Ondansetron: In a class (5HT3) of its own

Ondansetron: In a Class (SHT3) of Its Own C. Rick Roberson and Charles H. McLeskey O

NDANSETRON is a serotonin (5HT3) antagonist which has been recently approved by the Food and Drug Administration as an antiemetic for postoperative nausea and vomiting (PONV). Numerous studies have shown ondansetron to be more effective than placebo for prophylaxis and treatment of PONV in selected populations. However, ondansetron has a higher acquisition cost than any other currently available antiemetic. In today's increasingly cost-conscious health care environment, new drugs must prove to be superior to currently available drugs or have fewer side effects. Hospital pharmacies and therapeutics committees are interested in a favorable cost-effectiveness analysis before drugs are added to the formulary. In this article we discuss the incidence and physiology of PONV and the factors associated with PONV. We then look at the data accumulated comparing ondansetron with placebo and other antiemetics. Postoperative N a u s e a a n d V o m i t i n g

To determine the cost-effectiveness of ondansetron, we must understand problems associated with PONV, patients at high risk for PONV, and the effectiveness of some of the more commonly used antiemetics. Dr Patricia Kapur has labeled PONV, "the big little problem following ambulatory surgery. ''1 With ambulatory surgery now accounting for more than 50% of surgery performed in the United States, shorter acting anesthesia agents are used to facilitate earlier emergence from anesthesia and quicker discharge from the post anesthesia care unit and step-down units. There is increasing public and clinician awareness of PONV as a problem. For example, almost 75% of potential patients surveyed indicated that PONV was their primary perioperative concern.2 They further indicated a willingness to accept a variety of trade-offs, including dysphoria, increased cost, even temporary decreased postoperative mental acuity and increased pain in order to avoid PONV. Today's patients express awareness and concern about quality of care and quality of life issues. In an increasingly managed health care Seminars in Anesthesia, Vol 15, No ! (March), 1996: pp 41-46

environment, negotiated contracts will more commonly consider the speed with which patients return to their activities of daily living and return to productive work. Techniques and agents which reduce PONV may be valuable in selling health care delivery to target markets. In addition, the costs associated with PONV encompass more than the simple acquisition cost for antiemetic therapy. Other so-called indirect costs include the expenses associated with an increased length of stay and the increased nursing acuity required in PACU and day surgery units when patients experience PONV (Fig 1). In addition to cost, PONV also has potential medical consequences including increased discomfort with associated tachycardia and hypertension. Protracted nausea and vomiting can also lead to dehydration and interruption of oral drug intake. Straining in the course of emesis can increase intraocular and intracranial pressures, surgical bleeding, and wound dehiscence. Vomiting increases the chances for pulmonary aspiration. Finally, severe and protracted PONV occasionally mandate unanticipated hospital admission. The implications of the effective management and prevention of PONV are broad indeed. Incidence o f Postoperative N a u s e a a n d Vomiting

What is the incidence of PONV? There are many regional and local variables in patient population, surgical technique, and anesthetic practice. Studies also lack a standard definition of nausea or retching or vomiting. However, a review of the literature shows a decrease in the overall incidence of PONV from approximately From the Department of Anesthesiology, Scott and White Clinic and Memorial Hospital Scott, Sherwood and Brindle), Foundation, Texas A&M University Health Science Center, Temple. TX. Address reprint requests to C.R. Roberson, MD, Department of Anesthesiology, Scott & White Clinic, 2401 S 31st St, Temple, TX 76508. Copyright 9 1996 by W.B. Saunders Company 0277-0326/96/1501-000555.00/0 41

42

ROBERSON AND McLESKEY

PACU

Day Surgery

[IINoPONV r']PONV ]

Fig 1. PONV significantly increases length of stay in the postanesthesia care unit and day surgery unit. Symbols: *P < .02; **P < .0001. (Adapted from Roberson and Walker. Anesthesia and Analgesia, 76: $350, 1993, p 79)

50% in the days of ether anesthesia to a more commonly reported current rate between 20% and 30%. 3

Factors Predictive of Postoperative Nausea and Vomiting Factors that determine the incidence of PONV include a variety of patient characteristics (Table 1), surgical factors, anesthetic factors and postoperative factors. 3 Surgical factors. Certain types of surgery are known to have a higher associated incidence of PONV. For example, where the average incidence of PONV is 20% to 30%, 125 children anesthetized for magnetic resonance imaging evaluation had an incidence of PONV of less than 10%. 6 On the other hand, strabismus surgery has been associated with an incidence of PONV as high as 80%.7 Surgical procedures performed laparo-

scopically and otolaryngologic, plastic, gynecologic, and ophthalmologic surgical procedures have a higher incidence of associated PONV. 3 Anesthetic factors. Perhaps the variable over which we exercise greatest control is the selection of anesthetic technique. Anesthetic techniques associated with an increased incidence of PONV include mask ventilation; the use of opioids; the use of nitrous oxide; the lack of use of propofol; the failure to use gastric emptying; and the use of reversal drugs for neuromuscular blocking agents. Horvorka and Kortilla8 have shown that patient care managed by practitioners inexperienced with ventilation have a higher incidence of PONV compared with those experienced at mask ventilation. Presumably the greater amount of air introduced into the stomach by less skillful mask ventilation techniques result in a greater incidence of PONV. McCarroll et al 3 have shown that aspirating the stomach after induction of general anesthesia significantly reduces the incidence of PONV in patients undergoing laparoscopic surgical procedures with a standard anesthetic technique compared with those in whom the stomach was not emptied. 9 However, other studies have not substantiated this benefit. 3 A variety of studies have suggested that the use ofpropofol as an anesthetic has the associated benefit of reduced PONV. For example, Valanne io found that patients anesthetized with propofol were discharged home earlier, and had a lower incidence of postoperative emesis for the first 24 hours compared with those receiving isoflurane. Growing evidence suggests that agents used to reverse neuromuscular block, especially neostigmine, result in an increased incidence of PONV. TM

Table 1.

Patient Characteristics Associated With an Increased Incidence of PONV

Female (probably because of hormonal variations during menses4) Young Obese History of motion sickness History of PONV with previous surgery Anxiety/pain GI disorders (eg, hiatal hernia) Low ASA physical statuss Abbreviations: GI, gastrointestinal; ASA, American Society of Anesthesiologists.

Postoperative factors. Postoperative factors also play a role in determining the incidence of PONV. For example, increased pain and early oral intake seem to increase the incidence of PONV. Also, use of opioids, early ambulation (presumably caused by movement and stimulation of the vestibular apparatus), and anxiety increase the likelihood of PONV. PHYSIOLOGY OF NAUSEA AND VOMITING

Before discussing available options for prophylaxis and treatment of PONV, a brief review of the physiology of nausea and vomiting may

ONDANSETRON AND POSTOPERATIVE EMESIS

be helpful. A variety of inputs directly effect the emetic center. For example, ophthalmic, olfactory, and pharyngeal stimulation, vestibular activation resulting from movement, and input from the cerebral cortex all influence the emetic center. Drugs and hormones affect the emetic center indirectly by first stimulating the chemoreceptor trigger zone, located in the medulla. Table 2 indicates humoral agents or neurotransmitters that are thought to stimulate the chemoreceptor trigger zone and selected pharmacological drugs that act to inhibit their effects. Unfortunately, studies have shown that no single neurotransmitter controls PONV completely. Consequently, there is no gold standard antiemetic. The most commonly used antiemetics for PONV include droperidol, metoclopramide, scopolamine, and prochlorperazine. Ondansetron is the most recent addition to this list. Some studies have shown droperidol to be effective for both prophylaxis and treatment of PONV, j3"15whereas other studies have reported droperidol to be no more effective than placebo.16 Droperidol is also associated with significant side effects including drowsiness and extrapyramidai symptoms, resulting in potential delayed discharge of ambulatory patients. ~61s Similarly, metoclopramide has been shown to have efficacy for PONV in some studies, ~9whereas others suggest it is ineffective. 2~ Metoclopramide can also cause the side effects of restlessness and occasional extrapyramidal symptoms. ONDANSETRON

Ondansetron was the first serotonin antagonist to be introduced for management of emesis associated with chemotherapy and radiotherapy. Its mechanism of action seems to be both central at the chemoreceptor trigger zone and peripheral in the gastr "ntestinai tract. By blocking the 5HT3 receptors in the mucosal vagal afferents, ondansetron inhibits the afferent arm of the vomiting reflex. It has been shown to be extremely effective in managing chemotherapy-induced emesis. In two studies comparing ondansetron with metoclopramide in patients receiving cisplatin, ondansetron was superior to metoclopramide in eliminating acute emesis (complete response, 44% v 17% respectively, P < .001).21 It received Food and Drug Administration approval for management of PONV in 1993.

43 Table 2. Substances Stimulating the Chemoreceptor Zone and Antagonist Drug Therapy Stimulators

Antagonists

Dopamine (D2) Central muscarinic receptors Histamine (Hi)

Droperidol, metoclopramide Anticholinergics (atropine, scopolamine) Antihistamines (diphenhydramine, promethazine, hydroxyzine) 5HTa antagonist (ondansetron)

Serotonin (5HT3)

Is ondansetron better than the currently available antiemetics? As previously mentioned, studies have universally shown that ondansetron is superior to placebo for both prophylaxis and treatment of P O N V . 22"26 Of all of the therapeutic agents available for prophylaxis or treatment of PONV, ondansetron has the advantage of efficacy at least equal to that of other available agents, but with an essentially clean side effect profile. The incidence of side effects from ondansetron administration are not significantly different from placebo. There have been two reports of symptoms consistent with, but not diagnostic of extrapyramidal reactions possibly associated with ondansetron. 27'28 Also, early studies of ondansetron noted transient elevation of liver enzymes. However, these observations were reported only in patients receiving simultaneous antineoplastic drugs. Follow-up studies of patients receiving ondansetron for PONV have shown no side effects. Ondansetron has also been shown to provide relief of PONV that persists for a longer period of time than that produced by other agents. For example, Khalil et al2a have shown in women undergoing elective ambulatory surgery, that patients receiving ondansetron in either a 4- or an 8-mg dose had significantly greater complete prevention of PONV over a 24 hour study period than patients receiving placebo. 2a Yung-Fong Sung2s has similarly shown that 62% of women patients administered ondansetron intravenously in an 8-mg dose were emesis free over a 24-hour period after outpatient laparoscopic surgery compared with only 40% of placebo-treated patients.24 McKenzie et a125 in a large multi-center trial also showed that ondansetron in doses of l, 4, or 8 mg were more effective than placebo in reducing the incidence of emesis during the first 24 postoperative hours. 25 Although ondansetron

44

ROBERSON AND McLESKEY

was not as effective in patients with a history of PONV, compared with patients with no previous history, ondansetron treatment was superior to placebo in both patient populations (Fig 2). Scuderi et a126further reported that patients suffering from nausea or vomiting in the PACU can also be effectively treated. 26 In this study, complete freedom from recurrent nausea and vomiting during a 24-hour period after receiving ondansetron doses of 1, 4, or 8 mg was observed in 40% to 50% of ondansetron-treated patients versus only 15% of those treated with placebo (Fig 3). The mechanism for the prolonged duration of action of ondansetron is unclear because its plasma elimination half-life is 3 to 4 hours in normal volunteers. Ondansetron has been shown to be free of side effects and to have efficacy compared with placebo. However, how does it fare when compared with other available antiemetic agents? Alon and Himmelseher 29 have shown in 66 young healthy women undergoing general anesthesia for dilatation and curettage that in the first 3 hours after surgery, PONV occurred in only 13% of ondansetron-treated patients (8 mg) versus 45% o f droperidol-treated patients and 54% of metoclopramide-treated patients. The incidence of nausea was not statistically different in the three groups (ondansetron 40%, metoclopramide 63%, and droperidol 55%). Gan et al 3~ compared the efficacy of ondansetron with droperidol and placebo administered prophylactically to 120 patients undergoing knee and hip surgery. They found both ondansetron and droperidol to be superior to placebo but with no difference between the two. However, the droperidol group required significantly more rescue medication for subse-

100%T

% 80%t ~ Patients Without Emesis

(0-24

hr)

60% 40%

78%"

86%" 56%** ~ 1 ~ 5 5 % m

%

20%t

~ii 25%

0%1

I

All Patients [ ] Placebo

Hx PONV

I

I No Hx PONV

9 Ondansetron 4rng

Fig2. The percentage of patients without emesis during the 24-hour study. Ondansetron was less effective for patients with a history of PONV. Symbols: *P < .001; **P < .005. (Adapted and reprinted with permission from McKenzie, et a l ? s)

%

Patients Without Emesis

70% 9 60% 50% 9 40%, 30%. 20%, 10%. 0%. 0-2 hours [ FI Placebo

0-24 hours " Ondansetron 4rag ]

Fig 3. The percentage of patients having no emetic episodes during the initial observation period (0-2 hour) and during the follow-up period (0-24 hour). Symbol: *P < .001. (Adapted and reprinted with permission from Scuderi et al. 2e)

quent PONV than the ondansetron group (34% v 17%). The investigators postulate the difference in rescue medication requirements is attributable to a significantly lower nausea score in the ondansetron group compared with the droperidol group. Whereas the severity of nausea was reduced with ondansetron, they found no difference in the incidence of nausea among the three groups. When compared against placebo, ondansetron seems in some studies to be more effective in preventing postoperative vomiting than in reducing nausea. 29'3~Dundee and McMillan 3~ suggest this is in agreement with their experience in oncology patients where they found ondansetron to be a better antiemetic than antinauseant. 3~ However, other studies have found ondansetron to be equally effective at reducing postoperative nausea and emesis. 25'26'32 Rose et aP 3 have shown ondansetron to be superior to metoclopramide in preventing postoperative vomiting in children undergoing strabismus repair.33 The incidence of vomiting before discharge was significantly reduced in the ondansetron group (10%) compared with the placebo group (50%). While the incidence of vomiting was reduced in the metoclopramide group (27%) it was not significantly different from placebo or ondansetron. The incidence of vomiting increased in all three groups after discharge (Fig 4). Malins et a134 compared oral premedication with ondansetron 4 mg, metoclopramide 10 mg, or placebo in 153 women undergoing gynecological laparoscopy. They found a decreased incidence of PONV with

ONDANSETRON AND POSTOPERATIVE EMESIS 67%

70% 60% 50% % With 40% E m e e l s 30% 20% 10% 0% Prior to Discharge

[ ] Normal Saline

Within 24 hours

9 Metoclopramide 9 Ondansetron

Fig 4. Incidence of vomiting in children after strabismus surgery. Symbols: *P < .003 compared with placebo. **P < .015 compared with placebo. (Adapted from Rose et al, Ondansetron reduces the incidences and severity of poststrabismus repair vomiting in children, Anesthesia and Analgesia, 79:486-489. aa)

ondansetron (26%) compared with placebo (50%) and metoclopramide (42%). 34

COMBINATION THERAPY There are very little data on combination therapy for postoperative nausea and vomiting. Because no single neurotransmitter controls PONV, it would seem logical that combining antiemetics which act on different receptors in the chemoreceptor trigger zone would improve their overall effectiveness. A n u m b e r of studies of combinations of metoclopramide, droperidol, dexamethasone, diphenhydramine and others in chemotherapy-induced emesis support the role of combination therapy. 3s'36 A recent study suggests ondansetron plus dexamethasone may significantly improve antiemetic efficacy against PONV in women undergoing gynecologic procedures. 37 Doze et al ~a the combination of droperidol and metoclopramide was more efficacious than droperidol alone, decreasing the recovery time in outpatients.~8 However, in a recent study by Belo and Koutsoukos, 38 the combination of ondansetron and droperidol did not significantly decrease the incidence of emesis when compared with either drug alone in the same patient population. 38 Further studies on combination drug therapy for postoperative emesis are needed.

SUMMARY PONV is increasing in importance for the practice of anesthesiology today. Patients are more commonly aware of this problem and desire that it be prevented. An understanding of the factors which predict an increased likelihood of

45 P O N V aids the selection of techniques to reduce its frequency. Ondansetron seems to be at least as effective as other antiemetics with a lack of significant sedation or major side effects. This suggests that ondansetron m a y be particularly useful in the ambulatory surgery setting. However, ondansetron must be judged in light of its somewhat greater acquisition cost. Some questions remain to be answered. The majority o f studies reported to date have evaluated w o m e n receiving general anesthesia for gynecological surgery because this is such a high-risk population for PONV. Future studies must address different patient populations, both adult and pediatric, having a variety of surgical procedures and anesthetic techniques. Other questions which need further clarification include the timing of administration o f antiemetic drugs. Should they be administered prophylactically or only therapeutically? Also, what about combination therapy? Is the coadministration of an agent like droperidol and metoclopramide superior to either alone? As Fred Orkin comments, the fact that "almost 75% of subjects base their preferences on whether emetic sympt o m s were present suggests that greater efforts should be made to prevent these symptoms. ''2

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46 of postoperative nausea and vomiting. Anesth Analg 70:$262, 1990 (abstr) 10. Valanne J: Recovery and discharge of patients after long propofol infusion vs. isoflurane anaesthesia for ambulatory surgery. Acta Anaesthesiol Scand 36:530-533, 1992 I 1. Ding W, Fredman B, White PF: Use of mivacurium during laparoscopic surgery: Effect of reversal drugs on postoperative recovery. Anesth Ana|g 78:450-454, 1994 12. Grasela TH, McLeskey CH, Waluwander CA, et al: Postoperative nausea/vomiting and the effect of anticholinesterase agents. Anesthesiology 81 :A 1278, 1994 (abstr) 13. Jorgensen NH, Coyle JP: Intravenous droperidol decreases nausea and vomiting after alfentanil anesthesia without increasing recovery time. J Clin Anesth 2:312-316, 1990 14. Korttila K, Kauste A, Auvinen J: Comparison ofdomperidone, droperidol and metoclopramide in the prevention and treatment of nausea and vomiting after balanced general anesthesia. Anesth Analg 58:396-400, 1979 15. Pandi SK, Kothary SP, Pandit UA, et al: Dose response study of droperidol and metoclopramide as antiemetics for outpatient anesthesia. Anesth Analg 68:798-802, 1989 16. Valanne J, Korttila K: Effect of a small dose of droperidol on nausea, vomiting and recovery after outpatient enflurane anesthesia. Acta Anaesthesiol Scand 29:359-362, 1985 17. Melnick B, Sawyer R, Karambelkar D, et al: Delayed side effects of droperidol after ambulatory general anesthesia. Anesth Analg 69:748-751, 1989 18. Doze VA, Shafer A, White PF: Nausea and vomiting after outpatient anesthesia: Effectiveness of droperidol alone and in combination with metoclopmmide. Anesth Analg 66: $41, 1987 (abstr) 19. Miller CD, Anderson WG: Silent regurgitation in day case gynecological patients. Anaesthesia 43:321-323, 1988 20. Pandit SK, et al: Premedication with cimetidine and metoclopramide. Anaesthesia 41:485-492, 1986 2 I. Kidgell AE, Butcher ME, Brown GW: Antiemetic control; 5-HTa antagonists: Review of clinical results, with particular emphasis on ondansetron. Cancer Treat Rev 17:311317, 1990 22. Leeser J, Lip H: Prevention of postoperative nausea and vomiting using ondansetron, a new, selective, 5-HT3 receptor antagonist. Anesth Analg 72:751-755, 1991 23. Khalil SN, Kataria B, Pearson K, et al: Ondansetron prevents postoperative nausea and vomiting in women outpatients. Anesth Analg 79:845-851, 1994 24. Sung YF, Wetchler BV, Duncalf D, et al: A doubleblind, placebo-controlled pilot study examining the effective-

ROBERSON AND McLESKEY ness of IV ondansetron in the prevention of post operative nausea and vomiting. J Clin Anesth 5:22-29, 1993 25. McKenzie R, Kovac A, O'Connor T, et al: Comparison of ondansetron versus placebo to prevent postoperative nausea and vomiting in women undergoing ambulatory gynecologic surgery. Anesthesiology 78:21-28, 1993 26. Scuderi P, Wetchler B, Sung YF, et al: Treatment of postoperative nausea and vomiting after outpatient surgery with the 5HT3 antagonist ondansetron. Anesthesiology 78: 15-20, 1993 27. Garcia-del-Muro X, Cardenal F, Ferrer P: Extrapyramidal reaction associated with ondansetron. Eur J Cancer 29A(2):288, 1993 (letter) 28. Halperin JR, Murphy B: Extrapyramidal reaction to ondansetron. Cancer 69:1275, 1992 29. Alon E, Himmelseher S: Ondansetron in the treatment of postoperative vomiting. A randomized double-blind comparison with droperidol and metoclopramide. Anesth Analg 75:561-565, 1992 30. Gan TJ, Collis R, Hetreed M: Double-blind comparison of ondansetron, droperidol and saline in the prevention of postoperative nausea and vomiting. Br J Anaesth 72:544-547, 1994 31. Dundee JW, McMillan CM: Antiemetic or Antinauscant Effect ofOndansetron? Anesth Analg 74:473-474, 1992 32. Claybon L: Single dose intravenous ondansetron for the 24-hour treatment of postoperative nausea and vomiting. Anaesthesia 49:24-29, 1994 (suppl) 33. Rose JB, Martin TM, Corddry DH, et al: Ondansetron reduces the incidences and severity of poststrabismus repair vomiting in children. Anesth Analg 79:486-489, 1994 34. Malins AF, Field JM, Nesling PM, et al: Nausea and vomiting after gynaecological laparoscopy: Comparison of premedication with oral ondansetron, metoclopramide and placebo. Br J Anaesth 72:231-233, 1994 35. Triozzi PL, Laszio J: Optimum management of nausea and vomiting in cancer chemotherapy. Drugs 34:136-149, 1987 36. Sridhar KS, Donnelly E: Combination ofantiemetics for cisplatin chemotherapy. Cancer 61:1508-1517, 1988 37. McKenzie R, Tantisira B, Riley T, et al: Does ondansetron plus dexamethasone enhance the antiemetic efficacy ofondansetron? Anesth Analg 78:$280, 1994 (abstr) 38. Belo S, Koutsoukos G: Combination ofondansetron and droperidol for anti-emetic prophylaxis. Anesth Analg 78: $30, 1994 (abstr)