(6): 1553–7PubMedGoogle Scholar
  30. 30.
    Hammonds B, Sidebotham DA, Anderson BJ. Aspects of tramadol and ondansetron interactions. Acute Pain 2003; 5: 31–4CrossRefGoogle Scholar
  31. 31.
    Scuderi PE. Pharmacology of antiemetics. Int Anesthesiol Clin 2003; 41(4): 41–66PubMedCrossRefGoogle Scholar
  32. 32.
    Diemunsch P, Schoeffler P, Bryssine B, et al. Antiemetic activity of the NK1 receptor antagonist GR205171 in the treatment of established postoperative nausea and vomiting after major gynaecological surgery. Br J Anaesth 1999; 82(2): 274–6PubMedCrossRefGoogle Scholar
  33. 33.
    Gesztesi Z, Scuderi PE, White PF, et al. Substance P (neurokinin-1) antagonist prevents postoperative vomiting after abdominal hysterectomy procedures. Anesthesiology 2000; 93(4): 931–7PubMedCrossRefGoogle Scholar
  34. 34.
    Gan TJ, Apfel CC, Kovac A, et al. A randomized, double-blind comparison of the NK1 antagonist, aprepitant versus ondansetron for the prevention of postoperative nausea and vomiting. Anesth Analg 2007; 104(5): 1082–9PubMedCrossRefGoogle Scholar
  35. 35.
    Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004; 350(24): 2441–51PubMedCrossRefGoogle Scholar
  36. 36.
    Kranke P, Morin AM, Roewer N, et al. The efficacy and safety of transdermal scopolamine for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg 2002; 95(1): 133–43PubMedCrossRefGoogle Scholar
  37. 37.
    Kranke P, Morin AM, Roewer N, et al. Dimenhydrinate for prophylaxis of postoperative nausea and vomiting: a meta-analysis of randomized controlled trials. Acta Anaesthesiol Scand 2002; 46(3): 238–44PubMedCrossRefGoogle Scholar
  38. 38.
    Henzi I, Walder B, Tramer MR. Metoclopramide in the prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized, placebo-controlled studies. Br J Anaesth 1999; 83(5): 761–71PubMedCrossRefGoogle Scholar
  39. 39.
    Domino KB, Anderson EA, Polissar NL, et al. Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: a meta-analysis. Anesth Analg 1999; 88(6): 1370–9PubMedGoogle Scholar
  40. 40.
    Hirayama T, Ishii F, Yago K, et al. Evaluation of the effective drugs for the prevention of nausea and vomiting induced by morphine used for postoperative pain: a quantitative systematic review. Yakugaku Zasshi 2001; 121(2): 179–85PubMedCrossRefGoogle Scholar
  41. 41.
    Tramer MR, Moore RA, Reynolds DJ, et al. A quantitative systematic review of ondansetron in treatment of established postoperative nausea and vomiting. BMJ 1997; 314(7087): 1088–92PubMedCrossRefGoogle Scholar
  42. 42.
    Figueredo ED, Canosa LG. Ondansetron in the prophylaxis of postoperative vomiting: a meta-analysis. J Clin Anesth 1998; 10(3): 211–21PubMedCrossRefGoogle Scholar
  43. 43.
    Figueredo E, Canosa L. Prophylactic ondansetron for postoperative emesis: meta-analysis of its effectiveness in patients with previous history of postoperative nausea and vomiting. Acta Anaesthesiol Scand 1999; 43(6): 637–44PubMedCrossRefGoogle Scholar
  44. 44.
    Philip BK, McLeskey CH, Chelly JE, et al. Pooled analysis of three large clinical trials to determine the optimal dose of dolasetron mesylate needed to prevent postoperative nausea and vomiting. The Dolasetron Prophylaxis Study Group. J Clin Anesth 2000; 12(1): 1–8Google Scholar
  45. 45.
    Eberhart LH, Morin AM, Bothner U, et al. Droperidol and 5-HT3-receptor antagonists, alone or in combination, for prophylaxis of postoperative nausea and vomiting: a meta-analysis of randomised controlled trials. Acta Anaesthesiol Scand 2000; 44(10): 1252–7PubMedCrossRefGoogle Scholar
  46. 46.
    Habib AS, El Moalem HE, Gan TJ. The efficacy of the 5-HT3 receptor antagonists combined with droperidol for PONV prophylaxis is similar to their combination with dexamethasone: a meta-analysis of randomized controlled trials. Can J Anaesth 2004; 51(4): 311–9PubMedCrossRefGoogle Scholar
  47. 47.
    Leslie JB, Gan TJ. Meta-analysis of the safety of 5-HT3 antagonists with dexamethasone or droperidol for prevention of PONV. Ann Pharmacother 2006; 40(5): 856–72PubMedCrossRefGoogle Scholar
  48. 48.
    Kovac AL. Meta-analysis of the use of rescue antiemetics following PONV prophylactic failure with 5HT3 antagonist/ dexamethasone versus single-agent therapies. Ann Pharmacother 2006; 40(5): 873–87PubMedCrossRefGoogle Scholar
  49. 49.
    Buttner M, Walder B, von Elm E, et al. Is low-dose haloperidol a useful antiemetic? A meta-analysis of published and unpublished randomized trials. Anesthesiology 2004; 101(6): 1454–63PubMedCrossRefGoogle Scholar
  50. 50.
    Henzi I, Walder B, Tramer MR. Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg 2000; 90(1): 186–94PubMedCrossRefGoogle Scholar
  51. 51.
    Tramer MR, Walder B. Efficacy and adverse effects of prophylactic antiemetics during patient-controlled analgesia therapy: a quantitative systematic review. Anesth Analg 1999; 88(6): 1354–61PubMedGoogle Scholar
  52. 52.
    Habib AS, Gan TJ. Food and drug administration black box warning on the perioperative use of droperidol: a review of the cases. Anesth Analg 2003; 96(5): 1377–9PubMedCrossRefGoogle Scholar
  53. 53.
    Gold BS, Kitz DS, Lecky JH, et al. Unanticipated admission to the hospital following ambulatory surgery. JAMA 1989; 262(21): 3008–10PubMedCrossRefGoogle Scholar
  54. 54.
    White PF, Song D, Abrao J, et al. Effect of low-dose droperidol on the QT interval during and after general anesthesia: a placebo-controlled study. Anesthesiology 2005; 102(6): 1101–5PubMedCrossRefGoogle Scholar
  55. 55.
    Charbit B, Albaladejo P, Funck-Brentano C, et al. Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron. Anesthesiology 2005; 102(6): 1094–100PubMedCrossRefGoogle Scholar
  56. 56.
    Scuderi PE. You (still) can’t disprove the existence of dragons. Anesthesiology 2005; 102(6): 1081–2PubMedCrossRefGoogle Scholar
  57. 57.
    Notification of the Health Products and Food Branch (HPFB) from Health Canada, June 30, 2006 [online]. Available from URL: [Accessed 2007 Jan 3]
  58. 58.
    Gan TJ, Ginsberg B, Glass PS, et al. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology 1997; 87(5): 1075–81PubMedCrossRefGoogle Scholar
  59. 59.
    Maxwell LG, Kaufmann SC, Bitzer S, et al. The effects of a small-dose naloxone infusion on opioid-induced side effects and analgesia in children and adolescents treated with intravenous patient-controlled analgesia: a double-blind, prospective, randomized, controlled study. Anesth Analg 2005; 100(4): 953–8PubMedCrossRefGoogle Scholar
  60. 60.
    Joshi GP, Duffy L, Chehade J, et al. Effects of prophylactic nalmefene on the incidence of morphine-related side effects in patients receiving intravenous patient-controlled analgesia. Anesthesiology 1999; 90(4): 1007–11PubMedCrossRefGoogle Scholar
  61. 61.
    Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med 2001; 345(13): 935–40PubMedCrossRefGoogle Scholar
  62. 62.
    Golden GA, Mason PE, Rubin RT, et al. Biophysical membrane interactions of steroid hormones: a potential complementary mechanism of steroid action. Clin Neuropharmacol 1998; 21(3): 181–9PubMedGoogle Scholar
  63. 63.
    Floman Y, Zor U. Mechanism of steroid action in inflammation: inhibition of prostaglandin synthesis and release. Prostaglandins 1976; 12(3): 403–13PubMedCrossRefGoogle Scholar
  64. 64.
    Fujii Y, Tanaka H, Toyooka H. The effects of dexamethasone on antiemetics in female patients undergoing gynecologic surgery. Anesth Analg 1997; 85(4): 913–7PubMedGoogle Scholar
  65. 65.
    Liu K, Hsu CC, Chia YY. Effect of dexamethasone on postoperative emesis and pain. Br J Anaesth 1998; 80(1): 85–6PubMedCrossRefGoogle Scholar
  66. 66.
    Liu K, Hsu CC, Chia YY. The effect of dose of dexamethasone for antiemesis after major gynecological surgery. Anesth Analg 1999; 89(5): 1316–8PubMedCrossRefGoogle Scholar
  67. 67.
    Wang JJ, Ho ST, Lee SC, et al. The use of dexamethasone for preventing postoperative nausea and vomiting in females undergoing thyroidectomy: a dose-ranging study. Anesth Analg 2000; 91(6): 1404–7PubMedCrossRefGoogle Scholar
  68. 68.
    Wang JJ, Ho ST, Tzeng JI, et al. The effect of timing of dexamethasone administration on its efficacy as a prophylactic antiemetic for postoperative nausea and vomiting. Anesth Analg 2000; 91(1): 136–9PubMedGoogle Scholar
  69. 69.
    Tramer MR. Rational control of PONV: the rule of three. Can J Anaesth 2004; 51(4): 283–5PubMedCrossRefGoogle Scholar
  70. 70.
    Andrews PL, Richards CA, Smith JE. The neurophysiology of emesis: lessons from basic science for understanding paediatric problems. J Pediatr Gastroenterol Nutr 2001; 32Suppl. 1: S12–13PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Department of AnesthesiologyDuke University Medical CenterDurhamUSA

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