Current research on PONV/PDNV: Practical implications for today’s pharmacist

Current guidelines for the management of patients at risk of developing perioperative nausea and vomiting/postdischarge nausea and vomiting (PONV/PDNV), include the 2002 American Society of Anesthesiologists (ASA) recommendations,¹ the 2006 guidelines assembled by an American Society of PeriAnesthesia Nurses task force (ASPAN),² and another set published in 2007 with the support of the Society for Ambulatory Anesthesia (SAMBA).³

Overall the treatment recommendations from the Report by the ASA Task Force in 2002 were to use antiemetic agents for the prevention and treatment of nausea and vomiting and to administer multiple agents for prophylaxis or treatment when indicated.¹ Evidence suggests that prophylactic monotherapy with 5-HT₃ antagonists, droperidol, dexamethasone, or metoclopramide is preferred, while for combination treatment a 5-HT₃ antagonist plus dexamethasone is more effective than monotherapy. According to the 2002 guidelines, when rescue therapy is required for nausea and vomiting, a 5-HT₃ antagonist should be given, regardless of the previous agents provided. Yet, current evidence indicates that not all 5-HT₃ antagonists are appropriate for repeated administration; for example, studies of ondansetron have indicated that when poor efficacy is obtained initially, repeat dosing does not enhance the antiemetic effect.⁴

Since the 2002 ASA guidelines were released, another >250 comparative trials on anti-emetic agents have been published; these data were considered in the 2007 revised set of evidence-based recommendations for treating PONV and PDNV, created with the support of SAMBA, by a multidisciplinary international panel of experts.⁵ Both this review of the literature, as well as the ASPAN publication, noted patient risk factors such as being female, a nonsmoker, or having a history of PONV or motion sickness, as well as anesthesia- and surgery-related elements including the use of general anesthesia with volatile anesthetics, nitrous oxide, or postoperative opioids, as well as the duration of the surgery (>2 hours).^2,3 An algorithm for managing PONV is described in Figure 1.³

For low-risk patients, a “wait-and-see” approach is recommended. For medium-risk patients, the use of one or two interventions from the algorithm in Figure 1 is recommended. For prophylaxis of PONV in high-risk patients, two or more multimodal therapies with as many as three interventions were advocated by the expert panel.³

Combination therapy with one or more drugs from different classes is recommended for adults at moderate risk for PONV. The 5-HT₃ antagonists can be combined with droperidol or dexamethasone for good antiemetic effect. Optimal antiemetic dosing has not been established, but it is suggested that dexamethasone not exceed 10 mg i.v. and that droperidol not exceed 1 mg i.v. When combined with other drugs, ondansetron should not exceed 4 mg.

In the 2006 ASPAN publication, the current literature was used as the basis to assemble an evidence-based recommendation for managing PONV and PDNV. In addition to the previously mentioned pharmacologic agents for PONV prophylaxis, H₁ receptor blockers (antihistamines) and the scopolamine patch were recommended, and neurokinin (NK-1) antagonists were noted for their potential to play a role in PONV management, although based only on preliminary studies.² These same agents were also recommended for use as rescue interventions (although, not if already administered unsuccessfully; rather, another drug class should be tried). For prophylaxis of PDNV, dexamethasone and the scopolamine patch were listed, as well as acupuncture and patient education.

Practical implications for today’s pharmacist

The Prospective Observational Study of Treatments, Outcomes, and Patterns of Care (POSTOP) study has provided valuable insight into the state of care for PONV and PDNV. This multicenter, observational study assessed the incidence of PONV over 72 hours following surgery in 376 patients.⁷ In addition, the prophylaxis and rescue treatment patterns regarding these common adverse effects were documented, as well as the concordance of clinical practice with the guideline recommendations that were available (the 2002 ASA and 2006 ASPAN guidelines).^1,2,7

There are several key takeaway messages from the POSTOP study. Firstly, the current prophylactic strategies for PONV and PDNV are inadequate. The incidence of PONV in high-risk patients is highest (42%) in those patients receiving no or only one antiemetic. Furthermore, 47% of patients experienced moderate-to-severe nausea, and depending on the number of antiemetic agents administered, 18% to 40% vomited during the 72-hour period after surgery, 44% of patients reported functional interference due to their emetic symptoms, only 39% had complete control of emesis, and 45% of patients required rescue antiemetic medication.⁷ Secondly, the POSTOP study data demonstrated that adherence to either the 2002 ASA or 2006 ASPAN guidelines for managing PONV and PDNV correlated with a higher complete response rate (63% to 69%) than nonadherent clinical practice (17% to 34%).⁷ Finally, the study’s results indicated that three or more effective antiemetic agents and strategies are required in order to achieve good control (70% control of emesis) of PONV and PDNV.

The currently available antiemetic agents that have demonstrated efficacy at providing prophylaxis of PONV and PDNV are the 5-HT₃ antagonists: ondansetron 4 mg, dolasetron 12.5 mg, granisetron 1 mg, and palonosetron 0.075 mg, as well as dexamethasone 8 mg, droperidol 0.625 mg, and metoclopramide 20 mg. Patients have substantially different outcomes when they are administered these recommended antiemetic agents; current evidence indicates that they do not provide the same level of efficacy. Furthermore, the pharmacological data for palonosetron indicate that this newer 5-HT₃ receptor antagonist has unique properties that confer longer-lasting effects clinically. Additionally, studies of prophylaxis for acute and delayed chemotherapy-induced nausea and vomiting (CINV) indicate that combining palonosetron with antiemetic agents from other drug classes, such as the NK-1 antagonists aprepitant or dexamethasone, appear to confer a synergistic benefit; potentially a similar result may be obtained with palonosetron combinations for prophylaxis of PONV and PDNV.⁸

Although the revised SAMBA consensus guidelines from 2007 indicate that the 5-HT₃ receptor antagonists dexamethasone and droperidol provide the same level of efficacy for managing nausea and vomiting,⁵ evidence indicates that the 5-HT₃-based regimens are more effective then droperidol or metoclopramide.⁹ A systematic review of the literature found that the 5-HT₃ receptor antagonists are superior to traditional antiemetic agents for the prevention of nausea and vomiting.⁹ This meta-analysis of 41 clinical trials illustrated that prophylaxis with 5-HT₃ antagonists led to a 39% reduction in PONV compared to droperidol (0.61 [95% CI, 0.42–0.89], p = 0.24), and a 56% reduction compared with metoclopramide (0.44 [95% CI, 0.31–0.62], p < 0.36) (Table 1). It should be noted that the efficacy achieved by these antiemetic agents was also dependent on the type of surgery being performed—each of which has different associated risks of PONV⁶—as well as the method of delivery of anesthesia.

Probably the best recommendation for managing patients at high risk of developing PONV and PDNV is to administer a combination regimen that includes a 5-HT₃-based therapy. No currently available regimen is entirely effective on its own, so combining antiemetic agents from different drug classes can be beneficial, especially for high-risk patients.¹⁰ Because the 5-HT₃ receptor antagonists dexamethasone and droperidol act independently, the risk reduction of developing PONV or PDNV for combined interventions escalates proportionally to the product of the individual relative risk reductions.⁶ Therefore, the combination of a 5-HT₃ antagonist with dexamethasone or droperidol is more effective than any monotherapy—without an increased adverse effect burden—as demonstrated by large, randomized controlled trials, as well as meta-analyses.^6,11 Furthermore, the higher the risk of PONV, the greater the number of antiemetic interventions that should be utilized for prophylaxis. Hence, the patient’s baseline risk is a key determinant in whether and how many interventions will produce a clinically relevant risk reduction in PONV.⁶

Rescue treatments are too often required to treat PONV and PDNV when prophylaxis fails. A detailed meta-analysis of antiemetic monotherapy versus combination rescue therapies for patients who experience PONV found that rescue medications are more infrequently required for patients who receive 5-HT₃ antagonists plus dexamethasone, rather than either individual agent alone for prophylaxis.¹² Importantly, rescue treatments are rendered ineffective when the same drug has already been used prophylactically.⁶ Therefore, rescue medications during the immediate postoperative period should be limited to drugs that have different mechanisms of action.¹³ For example, if ondansetron is administered for prophylaxis but PONV occurs, then promethazine or diphenhydramine could be given for rescue treatment rather than a repeat dose of ondansetron.¹⁴

Other factors to consider when managing PONV and PDNV include the pharmacologic differences among 5-HT₃ antagonists, as molecular distinctions between the members of drug class may impact outcomes for patients. In particular, agents with higher binding affinities and longer times spent bound may improve the complete control rate.¹⁵ Phase III trial data in 544 adult women undergoing elective inpatient gynecologic surgery or breast surgery using 0.075 mg of palonosetron demonstrated a significant reduction in nausea from 0 to 72 hours after surgery compared to placebo or lower doses (p = 0.0008).¹⁵ A previously performed dose-ranging study showed that a higher dose (30 μg/kg) was more effective than 1 μg/kg (typically used effectively for elective laparascopic outpatients) in an inpatient population undergoing major gynecologic procedures.¹⁶ Another dose-ranging study in 574 patients undergoing either abdominal or gynecologic laparascopic surgery found similar responses to intravenous (i.v.) palonosetron at doses of 0.025 mg, 0.050 mg, or 0.075 mg.¹⁷ Administration of any of these three doses of i.v. palonosetron to 438 patients located in the U.S. and Romania resulted in a significant delay in time to treatment failure compared with placebo (p = 0.0242).¹⁷ In this second study,¹⁷ the relative risk reductions associated with palonosetron 0.075 mg compared with placebo for complete response were 24% (0 to 6 hrs), 20% (6 to 72 hrs), and 25% (0 to 72 hrs).¹⁷ These results led to FDA approval of palonosetron for the prevention of PONV.

The newest class of antiemetic agents are the NK-1 antagonists. Two large studies with double-blind designs were conducted to assess the effectiveness of the NK-1 antagonist aprepitant in the prevention of PONV. The data were pooled from both trials for a post hoc analysis.¹⁸ A total of 1599 participants who underwent abdominal surgery under general anesthesia were randomized to receive either a preoperative dose of aprepitant 40 mg PO, 125 mg PO, or ondansetron 4 mg i.v. Then nausea, vomiting, and the use of rescue medications were assessed over the 48 hours following surgery. Aprepitant was demonstrated to provide better nausea and emetic control than ondansetron¹⁸ (Table 2) through 48 hours after surgery.¹⁹ The adverse effects of aprepitant treatment most commonly include pruritus, constipation, and nausea beyond 48 hours after surgery.¹⁹ Aprepitant is a single-dose oral medication, however, its clinical use is limited by its price and potential for drug interactions with other inhibitors or drugs metabolized by CYP3A4.¹⁹ A pharmacoeconomic study with a cost-benefit analysis may be required before any significant changes are made to the established treatment paradigm for PONV. However, a combination of therapies that includes aprepitant may be an option for patients with a history of emesis following previous surgeries.

Conclusion

The following four strategies may help pharmacists improve emetic outcomes for surgical patients. First, it is critical to identify high-risk patients in order to provide appropriate prophylaxis, as this management approach is more successful than attempting to treat established PONV or PDNV. In particular, patients undergoing abdominal surgery, especially gynecological procedures, should be considered for prophylaxis, as these patients tend to have a higher risk of developing PONV. Secondly, prophylaxis for PONV should be maintained throughout the period of risk. Thirdly, the number of anti-emetic agents prescribed should be appropriate for the individual’s risk level, once again emphasizing the importance of patient risk stratification. Finally, adherence to the anti-emetic regimen should be stressed to patients, as this is an important way to have a significant impact on outcomes.

References

Author notes