The last decade has seen considerable advances in the management and prevention of complications occurring after anaesthesia and surgery, especially of acute pain. Can the same be said for postoperative nausea and vomiting (PONV)? There is no doubt that a vast amount of research has been published in this area and new classes of antiemetics have been introduced. However, although data are not available to compare precisely the present incidence of PONV with that 1015 yr ago, there is a general impression that there has been little progress.1
The 1990s was the decade of the 5-HT3 receptor antagonist. Their effectiveness in the prevention of chemotherapy-induced nausea and vomiting was very impressive2 and this begot great expectations with respect to potential efficacy for PONV. Ondansetron, and to a lesser extent other 5-HT3 antagonists, have now been evaluated extensively. Although they are very effective compared with placebo and have relatively favourable side-effect profiles, their absolute efficacy is disappointing. For example, in a systematic review of ondansetron for the prevention of PONV, the best numbers-needed-to-treat for the prevention of PONV was 56.3 Most consider droperidol as an effective antiemetic but it is associated with side-effects such as agitation, sedation and extrapyramidal reactions.4 Its efficacy has been compared with ondansetron by several investigators and a recent meta-analysis suggested a similar efficacy for droperidol and ondansetron, although ondansetron may be superior in children.5 This study also confirmed the conclusions of others4 6 that metoclopramide is relatively ineffective for the prevention of PONV.
Antagonists at the NK1 receptor represent another new class of antiemetics. Emetic inputs converge in the brainstem in areas where the NK1 receptor is in abundance and animal studies indicate that NK1 receptor antagonists have a wide spectrum of antiemetic activity.7 8 There are some data suggesting efficacy in humans after chemotherapy9 but there is a paucity of published information with respect to prevention of PONV. However, in a study investigating the treatment of patients with established PONV, 44% required rescue antiemesis during a 6-h period after administration of an NK1 antagonist (GR205171) compared with 67% after placebo.10 These early data suggest that NK1 antagonists have antiemetic properties and may be useful agents but it seems unlikely that they will be the final solution for PONV.
Dexamethasone has now emerged as potentially useful prophylaxis for PONV. Its efficacy is comparable with other antiemetics but it may be more effective in the prevention of late PONV with a numbers-needed-to-treat of 4.3.11 Cannabinoids have antiemetic properties12 and these drugs may be available for medical use in the future. We can only speculate at present as to the effect of cannabis or any of its constituents on PONV. However, there was no difference between the effect of nabilone and metoclopramide in patients after hysterectomy.13
Non-pharmacological methods can be effective. Traditional and laser stimulation acupuncture14 15 and acupressure16 have been shown to be more effective than placebo. Their efficacy is comparable with, but no better than, available antiemetics. Of great interest is the recent work of Greif and colleagues who showed that, after colonic resection, supplemental oxygen therapy reduced the incidence of PONV significantly.17
Clearly, many treatments are available for PONV but none can be described as a panacea. Combination drug therapy may be the answer. Amongst the first groups to demonstrate that a combination of antiemetics can be more effective that single drug therapy alone were those of McKenzie and colleagues18 and Pueyo and co-workers.19 For example, the latter showed that, after major gynaecological surgery, the incidence of a complete response to treatment (defined as no PONV in the first 48 h after surgery) in patients receiving placebo, droperidol 2.5 mg at induction of anaesthesia and droperidol 1.25 mg 12 h later, ondansetron 4 mg at induction of anaesthesia or a combination of droperidol and ondansetron at the same doses and time intervals was 28, 60, 56 and 92%, respectively. Only 8% of patients experiencing any degree of PONV during the first 48 h after major gynaecological surgery is very impressive indeed. Others have confirmed this phenomenon11 20 but it is not a consistent finding. For example, a combination of ondansetron and droperidol was not superior to droperidol alone for the prevention of PONV in children undergoing strabismus surgery21 or in adults after major gynaecological surgery.22
Clearly more work is required in this area and the article by Ahmed and colleagues investigating the efficacy of a combination of ondansetron and cyclizine published in this issue of the British Journal of Anaesthesia is a useful addition to the literature.23 In a randomized, double-blind trial of 139 females undergoing day-case gynaecological laparoscopic surgery, patients were given at induction of anaesthesia either ondansetron 4 mg, ondansetron 4 mg and cyclizine 50 mg or saline. Compared with the ondansetron only group, there was a significantly decreased incidence of vomiting (11/59 vs 2/60, P=0.01) and need for rescue antiemetic (29/59 vs 2/60, P=0.03) in the combination group before discharge. There was also a significant decrease in the incidence and severity of nausea. The study would have been more elegant if a cyclizine only group had been included but the data are striking and add further weight to the suggestion that combination therapy may be the way forward.
We need considerably more data in this area but it seems likely that combination therapy may offer improved efficacy for the prevention, or even treatment, of PONV. Antiemetics may act at the dopamine (D2), cholinergic, histamine (H1), 5-HT3 and NK1 receptors and, when deciding upon a combination, it is logical to choose drugs acting at different receptors. The precise site of action of dexamethasone is, as yet, unclear.
Perhaps an analogy can be made between the present status of antiemetic therapy and that of postoperative pain relief approximately 10 yrs ago. At that time, we realized that the perfect analgesic was not likely to be forthcoming. We accepted the concept of inhibiting opioid receptors (opioid analgesics), cyclo-oxygenase (non-steroidal anti-inflammatory drugs) and neuronal sodium channels (local anaesthetics) with standard drugs in order to provide effective analgesia with an acceptable incidence of side-effects, i.e. balanced analgesia. The most effective combinations of antiemetics and their doses have yet to be elucidated but perhaps we should begin to embrace the concept of balanced antiemesis.
Anne M. Heffernan
David J. Rowbotham
Department of Anaesthesia
University of Leicester
Leicester Royal Infirmary
Leicester LE1 5WW
UK
References
1 Scholz J, Steinfath M, Tonner PH. Postoperative nausea and vomiting. Curr Opin Anaesth 1999; 12: 65761
2 Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomitinga comparison of their pharmacology and clinical efficacy. Drugs 1998; 55: 17389[ISI][Medline]
3 Tramer MR, Reynolds DM, Moore RA, McQuay HJ. Efficacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting: A quantitative systematic review of randomized placebo-controlled trials. Anesthesiology 1997; 87: 127789[ISI][Medline]
4 Rowbotham DJ. Current management of postoperative nausea and vomiting. Br J Anaesth 1992; 69: 46S59S[Medline]
5 Domino KB, Anderson EA, Polissar NL, Posner KL. Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: A meta- analysis. Anesth Analg 1999; 88: 13709
6 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: 76171
7 Andrews PLR. Towards an understanding of the mechanisms of PONV. In Strunin L, Rowbotham DJ, Miles A, eds. UK Advances in Clinical Practice 1999. The Effective Management of Post-Operative Nausea and Vomiting. London: Aesculapius Medical Press, 1999; 1330
8 Fukuda H, Nakamura E, Koga T, Furukawa N, Shiroshita Y. The site of the anti-emetic action of tachykinin NK1 receptor antagonists may exist in the medullary area adjacent to the semicompact part of the nucleus ambiguus. Brain Res 1999; 818: 43949[ISI][Medline]
9 Navari RM, Reinhardt RR, Gralla RJ, Kris MG, Hesketh PJ, Khojasteh A, Kindler H, Grote TH, Pendergrass K, Grundberg SM, Carides AD, Gertz BJ. Reduction of cisplatin-induced emesis by a selective neurokinin-1- receptor antagonist. N Eng J Med 1999; 340: 1905
10 Diemunsch P, Schoeffler P, Bryssine B, Cheli-Muller LE, Lees J, McQuade, BA, Spraggs CF. 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: 2746
11 Henzi I, Walder B, Tramer MR. Dexamethasone for the prevention of postoperative nausea and vomiting: A quantitative systematic review. Anesth Analg 2000; 90: 18694
12 Hirst RA, Lambert DG, Notcutt WG. Pharmacology and potential therapeutic uses of cannabis. Br J Anaesth 1998; 81: 7784
13 Lewis IH, Campbell DN, Barrowcliffe MP. Effect of nabilone on nausea and vomiting after total abdominal hysterectomy. Br J Anaesth 1994; 73: 2446[Abstract]
14 Schlager A, Offer T, Baldissera I. Laser stimulation of acupuncture point P6 reduces postoperative vomiting in children undergoing strabismus surgery. Br J Anaesth 1998; 81: 52932
15 Vickers AJ. Can acupuncture have specific effects on health? A systematic review of acupuncture antiemetic trials. J R Soc Med 1996; 89: 30311[Abstract]
16 Harmon D, Gardiner J, Harrison R, Kelly A. Acupressure and the prevention of nausea and vomiting after laparoscopy. Br J Anaesth 1999; 82: 38790
17 Greif R, Laciny S, Rapf B, Hickle RS, Sessler DI. Supplemental oxygen reduces the incidence of postoperative nausea and vomiting. Anesthesiology 1999; 91: 124652[ISI][Medline]
18 McKenzie R, Tantisira B, Karambelkar DJ, Riley TJ, Abdelhady H. Comparison of ondansetron with ondansetron plus dexamethasone in the prevention of postoperative nausea and vomiting. Anesth Analg 1994; 79: 9614[Abstract]
19 Pueyo FJ, Carrascosa F, Lopez L, Iribarren MJ, Garcia-Pedrajas F, Saez. Combination of ondansetron and droperidol in the prophylaxis of postoperative nausea and vomiting. Anesth Analg 1996; 83: 11722[Abstract]
20 Riley TJ, McKenzie R, Tantisira BR, Hamilton DL. Droperidol-ondansetron combination versus droperidol alone for postoperative control of emesis after total abdominal hysterectomy. J Clin Anesth 1998; 10: 612[ISI][Medline]
21 Klockgether-Radke A, Neumann S, Neumann P, Braun U, Muhlendyckt H. Ondansetron, droperidol and their combination for the prevention of post-operative vomiting in children. Eur J Anaesth 1997; 14: 3627[ISI][Medline]
22 Bugedo G, Gonzalez J, Asenjo C, De la Cuadra JC, Gajardo A, Castillo L, Munoz H, Dagnino J. Ondansetron and droperidol in the prevention of postoperative nausea and vomiting. Br J Anaesth 1999; 83: 8134
23 Ahmed AB, Hobbs GJ, Curran JP. Randomised, placebo-controlled trial of combination antiemetic prophylaxis for day-case gynaecological laparoscopic surgery. Br J Anaesth 2000; 85: 67882