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Journal of Clinical Anesthesia (2006) 18, 304 – 318

Review article

Prophylaxis of postoperative nausea and vomiting: controversies in the use of serotonin 5-hydroxytryptamine subtype 3 receptor antagonistsB
Anthony L. Kovac MD (Professor of Anesthesiology)*
Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
Received 4 February 2005; accepted 22 June 2005

Keywords:
Emesis control; Postoperative nausea and vomiting; PONV; Serotonin; 5-hydroxytryptamine-3 antagonist; 5-HT3 receptor antagonist; Prophylaxis

Abstract Postoperative nausea and vomiting (PONV) continues to be a bbig little problemQ despite recent advances in anesthesia. Because of an increased interest in, and the abundant publications on this topic, guidelines for the management of PONV were published in 2003. Several key but controversial issues regarding PONV prophylaxis were left unaddressed, however. These included whether clinical differences exist between the 5-hydroxytryptamine subtype 3 (5-HT3) receptor antagonists, concern over optimal dosage and timing of administration, optimal 5-HT3 receptor antagonist combination therapy, and whether rescue therapy is effective after prior administration of the same or a different 5-HT3 receptor antagonist. The application of these antiemetics in clinical practice has raised questions regarding the role of the 5-HT3 receptor antagonists in the treatment of postdischarge nausea and vomiting and opioid-induced nausea and vomiting. A brief overview of the incidence, risk factors and current management recommendations for PONV and current controversies with special emphasis on the 5-HT3 receptor antagonists, is discussed. D 2006 Elsevier Inc. All rights reserved.

1. Introduction
Postoperative nausea and vomiting (PONV) is a common complication of general anesthesia that can lead to increased
This article was supported by an unrestricted educational grant from Roche Laboratories, Inc. The company had no input into the content of this article. Dr Kovac has previously received grant support from GlaxoSmithKline, Roche Laboratories, Inc, Aventis Pharmaceuticals, Baxter Pharmaceuticals, and Merck & Co, Inc. Dr Kovac has served as a member of the speakers’ bureau for GlaxoSmithKline, Abbott Laboratories, and Baxter Pharmaceuticals. Dr Kovac has served as an advisory consultant for Aventis Pharmaceuticals, Roche Laboratories, Inc, GlaxoSmithKline, Merck & Co, Inc, Adolor Corporation, and Helsinn, Inc. * Tel.: +1 913 588 6670; fax: +1 913 588 3365. E-mail address: akovac@kumc.edu. 0952-8180/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2005.06.012
B

recovery room time and unexpected hospital admissions [1,2]. Although the causes of PONV are multifactorial, antiemetic agents are now available that act at different areas of the emetic pathway to effectively prevent its occurrence (for a more comprehensive discussion, see reviews by Kovac [3,4] and Watcha and White [5]). The management of PONV, most recently, has been advanced by the development of the serotonin (5-hydroxytryptamine [5-HT]) subtype 3 (5-HT3) receptor antagonists, which inhibit the stimulatory effects of serotonin on afferent vagal nerve pathways and on the chemoreceptor trigger zone [6,7]. Because of the broad and potentially costly therapeutic armamentarium now available, an international multidisciplinary panel of expert anesthesiologists, a surgeon, a

PONV prophylaxis and 5-HT3 antagonists nurse anesthetist, and a pharmacist recognized the need for guidelines for antiemetic use in the setting of PONV [8]. Published in 2003, these guidelines (hereinafter referred to as bthe 2003 PONV guidelinesQ) provide a strategy for prevention based on the risk of PONV in individual patients. Although the 2003 PONV guideline [8] recommendations included the use of 5-HT3 receptor antagonists as the first-line preventive agents in patients categorized as highrisk, several key but controversial issues surrounding the selection of a 5-HT3 receptor antagonist for PONV prevention were left unaddressed. These included whether clinical differences between the 5-HT3 receptor antagonists exist; concern over the optimal dosage and timing of administration; whether rescue therapy after prior administration of the same or another 5-HT3 receptor antagonist is effective; and questions about the optimal combinations of 5-HT3 receptor antagonists with other antiemetics. In addition, the application of these agents in clinical practice has led to new questions about the role of 5-HT3 receptor antagonists in the treatment of postdischarge nausea and vomiting (PDNV) and opioid-induced nausea and vomiting (OINV). After a brief overview of incidence, risk factors, and current management recommendations for PONV, the current controversies in PONV prophylaxis, with special emphasis on the 5-HT3 receptor antagonists, are discussed.

305 (ie, in the postanesthesia care unit [PACU]) [13], and over the 24-hour postoperative period, these figures increased to 52% and 25%, respectively. Similarly, in a study of 29 220 pediatric patients undergoing a wide variety of inpatient or outpatient surgeries [9], the incidence of vomiting in the PACU was 6%, with an overall risk of nausea or vomiting of 25% within 72 hours of the procedure. Population-based surveys have found that the incidence of postoperative vomiting (POV) within the first 24 hours after procedures varies with the type of anesthetic regimen. Of 3244 patients receiving general anesthesia (unspecified technique) for various surgical procedures, 37% reported nausea and 23% vomited [12]. A randomized clinical trial comparing the safety and efficacy of different inhalation anesthesia agents reported a 20% overall incidence of nausea and a 13% incidence of vomiting within 7 postsurgical days in 16 023 patients [10]. In a clinical trial comparing inhalation with IV anesthesia, the total incidence of nausea and vomiting in 2010 patients ranged from 29% (14% had only nausea) to 61% (16% had only nausea), depending on the surgical venue (inpatient vs outpatient) and the type of anesthesia administered [19]. Meta-analyses of the outcomes of placebo-controlled trials of antiemetic therapy have found higher average frequencies of PONV. Combined results of studies published between April 1997 and January 1999 yielded an incidence of 41% for nausea (33% for vomiting only) in the 5712 placebo-treated patients during the 0- to 6-hour period. In the 0- to 48-hour period, the PONV incidence was 68% for nausea (53% for vomiting only) [14]. A separate metaanalysis of placebo-controlled trials published between January 1990 and July 1997 reported that 56% of 4285 placebo-treated patients experienced POV [15]. These incidences are at the high end of the ranges described above because either high-risk patients or those receiving anesthetic regimens associated with a high incidence of PONV were enrolled.

2. Incidence of PONV
The incidence of PONV derived from population-based studies and clinical trials varies in part because of differences in study design, such as the types of endpoints assessed (nausea and/or vomiting assessed separately or combined with rescue medication administered), the assessment intervals (early or late, with varying definitions of each), surgical venues (inpatient or outpatient), surgical procedures (general or specific types), and anesthetic techniques (inhalation or intravenous [IV]). Widely quoted studies of postoperative emesis published after the bether Q era and including studies of 500 patients or greater report a PONV incidence range of 20% to 30% [5]. Table 1 lists the incidence of PONV from studies published since 1990 [9-18]. Findings of more recent observational studies reflect the tendency to an increasing incidence of PONV and, consequently, PDNV as patients resume ambulation and oral intake, experience postoperative pain, and initiate postoperative opioid therapy. For example, the combined incidence of nausea and vomiting reported in the immediate (approximately 90 min) postoperative period is estimated to be 5% [17] and 8% [18] in 17 638 ambulatory surgery patients and in 27 626 inpatients, respectively, and rose during the first 24 postsurgical hours to 9% [17] in one of these patient series. In a report of 1107 inpatients (N50% underwent gynecologic procedures), the incidence of nausea and vomiting was 18% and 5%, respectively, in the 0- to 2-hour postoperative period

3. Risk factors for PONV
An in-depth discussion of risk assessment in PONV is beyond the scope of this review. Excellent discussions of risk assessment are provided in recent articles by Apfel and Roewer [20] and Gan et al [8]. In short, established patientspecific risk factors for PONV include female gender, smoking status, and a history of PONV or motion sickness [16,21], whereas nonspecific factors are postoperative opioid use and duration of surgery [16,21,22]. There is no definitive explanation for the higher incidence of PONV found in female patients. In fact, certain hormones, including 17-b-estradiol and progesterone, have been shown to have inhibitory effects on 5-HT3 receptors in vitro [23]. Furthermore, a recent large study found no difference in the incidence of PONV between women in different phases of the menstrual cycle or between those

306

Table 1 Reference

Incidence of PONV: reports from 1990 to present Design No. of patients Type of surgerya Surgical setting Immediate postoperative (inpatient/outpatient) period (V6 h) Otolaryngologic; Inpatient (55%); outpatient (45%) orthopedic; abdominal Orthopedic; gynecologic; abdominal NR General; gynecologic; otolaryngologic NR Inpatient 6% Extended postoperative period (V48 h) 25% (within 72 h)

Nausea and vomiting Nausea Vomiting Nausea and vomiting Nausea Vomiting Cohen et al [9] Retrospective chart review Pediatric patients; 29 220 for vomiting only; 22 760 for nausea and vomiting 16 023

Forrest et al [10,11] Quinn et al [12] Koivuranta et al [13] Tramer et al [14]

Prospective, randomized controlled trial Prospective survey Prospective survey

20%

13%

3244 1107

NR Inpatient 18% 5%

37% 52%

23% 25%

Meta-analysis; 5712 randomized controlled trials Figueredo and Meta-analysis; 4285 Canosa [15] randomized controlled trials Apfel et al Prospective; 2722 [16] population-based Sinclair et al [17] Junger et al 2001 [18] Prospective and 17 638 retrospective; population-based Prospective; 27 626 population-based

NR

41%

33%

68%

53%

Gynecologic; otolaryngologic; general Otolaryngologic; bother Q; ophthalmologic Ophthalmologic; gynecologic; orthopedic Trauma; otolaryngologic; ophthalmologic

NR

56%

NR

56%b 31% 5% 9%

Ambulatory-Surgical Unit Inpatient (86%); outpatient (14%)

8%

NR, not reported. a Lists the 3 most commonly performed procedures in order of number performed. b Two different medical centers.

A.L. Kovac

PONV prophylaxis and 5-HT3 antagonists who were premenopausal or postmenopausal [22]. Smokers have a lower risk of PONV [22,24,25] that may be related to the induction of cytochrome P450 (CYP450) enzymes (including CYP1A2 and possibly CYP2E1) by polycyclic aromatic hydrocarbons found in tobacco smoke [26]. Because these enzymes contribute to the metabolism of volatile anesthetics and other drugs used during anesthesia, it has been proposed that metabolism of these agents is enhanced in smokers, leading to a decrease in PONV. The presence of an antiemetic substance in tobacco smoke has not been found. An alternate hypothesis is that the reduction of PONV in smokers may be seen as an adaptive response to a reported emetic stimulus [25]. The role of other factors in causing PONV is controversial [20]. Although several surgical procedures have been implicated, a recent comprehensive study by Apfel et al [22] found that only hysterectomy ( P b 0.001) and cholecystectomy ( P = 0.04) were associated with a significantly increased risk of PONV. Duration of anesthesia also was found to be an independent risk factor for PONV in that study. In a randomized clinical trial of various combinations of anesthetics, opioids, and antiemetics, the use of volatile anesthetics was the single greatest factor contributing to early (within 2 h) but not delayed (within 2-24 h) POV [27]. However, another study was unable to establish a relationship between the use of volatile anesthetics and PONV [23]. Pediatric patients have been reported to have a higher incidence of POV than that occurring in adults [8,28-30]. A study of 1183 children [30] conducted in the early 1980s found that the incidence of vomiting during 18 postsurgical hours was lowest for those younger than 3 years and then varied between 42% and 51% until puberty. Patients premedicated with hyoscine and papaveretum were at greatest risk. A retrospective study [9] conducted a few years later found incidences of vomiting only to be 25%. Because of the inability of many pediatric patients to adequately recognize the subjective sensation of nausea and/ or to verbally describe their symptoms, most studies of PONV in pediatric patients only evaluate POV. This may skew efficacy data in favor of drugs whose predominant effects are in preventing vomiting (5-HT3 receptor antagonists) over those whose predominant effect is in preventing nausea (droperidol) [31]. Surgical procedures reported to be associated with a high risk of PONV in pediatric patients include adenotonsillectomy, strabismus repair, orchiopexy, herniorrhaphy, middle ear surgery, and laparotomy [29,30].

307 events, such as extrapyramidal reactions (more common in pediatric patients) and excess drowsiness, which may occur with the use of droperidol, are factors that might affect the selection of this drug. The 5-HT3 receptor antagonists were described as generally well tolerated, with headache being a common side effect [32]. In 1999, White and Watcha [33] recommended the combined use of dexamethasone at the start of surgery and a 5-HT3 receptor antagonist administered near the end of surgery for the prevention of PONV. At that time, droperidol was suggested for moderate-risk adult patients, reserving the use of 5-HT3 receptor antagonists for pediatric patients, who are at greater risk of developing extrapyramidal reactions with droperidol [33]. In addition, 5-HT3 receptor antagonists were thought to be more effective than other antiemetic agents in preventing POV in pediatric patients [34]. In the 2003 PONV guidelines [8], the first-line use of 5-HT3 receptor antagonists for PONV prophylaxis in adults and for POV prophylaxis in children was promoted. The change from first-line recommendation of droperidol was largely in response to a US Food and Drug Administration [35] bblack boxQ warning. More recently, Apfel et al [22] found that the use of dexamethasone and total IV anesthesia for PONV prophylaxis was optimal and recommended reserving the use of 5-HT3 receptor antagonists for rescue treatment. These study results and recommendations were based largely on the anticipated cost savings with the use of dexamethasone, although use of dexamethasone is complicated by the potential for adrenal suppression and delay of wound healing [36]. To this author’s knowledge, there have been no studies or case reports describing the effect of a one-time low dose of dexamethasone on adrenal suppression, infection, or wound healing. In addition, dexamethasone requires administration before induction of anesthesia to be effective in preventing PONV during the first 2 hours after anesthesia [37]. According to the 2003 PONV guidelines [8], the initial step in the management of PONV (POV in children) is to identify patients at greatest risk (Fig. 1). Because a specific value for the level of risk (low, moderate, or high) was not assigned, each individual patient should be designated a risk category. In adults at moderate or high risk for PONV or children at moderate or high risk for POV, baseline risk factors should be modified, whenever possible, by considering the use of regional anesthesia, by reducing the use of opioids and nitrous oxide, and by avoiding high doses of muscle relaxant reversal agents while providing optimal IV hydration and supplemental oxygen (z80% O2). For adults and children at high risk, prophylactic antiemetic combination therapy with 2 or 3 agents from different classes is recommended. For adults and children at moderate risk, monotherapy or combination therapy prophylaxis should be considered. Because the 5-HT3 antagonists have demonstrated greater efficacy in the prevention of vomiting compared with nausea, they are recommended as the agents of first choice for POV prophylaxis in children. In the

4. Current management guidelines are based on estimated risk
In 1998, the American Society of Health-System Pharmacists [32] approved guidelines that recommended droperidol or one of the 5-HT3 receptor antagonists for high-risk adult and pediatric patients, with the choice dependent on individual patient factors and cost. Adverse

308
Evaluate risk of PONV in surgical patient Low Moderate Consider regional anesthesia Not indicated High

A.L. Kovac

Methods to Reduce Baseline PONV Risk • Avoid opioids • Avoid Nitrous Oxide • Avoid high-dose reversal agent • Adequate hydration • High oxygen concentration • Propofol anesthetic

No prophylaxis unless there is medical risk of sequelae from vomiting

If general anesthesia is used, reduce baseline risk factors when clinically practical and consider using nonpharmacologic therapies Patients at moderate risk Consider antiemetic prophylaxis with monotherapy (adults) or combination therapy (children and adults) Patients at high risk Initiate combination therapy with two or three prophylactic agents from different classes

Fig. 1 An algorithm for the prevention of postoperative nausea and vomiting (PONV). Reprinted with permission from Anesth Analg 2003;97:62-71 [8].

United States, ondansetron and dolasetron have Food and Drug Administration approval for POV prophylaxis in children. For low-risk patients, antiemetic prophylaxis is not routinely recommended unless there is a medically related risk of adverse sequelae resulting from PONV, such as with hernia repair or craniotomy. The 2003 PONV guidelines [8] recommend that combination therapy use 2 or 3 antiemetics from different pharmacologic classes to optimize efficacy. However, the most favorable antiemetic dosing in combination therapy needs to be determined. Apfel et al [22] have shown that only a 70% reduction in PONV could be expected, even with total IV anesthesia used in combination with 3 antiemetics. Thus, the increased costs and the increased potential for adverse events for multiple interventions must be balanced against the risk of PONV and the likelihood of complications from vomiting to occur.

of dolasetron, granisetron, ondansetron, and tropisetron have been reviewed elsewhere [3,57,58].

5.1. Receptor interactions
All of the 5-HT3 receptor antagonists bind to and inhibit vagal 5-HT3 receptors with high affinity relative to serotonin. Granisetron is reported to have the highest receptor affinity (Table 3) [43-56]. Interactions between the 5-HT3 receptor antagonists and other receptors are variable. Granisetron, tropisetron, and MDL-72222, a predecessor of dolasetron, bind to and inhibit 5-HT3 receptors present on duodenal enterochromaffin cells (ECs) [44]. Binding of serotonin to EC 5-HT3 receptors stimulates serotonin secretion by a positive feedback mechanism; the interaction of 5-HT3 receptor antagonists with EC 5-HT3 receptors may reduce further serotonin release [43]. However, 5-HT3 receptors on EC are of low affinity, requiring high local concentrations of 5-HT3 receptor antagonists to block the receptor. Because this inhibition likely would be most profound after oral administration of 5-HT3 receptor antagonists, it is not clear if this interaction has clinical relevance for IV PONV prophylaxis. In addition to blocking 5-HT3 receptors, high concentrations of tropisetron were found to interact with 5-HT4 receptors present on EC. Under normal conditions, activation of 5-HT4 receptors by serotonin provides negative feedback of serotonin secretion [43]. Again, the clinical relevance of this finding has not been determined. Ondansetron and tropisetron have affinity for other types of receptors, which include the serotonin reuptake site in the case of tropisetron and a-adrenergic and l-opioid receptors in the case of ondansetron (Table 3) [43-56]. Although the clinical relevance of these interactions is not clear, they may increase the potential for drug interactions between

5. 5-HT3 receptor antagonists available for PONV prophylaxis
If a patient’s risk of PONV is sufficient to require prophylactic therapy with a 5-HT3 receptor antagonist, a choice of 4 agents is available: dolasetron, granisetron, ondansetron, and tropisetron (not licensed for use in the United States) (Table 2) [8,32,38-41]. Palonosetron, with a half-life of 40 hours, recently has been approved in the United States for use in chemotherapy-induced nausea and vomiting (CINV) [42] but is not yet available for prophylaxis or treatment of PONV. The distinguishing pharmacologic characteristics of these agents, such as differences in receptor selectivity and affinity, drug metabolism, and effects on cardiac ion channels (Table 3) [43-56] are presented below. The general pharmacologic properties

PONV prophylaxis and 5-HT3 antagonists

309

Table 2 Recommendations for dosing and time of administration of the 5-HT3 receptor antagonists in the prevention of PONV [8,32,38-41] Drug and chemical name (proprietary name, manufacturer) Dolasetron; MDL 74 156 (Anzemet, Aventis Pharmaceuticals, Kansas City, MO) Granisetron; BRL 43694A (Kytril, Roche Laboratories, Nutley, NJ) Ondansetron; GR 38032F (Zofran, GlaxoSmithKline Research Triangle Park, NC) Tropisetron; ICS 205-930 (Navoban, Novartis Pharmaceuticals, North Ryde, NSW, Australia) Prescribing information [38-41] American Society of Health-System Pharmacists Guidelines [32] 12.5 mg IV intraoperatively or 100 mg orally 1 h before anesthesia induction 20-40 lg/kg IV (1.4-2.8 mg for 70-kg patient) 4 mg IV immediately before or 8 mg orally 1 h before anesthesia induction Not commercially available in the United States Timing per 2003 PONV Guidelines [8] 12.5 mg IV at end of surgery 0.35-1 mg IV at end of surgery 4-8 mg IV at end of surgery 5 mg IV at end of surgery

12.5 mg 15 min before the end of surgery [38] 1 mg before induction or just before end of anesthesia [40] 4 mg IV immediately before induction of anesthesia [39] 2 mg IV before anesthesia induction [41]

ondansetron or tropisetron and other classes of drugs. A discussion of some documented interactions between 5-HT3 receptor antagonists and other drugs is included below.

5.2. Hepatic metabolism of 5-HT3 receptor antagonists
The 5-HT3 receptor antagonists are extensively metabolized by hepatic enzymes of the CYP450 family, with CYP2D6 being the predominant enzyme responsible for metabolism of dolasetron [46] and tropisetron (Table 3) [43-56]. Although CYP2D6 also is involved in the metabolism of ondansetron [46,48], it appears to be only one of several enzymes that plays a role [46,47]. Metabolism of granisetron, unlike the other 5-HT3 receptor antagonists, is independent of CYP2D6 and primarily involves enzymes of the CYP3A subfamily [47]. Drugs that use CYP2D6 for metabolism may be subject to therapeutic failures or increased toxicity because of the wide variability in activity of CYP2D6 among different individuals [59]. Four levels of CYP2D6 activity have been described using debrisoquine hydroxylation as a measure of CYP2D6 metabolism: ultrarapid, extensive, intermediate, and poor [60]. The poor metabolizer phenotype is caused by any of several defects in the CYP2D6 gene [61] and is found in approximately 6% of Americans, in 7% to 10% of southern Europeans, in 10% of Middle Easterners, and in 20% of Saudi Arabians [58]. Ultrarapid metabolism results from gene duplication [62,63], with approximately 4% to 5% of the United States population exhibiting this trait [59]. Interethnic differences in levels of CYP2D6 activity vary widely, ranging from 1% to around 30%, depending on the population [59]. The amount of the poor metabolizer phenotype increases the closer one gets to the equator. It is rare in populations in northern Europe (eg, Norway and Finland) [59]. The clinical importance of differences in the CYP2D6 phenotype was demonstrated in a study of German patients [64] receiving tropisetron or ondansetron for CINV. Plasma

levels of tropisetron (not reported for ondansetron) were significantly higher in individuals with a poor metabolizer CYP2D6 phenotype, compared with those with an ultrarapid metabolizer phenotype. Ultrarapid metabolizers treated with tropisetron and, to a lesser extent, ondansetron, had significantly more nausea and vomiting after chemotherapy than did poor metabolizers [64]. Candiotti et al [63] also found that patients with 3 copies of the CYP2D6 gene, a genotype consistent with ultrarapid metabolizers, had an increased incidence of ondansetron failure for the prevention of vomiting, compared with patients of other genotypes. Similarly, the efficacy of dolesetron and, to a lesser extent, granisetron in the treatment of POV was dependent on the CYP2D6 genotype in a randomized controlled trial in patients with moderate to high risk for PONV [65]. These findings suggest that antiemetic treatment of POV may be made more efficacious by selecting agents that are consistent with the patients’ CYP2D6 genotype. The reported plasma terminal half-lives (t1/2) of each of the 5-HT3 receptor antagonists vary considerably between studies (Table 3) [43-56]; however, they generally are less than 8 hours. The t1/2 for ondansetron is highly dependent on the CYP2D6 metabolism phenotype. It is not clear to what extent plasma levels correlate with the duration of therapeutic effect for the 5-HT3 receptor antagonists because the relationship between plasma half-life and receptor half-life is poorly understood with these agents. Healthy volunteers demonstrated a significant reduction in cutaneous axon-reflex flare after intradermal injection of serotonin that lasted for at least 24 hours after receiving a single IV dose (40 lg/kg) of granisetron [50]. This suggests that extremely high affinity binding of granisetron for the 5-HT3 receptor may provide an extended duration of therapeutic effect that does not correlate well with plasma levels of the drug. The other 5-HT3 receptor antagonists may have prolonged activity as well, although there is no documentation in the literature.

310
Table 3 5-HT3 receptor antagonists approved for the prevention of PONV worldwide [43-56] Dolasetron Vagal 5-HT3; EC 5-HT3a Granisetron Vagal 5-HT3; EC 5-HT3 Ondansetron Vagal 5-HT3, weak binding to 5-HT1B, 5-HT1C, a-adrenergic and l-opioid receptors N400 CYP2D6; CYP2E1; CYP3A; CYP1A2 2.8 Yes (liver)
b

A.L. Kovac

Characteristic Receptor selectivity (inhibitory unless otherwise noted)

Tropisetron Vagal 5-HT3; EC 5-HT3; EC HT4 (at high concentrations); serotonin-reuptake site N184 CYP2D6 (major role); CYP2E1 (minor role); CYP3A4 (minor role) 7.3 (good metabolizers) 30.3 (poor metabolizers) None (elimination delayed with cirrhosis or moderate to severe renal insufficiency but dosage adjustment not required) Sodium, potassium, calcium (at high concentrations)

Affinity for 5-HT3 receptor relative to serotonin Hepatic metabolism

Unpublished CYP2D6 (major), CYP3A (minor) 6.9-7.3 None (clearance decreased in renal insufficiency but dosage adjustment not required) Sodium

N600 CYP3A3/4

t1/2 of active metabolite, IV administration (h) Adjustment of dosage for organ impairment

3.9; 10.6 None

Cardiac ion channel antagonism
a

Sodium, potassium

Potassium

Blocked by MDL-72222, a predecessor of dolasetron. Data for dolasetron were not reported. Ondansetron did not prevent release of 5-HT from guinea pig small intestine, whereas in ferret ileum assays, ondansetron exhibited nonlinear concentration-dependent inhibition.
b

5.3. Interactions between 5-HT3 receptor antagonists and other drugs
There are few reports describing interactions between the 5-HT3 receptor antagonists and other drugs. Of note are interactions involving inhibitors/inducers of CYP2D6 and drugs that affect the reuptake of serotonin. Because dolasetron and tropisetron are highly dependent on metabolism by CYP2D6, inhibitors of this enzyme have the potential to enhance the effects of these drugs. Some common drugs that inhibit CYP2D6 include quinidine, fluoxetine, paroxitene, and haloperidol [60]. Quinidine inhibited the metabolism of tropisetron by 70% in human liver microsomal fractions, although the authors [66] concluded that there would be no clinical relevance to this finding because of the wide therapeutic index of tropisetron and the rather high concentrations of quinidine needed for inhibition. Similarly, plasma levels of dolasetron increased by approximately 25% after coadministration of cimetidine, a nonspecific inhibitor of CYP450 enzymes, and decreased by approximately 25% after coadministration of rifampin, an inducer of CYP450 enzymes [67]. Competition between 5-HT3 receptor antagonists and serotonin, a situation that may occur in patients who have increased accumulation of serotonin in response to receiving selective serotonin reuptake inhibitors, is an interaction that may, in theory, impact on the efficacy of 5-HT3 receptor antagonists or other drugs [68]. Reduced protection against CINV was reported in 3 patients treated concurrently with ondansetron and fluoxetine. The author [68] suggested that the accumulation of serotonin resulting from the use of

fluoxetine may have reduced the antiemetic effects of ondansetron by competing with ondansetron at 5-HT3 receptors. Postoperatively administered ondansetron significantly increased patient demand for tramadol, an agent whose analgesic effects are dependent on enhanced serotonergic transmission [69,70]. It was hypothesized that ondansetron decreases the analgesic effects of tramadol through competitive inhibition of serotonin [69].

5.4. Cardiac ion channel interactions
All of the 5-HT3 receptor antagonists block human cardiac ion channels in vitro (Table 3) [42-55]. Granisetron has the greatest effect on sodium channels (Fig. 2) [71], whereas ondansetron has the greatest effect on potassium channels [38-40]. Drugs that block sodium channels have the potential to increase QRS intervals, whereas drugs that block potassium channels may potentially cause QT prolongation [71]. Based on the in vitro data, it is unlikely that plasma levels reached after a 40-lg/kg IV dose of granisetron will produce significant sodium channel blockade in vivo [71,72]. Numerous studies investigating the cardiac safety of granisetron and the other 5-HT3 receptor antagonists have been completed both in healthy adults and in patients receiving chemotherapy to assess these potential effects. In healthy volunteers, a 300-lg/kg dose of granisetron had no significant effect on PR interval, QRS duration, or QTc [50]. Transient small increases in PR interval and QRS complex duration were noted in some healthy male adults receiving z3 mg/kg dolasetron [73]. Both dolasetron and ondansetron

PONV prophylaxis and 5-HT3 antagonists prolonged the QTc interval in healthy volunteers in another study [74], with dolasetron also increasing QRS duration and ondansetron prolonging the JT interval. However, the changes were transient and asymptomatic, and doses of both drugs used in this study exceeded those recommended for PONV prophylaxis [74]. In another study [75] comparing the cardiovascular effects of granisetron and ondansetron in healthy adults, no clinically important changes were reported with the IV administration of granisetron 10 lg/kg over 30 seconds or 5 minutes or IV administration of ondansetron 32 mg over 15 minutes. The mean postdose QTc interval for 32 mg IV ondansetron over 5 minutes was significantly greater than for the other regimens [75]. Because cancer patients tend to be older and, thus, have additional comorbidities related to the cardiovascular system, studies evaluating cardiac safety of 5-HT3 receptor antagonists in chemotherapy patients may provide a measure of the safety of these agents in elderly postoperative patients. The safety of granisetron in chemotherapy patients has been established in at least 3 studies in which there were no clinically significant cardiac changes detected after IV administration of 3-mg granisetron [76,77]. In addition, there was no potentiation of cardiac effects with coadministration of granisetron and either doxorubicin or epirubicin [78]. Several studies have reported electrocardiogram (ECG) abnormalities in chemotherapy patients receiving dolasetron (see Keefe [79] for a review). It should also be noted that the prescribing information for dolasetron [38] and tropisetron [41] contains cardiac warnings. Ondansetron is reported to have less effect on ECG than dolasetron, but there have been rare reports of chest pain, ECG alterations, hypotension, and tachycardia with ondansetron [39]. In addition, 2 case reports [80,81] have indicated that

311 arrhythmias and myocardial ischemia can be associated with ondansetron.

6. Dosage and timing of administration of 5-HT3 receptor antagonists for prophylaxis
The 2003 PONV guidelines [8] recommended administration of each of the 5-HT3 receptor antagonists at the end of surgery for prophylaxis. These recommendations, although generally in line with current practice, are not entirely consistent with prescribing information (Table 2) [8,32,38-41] but were based on the panel’s review of the PONV literature up to February 2002 and the principles of evidence-based medicine. Timing of administration of ondansetron at the end of surgery has been found to reduce the need for rescue antiemetics in the PACU [82,83]. However, another study has shown no difference in the timing of administration of dolasetron [84]. Accumulation of empirical data has promoted evolution of dosage of some compounds in response to cost considerations. It should be noted that small-dose ondansetron one mg, granisetron 0.5 mg, and tropisetron 0.5 mg have been recommended for treatment of PONV for patients who have not receive prophylaxis or in whom prophylaxis failed [8]. The available evidence regarding the optimal time of administration and the minimal effective dose for the 5HT3 receptor antagonists is still controversial. This is perhaps not surprising because trials to study PONV are expensive and challenging to design and manage, making it difficult to justify additional studies to determine the least effective dose once an effective dose with acceptable safety has been established.

Fig. 2 In vitro effect of 5-HT3 receptor antagonists on human sodium channel inhibition (INa). Reprinted with permission from J Pharmacol Exp Ther 2000;295:614-20 [71].

312 The 2003 PONV guidelines [8] recommend the administration of 12.5 mg of dolasetron 15 minutes before the end of anesthesia. This regimen is consistent with the product’s prescribing information [38] and reflects a pooled analysis of 3 randomized, multicenter, placebo-controlled trials involving patients receiving balanced general anesthesia in which doses of dolasetron of 12.5, 25, 50, or 100 mg administered near the end of surgery had comparable reductions in nausea and vomiting when compared with placebo [85]. Although doses of dolasetron of less than 12.5 mg have not been tested, in one of the 3 trials, the 12.5 mg dose was less effective than 25 mg, leading the authors to conclude that 12.5 mg is near or at the low end of the effective dose range [85]. An ondansetron dose of 4 mg IV is recommended immediately before induction in the prescribing information [39] and a dose of 4 mg to 8 mg IV is recommended at the end of surgery in the 2003 PONV guidelines [8]. Most studies have reported that 4 mg ondansetron, when administered at or before induction, was as effective as 8 mg, whereas lower doses were less effective [86-90]. A meta-analysis of 48 trials of ondansetron vs placebo involving more than 12 000 patients determined that 4 mg was as effective as 8 mg, whereas one mg had minimal efficacy in preventing vomiting [15]. However, in patients with a prior history of PONV, 8 mg was more effective than 4 mg [88]. A quantitative review determined that 8 mg ondansetron was also more effective than 4 mg for late outcomes (within 48 hours), whereas 16 mg was more effective than 8 mg but did not offer any advantage over 8 mg after 48 hours [14]. Low-dose prophylaxis with ondansetron one mg has been proposed [8]. Dosage of granisetron for PONV prophylaxis is controversial [91], with a recent study [92] suggesting that doses lower than those listed in the prescribing information [40] (one mg) may have efficacy. The 2003 PONV guidelines [8] recommend 0.35 mg to 1.0 mg IV at the end of anesthesia based on studies demonstrating that doses of approximately 0.3 mg (based on patient weight) were as effective as approximately 1.2 mg when administered at induction [93]. By contrast, lower doses of 0.1 mg [94] and 2 lg/kg (approximately 0.1 mg based on patient weight in the treatment group) [93] were not effective when administered just before or immediately after induction. Still, the minimal effective dose for granisetron when administered as monotherapy at the end of surgery for PONV prophylaxis has not been determined. An 11-center, prospective, placebo-controlled pilot study conducted by D’Angelo et al [92] evaluated the use of low doses (0.1 mg, 0.2 mg, and 0.3 mg) of granisetron as monotherapy for the prevention of PONV in patients undergoing abdominal hysterectomy. All 3 doses resulted in a numerical reduction in vomiting with respect to placebo in the 0- to 6-hour period and reductions in the time to first use of rescue medication (4 h for placebo vs approximately 13 h for granisetron-treated patients). However, this study was not adequately powered to show statistical significance

A.L. Kovac between groups. The recently reported results of a multicenter, prospective, randomized double-blind trial [95] validated the hypothesis of using a lower granisetron dose in combination with dexamethasone. The efficacy and safety of granisetron 0.1 mg plus dexamethasone 8 mg, compared with ondansetron 4 mg plus dexamethasone 8 mg, were found to be similar in preventing PONV after abdominal hysterectomy. Dexamethasone was administered at induction, and granisetron or ondansetron was given approximately 15 minutes before extubation. Most patients in each group had no vomiting in the 0- to 2-hour interval after extubation: 94% for granisetron plus dexamethasone vs 97% for ondansetron plus dexamethasone [95]. Better or equal efficacy is achieved by combination of a low dose of a 5-HT3 receptor antagonist with an antiemetic such as dexamethasone. Tropisetron 2 mg IV is recommended before surgery in its prescribing information [41]. However, the 2003 PONV guidelines [8] recommended tropisetron 5 mg IV to be given at the end of surgery. In a PONV prophylaxis study [96] in patients undergoing gynecologic surgery, there was no difference between doses of 0.5 mg, 2 mg, and 5 mg tropisetron administered before anesthesia. Another study [97] determined that 5 mg of tropisetron administered before induction was effective, but it did not evaluate other doses. When administered before induction, 2 mg and 5 mg of tropisetron were equally effective during the first 6 hours, but 5 mg was more effective than 2 mg in the 6- to 18-hour period [98]. Thus, there appear to be insufficient data on the minimal effective dose of tropisetron when administered at the end of anesthesia to provide a firm recommendation. A prospective interventional study [99] found 2 mg tropisetron administered at the end of surgery to be effective while noting the lack of useful guidelines on dose and timing of administration.

7. Rescue therapy after failure of a 5-HT3 receptor antagonist
For patients in whom prophylaxis with 5-HT3 receptor antagonists fails within 6 hours of surgery, the 2003 PONV guidelines [8] recommend treatment with a drug from another class, such as droperidol (0.625 mg IV), dexamethasone (2 to 4 mg IV), or promethazine (12.5 mg IV). These recommendations are supported in a treatment study by Kovac et al [87] of 428 patients requiring rescue medication after prophylactic therapy for PONV with 4-mg ondansetron. After antiemetic failure, patients were randomized to receive placebo or a repeat dose of ondansetron. In this setting of PONV ondansetron prophylaxis, ondansetron was no more effective than placebo. The lack of retreatment efficacy may be due to a subset of patients who were refractory to treatment with the same 5-HT3 receptor antagonist, or it may reflect a contribution from mechanisms of emesis not involving serotonin receptor stimulation in these patients. Two recently published studies [100,101] have indicated that

PONV prophylaxis and 5-HT3 antagonists prophylaxis is improved when using promethazine for rescue, compared with redosing with ondansetron in patients who failed ondansetron prophylaxis. In addition, in patients who failed prophylaxis with droperidol, dimenhydrinate was also more effective than droperidol for the treatment of established PONV in the PACU. Two studies [98,99] involving patients with CINV demonstrate that patients who experience failure with one 5-HT3 receptor antagonist have benefited from retreatment with a different 5-HT3 receptor antagonist. An open-label trial [102] evaluating the efficacy and safety of granisetron in 517 patients (88% of whom had failed therapy with metoclopramide, dexamethasone, or ondansetron due to a lack of efficacy or to adverse effects) determined that 53% to 60% had a complete response to granisetron. In a study [103] of 40 patients who had failed therapy with ondansetron plus dexamethasone for CINV, switching to granisetron plus dexamethasone, resulted in significantly better protection against vomiting than remaining on ondansetron plus dexamethasone. A limitation of this study is the small number of patients evaluated (n = 40 [total]) and that the doses used in crossover arms (ondansetron 8 mg + dexamethasone vs granisetron 3 mg + dexamethasone) may not have been equivalent effective doses. These results suggest that retreatment with an alternate 5-HT3 receptor antagonist may rescue patients failing initial PONV prophylactic therapy with another 5-HT3 antagonist. A recently published study [104] evaluated the use of granisetron 0.1 or 1 mg vs ondansetron 4 mg for the treatment of PONV in patients who failed prophylaxis with ondansetron. Although this study was powered as a pilot study, the researchers concluded that patients with a history of PONV during prior surgeries benefited from repeat 5-HT3 receptor antagonist dosing, regardless of which drug was given as a second dose. In addition, no differences existed in the rates of rescue with the granisetron 0.1- and 1 mg doses. The study by Candiotti et al [63] provided evidence that patients with multiple CYP2D6 alleles are ultrametabolizers of certain drugs, including ondansetron and tropisetron. Janicki [65] found that 85% (81.3% with dolasetron and 88% with granisetron treatment) of 150 patients with moderate to high risk for PONV showed complete response to PONV prophylaxis. The genetically defined extensive and ultrametabolizers had a higher frequency of vomiting than all other patients in the short term (3 hours; P b 0.01) and up to 24 hours after surgery. Taken together, these findings [63,65] suggest that antiemetic prophylaxis with the 5-HT3 antagonists metabolized by the CYP2D6 system could be improved by adjustment for the CYP2D6 genotype. Repeating the 5-HT3 receptor antagonist also may be helpful if failure occurs more than 6 hours after surgery, although the optimal dose and time interval for readministration has not been determined [8]. This is an important question that needs to be addressed for the postdischarge aspects of PONV.

313

8. Combination therapy
For the most part, PONV prophylaxis with antiemetic monotherapy has not been entirely effective. The involvement of multiple mechanisms in the pathogenesis of PONV suggests that combination therapy with antiemetics of different classes may be required to reduce the incidence of PONV further than can be obtained with 5-HT3 receptor antagonists alone in certain patients. The combination of conventional doses of 5-HT3 receptor antagonists with either droperidol or dexamethasone has greater efficacy in PONV prophylaxis than does the 5-HT3 receptor antagonist alone [36,105]. Combination therapies involving 5-HT3 receptor antagonists with other agents such as metoclopramide, promethazine, and cyclizine have been less thoroughly studied [106]. Potential synergy between antiemetics of different classes may allow lower doses of 5-HT3 receptor antagonists to be used, resulting in cost savings over the use of the 5-HT3 receptor antagonist alone. However, very little currently is known about the role of potential synergistic effect in reducing dosages of the individual drugs [22]. Neurokinin-1 (NK1) receptor antagonists represent a potentially valuable antiemetic for use in combination with 5-HT3 receptor antagonists in PONV prophylaxis. A combination of the NK1 receptor antagonist aprepitant with ondansetron and dexamethasone had greater efficacy than with ondansetron and dexamethasone alone in the prevention of CINV over multiple cycles of chemotherapy [107]. A time course evaluation of CINV after administration of aprepitant or a 5-HT3 receptor antagonist (ondansetron or granisetron, alone or in various combinations that included dexamethasone) determined that early emesis (8-12 h) after cisplatin is mediated largely by serotonin, whereas NK1 receptors became dominant after that time [108]. If similar findings hold true for PONV, coadministration of an NK1 inhibitor with a 5-HT3 receptor antagonist may prolong the efficacy of PONV prophylaxis. Furthermore, concurrent administration of aprepitant had no effect on the pharmacokinetics of either ondansetron or granisetron, suggesting that these agents can be administered together without adjustment of dosage of the 5-HT3 receptor antagonists [109]. There is presently no published information available on the use of aprepitant in PONV prophylaxis. Still, other NK1 receptor antagonists have been shown to have efficacy in the treatment [110] and prophylaxis [111] of PONV after gynecologic surgery. When combined with ondansetron, emesis was almost completely prevented and time to rescue was significantly prolonged [111].

9. Postdischarge nausea and vomiting
With patients routinely being discharged within hours of ambulatory surgery, PDNV is a common problem. Lack of medical supervision and inadequate access to effective antiemetic agents may be distressing to the patient or may lead to potentially serious complications if PDNV is severe

314 or prolonged. The incidence of nausea and vomiting generally is higher after discharge from the ambulatory surgery facility than while still in the surgical facility. In one study, [112], the incidence of PONV in the recovery room was approximately 24%, whereas the incidence of PDNV within 5 days of the procedure was approximately 47%. Two systematic reviews [113,114] evaluated the incidence of PDNV. Wu et al [113] reported incidences of 17% for postdischarge nausea and 8% for postdischarge vomiting, with more than one third of these patients not experiencing any nausea or vomiting before discharge from the hospital. Gupta et al [114] evaluated patients participating in randomized trials of antiemetic prophylaxis to determine the incidence of PDNV. Placebo-treated patients in this analysis had a 36% incidence of nausea and a 20% incidence of vomiting. These rates are substantially higher than those reported by Wu et al perhaps because trials of antiemetics often enroll patients at higher-than-average risk of having PONV, which also may increase their risk for PDNV. There are few published studies evaluating the effect of anesthetic regimens incorporating the use of 5-HT3 receptor antagonists on the prevention of PDNV. In their systematic review, Gupta et al [114] reported a reduction in PDNV incidence for ondansetron (one mg, 4 mg, or 8 mg) and dexamethasone but not for droperidol or metoclopramide. However, it should be noted that the reductions in PDNV with either ondansetron 4 mg or dexamethasone, although statistically significant, are not clinically relevant (number needed to treat = 12.9 and 12.2, respectively). In contrast, the reduction in PDNV with combination therapy was clinically significant (number needed to treat = 5), illustrating the improved benefit with combination therapy. The mechanism by which the benefits of ondansetron administered at the time of anesthesia extend into the postdischarge period is not entirely clear, given the short plasma half-life of this compound, but it merits further investigation. One possible explanation is that this activity may reflect the effect, however minimal, of ondansetron on the l receptor. Oral therapy with ondansetron also decreased the incidence and severity of PDNV after ambulatory surgery in a small study [115], suggesting that oral therapy with 5-HT3 receptor antagonists may be an effective alternative or adjunct to IV 5-HT3 receptor antagonist therapy in preventing PDNV.

A.L. Kovac [117,127-129] have yielded inconsistent results. Two studies evaluating the effects of 5 mg IV tropisetron reported no effect of this drug over placebo [124,125]. However, a prophylactic dose of up to 5 mg tropisetron in children was demonstrated to be more effective than placebo in reducing the incidence of PONV using patient-controlled analgesia [126]. Similarly, several studies have demonstrated that IV ondansetron was effective in the control of opioid-induced emesis [117,127,128], whereas Davies et al [129] reported that ondansetron did not reduce nausea and vomiting among women who received morphine after hysterectomy.

11. Conclusions
Postoperative nausea and vomiting is a highly distressing condition, with an incidence of approximately 20% to 30% or greater in populations at highest risk. The 5-HT3 receptor antagonists are among the preferred drugs for first-line therapy in patients at moderate to high risk for PONV. Recent data have demonstrated the efficacy, safety, and costeffectiveness of using low-dose 5-HT3 antiemetics for PONV prophylaxis when used as monotherapy at the end of anesthesia. Use of 5-HT3 receptor antagonists in combination with other antiemetic medications can lead to enhanced efficacy for the highest risk patients. Guidelines for use of these agents and their optimal dosage and time of administration are still evolving. The 5-HT3 receptor antagonists have favorable sideeffect profiles, and serious adverse effects are rare. The ability of 5-HT3 receptor antagonists to affect cardiac ion channels raises concern that cardiac conduction problems may occur with the use of these agents. These concerns are of greater relevance in patients receiving antiemetic therapy with higher doses of cardiotoxic chemotherapeutic agents than those receiving therapy for PONV. Individuals with CYP2D6 deficiency receiving therapy with 5-HT3 receptor antagonists that require metabolism with CYP2D6 (dolasetron and tropisetron and, to a lesser extent, ondansetron) also may be at greater risk for cardiac adverse events, although this area requires further study. In addition, the genetic aspects of enzymatic metabolism are evolving. Recent data from studies of patients receiving CINV therapy suggest that patients failing prophylaxis after administration of one 5-HT3 receptor antagonist may be rescued within the 5-HT3 receptor antagonist class rather than switching to a different drug class. In addition, 5-HT3 receptor antagonists may have value in the treatment of PDNV and OINV. Further evaluation of these areas will be needed before firm recommendations can be made.

10. Opioid-induced nausea and vomiting
Nausea and vomiting are common side effects of opioid analgesics [5,116,117], and use of these agents may increase the risk of PONV more than 4-fold [18]. The reported incidence of OINV ranges from approximately 10% to 61% [117-123]. Although the precise cause of OINV is not known, contributing factors may include anesthetic regimen, type of surgery, age, and gender [117]. At this time, clinical studies evaluating the OINV antiemetic effects of tropisetron [124-126] and ondansetron

Acknowledgment
The author wishes to acknowledge the assistance of Diann Glickman, PharmD, in the preparation of this manuscript.

PONV prophylaxis and 5-HT3 antagonists

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