23. Impact of Multiple Patient-Related Risk Factors* Risk of PONV Increased Based on Number of Primary Risk Factors Present * Validated in 2,722 adult patients receiving inhalational anesthesia. Apfel CC et al. Anesthesiology . 1999;91:693–700. Primary Risk Factors: History of PONV or motion sickness ■ Female sex ■ Nonsmoking ■ Use of postoperative opioids Patients With PONV, %
35. EMEND ® (aprepitant) Blocks Substance P From Binding to NK 1 Receptors EMEND Substance P NK 1 receptor 1. Keller M et al. Biol Psychiatry . 2006;59:216–223. 2. Hargreaves R. J Clin Psychiatry . 2002;63(suppl 11):18–24. Binding of EMEND at the NK 1 Receptor Site 1,2
A study conducted at Stanford University Medical Center was designed to quantify patients’ preferences regarding common, low-morbidity anesthesia postoperative outcomes, such as incisional pain, nausea, or shivering. The survey instrument developed by researchers allowed patients to rank possible outcomes from 1 to 10 (1=most undesirable and 10=most desirable). One hundred one adult patients (aged ≥18 years) who were scheduled to undergo surgery in either the outpatient surgery center or main tertiary hospital surgery suite completed and returned the survey instrument to the preoperative evaluation anesthesia clinic. 1 As shown in this table, patients ranked vomiting as the least preferred outcome ( F -test <0.01), viewing postoperative vomiting as even less preferred than pain. Nausea also ranked among the 5 least preferred postoperative anesthesia outcomes. 1 In order from the least preferred to the most preferred, the other outcomes were ranked: 5) recall without pain (ie, patient remembers being awake during surgery, unable to move or talk); 6) residual weakness; 7) shivering; 8) sore throat; and 9) somnolence. 1 These results are consistent with other research involving patient preferences for symptoms during the immediate postoperative recovery period. A study involving 200 women who underwent elective gynecologic surgery showed that the relative importance to patients of not experiencing symptoms of PONV, pain, and sedation was 74%, 23%, and 3%, respectively. 2 References: 1. Macario A, Weinger M, Carney S, Kim A. Which clinical anesthesia outcomes are important to avoid? The perspective of patients. Anesth Analg . 1999;89:652–658. 2. Lee A, Gin T, Lau ASC, Ng FF. A comparison of patients’ and health care professionals’ preferences for symptoms during immediate postoperative recovery and the management of postoperative nausea and vomiting. Anesth Analg . 2005;100:87–93.
This slide depicts key neurotransmitters involved with emesis. The brainstem vomiting center contains high concentrations of several neurotransmitter receptors, including receptors for acetylcholine, histamine, dopamine, opioid, and serotonin. 1 This anatomic region is also rich in neurokinin 1 (NK 1 ) receptors, which have a high affinity for the recently identified emetic neurotransmitter, substance P. 2,3 By serving as sensors that can be stimulated by drugs, electrolytes, and metabolic chemicals, these receptors relay impulses to the vomiting center and initiate the vomiting reflex. 4 Blockade, or antagonism, of these receptor sites is the mechanism of action of many of the pharmacologic antiemetic agents commonly used for PONV. 1,4 Many currently available antiemetic medications for use in PONV were first developed to treat motion sickness as well as nausea and vomiting induced by chemotherapy and radiation therapy. 4 However, because afferent systems trigger the release of various neurotransmitters, an antiemetic that is effective against one type of vomiting can be ineffective against emesis induced by other stimuli. For example, serotonin 5-HT 3 receptor antagonists exhibit potent antiemetic activity against acute chemotherapy-induced nausea and vomiting but do not inhibit response to other emetogens, such as motion or opioid and dopaminergic agonists. 5 Some receptors, such as 5-HT 3 and NK 1 , are found both peripherally and in the CNS. 3,6 Whereas 5-HT 3 receptor antagonists exert their antiemetic activity primarily on abdominal vagal afferents, it appears that the substance P/NK 1 emetic pathway is primarily centrally mediated. 6 References: 1. Nelson TP. Postoperative nausea and vomiting: understanding the enigma. J Perianesth Nurs . 2002;17:178–189. 2. Cameron D, Gan TJ. Management of postoperative nausea and vomiting in ambulatory surgery. Anesthesiol Clin North America . 2003;21:347–365. 3. Harrison S, Geppetti P. Substance P. Int J Biochem Cell Biol . 2001;33:555–576. 4. Kovac AL. Prevention and treatment of postoperative nausea and vomiting. Drugs . 2000;59:213–243. 5. Diemunsch P, Grélot L. Potential of substance P antagonists as antiemetics. Drugs . 2000;60:533–546. 6. Saito R, Takano Y, Kamiya H. Roles of substance P and NK 1 receptor in the brainstem in the development of emesis. J Pharmacol Sci . 2003;91:87–94. Nelson p. 180/A; p. 182/A Cameron p. 348/A; p. 349/A Nelson p. 180/A; p. 182/A Kovac p. 220/A Cameron p. 348/A; p. 349/A Harrison p. 558/A; p. 559/A Diemunsch p. 534/A; p. 535/A Harrison p. 556/B Saito p. 91/A Kovac p. 216/A,B Nelson p. 182/A Apfel 1999 p. 693/B Cameron p. 348/A; p. 352/A Kovac p. 220/B Harrison p. 558/A; p. 559/A Nelson p. 180/A; p. 182/A Kovac p. 216/A
A simplified risk model developed by Apfel and colleagues was validated in 2 medical centers, involving a total of 2,722 adult patients. All patients received inhalational anesthesia, without antiemetic prophylaxis, for various types of surgery. If needed, nonsteroidal analgesic drugs or opioids (eg, oxycodone or tramadol) were used to treat postoperative pain. Statistical analyses identified 4 predictors of PONV: history of PONV or motion sickness, female sex, nonsmoking, and the use of postoperative opioids. 1 In addition, researchers correlated the incidence of PONV with the number of risk factors present. The risk of PONV increased with the presence of each additional primary risk factor, representing a 30% to 110% relative increase with each additional risk factor 1 : 0 risk factors present : Associated with 10% incidence of PONV 1 risk factor present : Associated with 21% incidence of PONV 2 risk factors present : Associated with 39% incidence of PONV 3 risk factors present : Associated with 61% incidence of PONV 4 risk factors present : Associated with 79% incidence of PONV Based on this approach to risk modeling, a prophylactic antiemetic strategy is recommended for patients with 2 or more of these identified risk factors. 1 Reference: 1. Apfel CC, Läärä E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting. Anesthesiology . 1999;91:693–700.
For more than 50 years, scientists have studied different classes of agents and their effectiveness in preventing PONV. Phenothiazines and antihistamines were developed in the 1950s. Butyropherones, substituted benzamides, and anticholinergics were introduced in the 1970s. In 1991, there was a significant breakthrough in emetic prevention with the development of 5-HT 3 receptor antagonists. These agents introduced substantial protection from PONV that previous classes did not offer. However, as shown previously, PONV remains a problem in up to 30% of all surgeries and patient populations despite current therapies. 1–3 Therefore, it was important to further the treatment paradigm to augment prevention of PONV. In 2006, more than 10 years after 5-HT 3 receptor antagonists were approved, the FDA approved EMEND ® (aprepitant)—the first and only substance P/NK 1 receptor antagonist for prevention of PONV. References: 1. Kovac AL. Prevention and treatment of postoperative nausea and vomiting. Drugs . 2000;59:213–243. 2. Habib AS, Gan TJ. Evidence-based management of postoperative nausea and vomiting: a review. Can J Anesth . 2004;51:326–341. 3. Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med . 2004;350:2441–2451.
As a selective substance P/NK 1 receptor antagonist, EMEND ® (aprepitant) has a high affinity for NK 1 receptors located throughout the body. 2,3 In the illustration on this slide, the large multicolored structure represents the NK 1 receptor site. EMEND (the yellow chemical structure) is seen preventing substance P from binding to the site. The NK 1 receptor is a member of the pGPCR (peptidergic G-protein coupled receptor) family of receptors. Its principal signal transduction mechanism is Gq/11. This protein is linked to activation of phospholipase, which mediates an increase in intracellular calcium. 1 The NK 1 receptor is sometimes referred to as the substance P receptor because substance P is its preferred ligand. EMEND is a selective substance P/NK 1 receptor antagonist with a high affinity for NK 1 receptors located throughout the body. 2,3 Substance P can be thought of as a neuromodulator that amplifies the effects of other transmitters acting on the same cells. Therefore, blockade of substance P can have both direct and indirect effects on signaling because the actions of other transmitters are not amplified or exaggerated. As an NK 1 receptor antagonist, EMEND prevents the binding of substance P to the NK 1 receptor, preventing the activation of the signal transduction pathways and subsequent effects on cell physiology and signaling. References: 1. Alexander SPH, Mathie A, Peters JA. Guide to receptors and channels, 2nd edition. Br J Pharmacol . 2006;147(suppl 3):S1–S180. 2. Keller M, Montgomery S, Ball W, et al. Lack of efficacy of the substance P (neurokinin 1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry . 2006;59:216–223. 3. Hargreaves R. Imaging of substance P receptors (NK 1 ) in the living human brain using positron emission tomography. J Clin Psychiatry . 2002;63(suppl 11):18–24.
