Update on Current Concepts for the Management of Post-operative nausea

Update on Current Concepts for the Management of Post-operative Nausea and Vomiting Deborah Wagner, PharmD Associate Clinical Professor of Pharmacy Assistant Clinical Professor of Anesthesiology University of Michigan Health Systems Many Patients Experience PONV Beyond the PACU  Of patients who experienced PONV, nearly 80% initially did so in the PACU and/or within 48 hours after discharge. Study Design: Data from a study examining patients’ experiences with PONV following discharge from outpatient surgery centers. Incidence of PONV was measured in the recovery room, by telephone the day after discharge, and by a questionnaire that patients were instructed to complete 5 days after discharge. A total of 143 outpatients (aged ≥18 years) who received general anesthesia and underwent 1 of 4 selected surgeries (laparoscopy, dilation and curettage, arthroscopy, or hernia repair) provided complete data. Some patients who initially experienced PONV within 48 hours after PACU discharge continued to experience PONV for up to 5 days after PACU discharge. PACU=postanesthesia care unit. Carroll NV et al. Anesth Analg. 1995;80:903–909. Apfel 2004 Comparison of Single, Double and Triple Prophylactic Therapies PONV May Incur Higher Costs • In a study conducted in 2000, PONV was associated with increased cost* — A single episode of emesis costs on average $305† — A single episode of nausea costs on average $82 PONV is a major factor limiting early discharge of ambulatory surgical patients PONV is a leading cause of unanticipated hospital admissions after outpatient surgery Preventing PONV can be cost-effective • • • *PACU personnel costs are biggest component. †Median cost $195. Hill et al. Anesthesiology. 2000;92:958-967. Better Therapies for PONV and PDNV? • Multicenter, prospective, observational study of 193 patients undergoing laparoscopy or plastic surgery: — ACR (0-72hrs) 41% in patients who received only 5HT3 prophylaxis vs 49% with combination therapy — 46% of patients had N/V that interfered with daily living — 10% of patients required outpatient services due to N/V O’Hara JF, Abstract, ASA meeting Chicago, 2006 Incidence of Vomiting Relative to Opioid Administration Roberts etal. Anesth Analg 2005 Logarithmic Dose Response Relationship  Vomiting ο Nausea How Useful are Risk Scoring for PONV • ―…simplified risk scores are useful both as a method to estimate individual risk of PONV and as a method for comparing groups of patients for antiemetic trials…‖ • ―…multiple are…superior to single predictor models…‖ • ―…the power to discriminate which individual will suffer from PONV will remain imperfect…‖ Br J Anaesth 2001 Evolution of Antiemetics for PONV Substance P/NK1 receptor antagonists 5-HT3 receptor antagonists Butyropherones Substituted benzamides Anticholinergics Phenothiazines Antihistamines 1950s 1960s 1970s 1980s 1990s 2000s 5-HT3=serotonin receptor type 3. Current Warnings with Promethazine • Classification as a vesicant drug • Deep IM injection is preferred over IV administration • Should be administered through a large vein at a maximum rate of 25mg/min • Reaction is dose and duration related • Lower doses as recommended in new Consensus Guidelines for PONV 2006. Promethazine vs Ondansetron Outcome PACU Nausea Vomiting PONV 24 Hours Nausea Vomiting PONV * P < 0.05 Ondan 19% 24% 29% 24% 38% 48% Prometh 5% 26% 26% 13%* 35% 39%* O+P 5% 13% 17% 17%* 17%* 29%* Placebo 16% 32% 37% 42% 63% 74% J Clin Anesth 1999; 11:596 Metoclopramide • Anesth Analg 1999 — Meta-analysis of 54 studies • Less effective than ondansetron or droperidol • Administered at induction BJA 1999 — Meta-analysis of 66 studies • No significant anti-nausea effect • NNT early 9.1, late 10 adults • NNT early 5.8, late – no effect, pediatrics BJA 2002 — 1180 patients – 237 received metoclopramide — No clinically relevant decrease in POV — EPS symptoms in 14/237 BMJ 2006 — 3140 patients — 10mg, 25mg, 50mg M + 8mg Dex vs 8mg Dex — Only 25 and 50mg effective • • • Metabolism of the 5-HT3 RAs CYP2D6 Ondansetron CYP3A4, 1A2 Carbonyl M Dolasetron Hydrodolasetron (active metabolite) CYP2D6 flavin monooxygenase reductase M CYP3A CYP3A subfamily Granisetron M Metabolism may be an important consideration Large arrows: Predominant metabolic pathway. Small arrows: Minor metabolic pathway. CYP2D6 Genetic Polymorphism: Ultrarapid Metabolizer (Kaiser et al.) • Ultrarapid metabolizer phenotype — Overactive CYP2D6 activity — Reduced effectiveness of ondansetron and tropisetron* • More nausea and vomiting with standard doses of CYP2D6-metabolized 5-HT3 RAs • Patient populations — Northern European countries, 2% to 4% — Mediterranean area, 7% to 12% — Saudi Arabia, 21% — Ethiopia, 29% *Not FDA approved. Kaiser R et al. J Clin Oncol. 2002;20:2805-2811. Intensity of Vomiting as a Function of CYP2D6 Genotype for Patients Treated With Tropisetron* *Not FDA approved. Kaiser et al. J Clin Oncol. 2002;20(12)2805-2811 Substance P: Overview  First discovered in the 1930s1,2  Belongs to tachykinin family of neurotransmitters3 — Neurokinins (NK): tachykinins found in mammals3 — Greatest affinity for NK1 receptor1  Plays integral role in relaying noxious and aversive sensory information to the brain4 Structure of Substance P 1. 2. 3. 4. Harrison S, Geppetti P. Int J Biochem Cell Biol. 2001;33:555–576. Gaddum JH, Schild H. J Physiol. 1934;83:1–14. Diemunsch P, Grélot L. Drugs. 2000;60:533–546. Cameron D, Gan TJ. Anesthesiol Clin North America. 2003;21:347–365. Distribution of Substance P in the Brain Prefrontal cortex Striatum Locus ceruleus (NE) Amygdala Hippocampus Brainstem vomiting center Raphe nuclei (5-HT) Substance P High Low Monoamine Pathways • Substance P is widespread throughout the brain. 1, 2 1. 2. Mantyh PW et al. Brain Res. 1984;307:147–165. Sergeyev V et al. Neuroreport. 1999;10:3967–3970. Documented Activity at Brain NK1 Receptors EMEND® (aprepitant) 40 mg Blocks 90% of Brain NK1 Receptors Binding of PET tracer to NK1 receptors before dosage with EMEND 40 mg Locus of action of aprepitant Binding of PET tracer to NK1 receptors after dosage with EMEND 40 mg Low High Tracer Binding PET=positron emission tomography. Keller M et al. Biol Psychiatry. 2006;59:216–223. Clinical Studies in PONV: Study Design All patients underwent general anesthesia for open abdominal surgery Aprepitant 40 mg Ondansetron 4 mg I.V. • 2 multicenter, randomized, double-blind, active comparator– controlled trials • Patients (Study 1, N=573; Study 2, N=494) were randomized to receive aprepitant 40 mg 1 to 3 hours before anesthesia or ondansetron 4 mg I.V. immediately before anesthesia. Prevention of Emesis at 24 Hours Aprepitant superior to Ondansetron • Study 2 demonstrated that aprepitant had a clinically meaningful effect with respect to the secondary end point ―no emesis‖ during the first 24 hours after surgery and showed that the use of aprepitant 40 mg was associated with a 16% improvement over ondansetron 4 mg I.V. for the ―no emesis‖ end point (90% vs 74%, P<0.001; not statistically significant after prespecified multiplicity adjustment). • Compared with ondansetron I.V. in Study 1, aprepitant did not affect time to first use of rescue medication in the 24 hours following the end of surgery, but aprepitant did delay time to first emesis. Analysis of Complete Response at 24 Hours* Complete response comparable for aprepitant and ondansetron • Study 2 did not satisfy its primary hypothesis that aprepitant is superior to ondansetron 4 mg I.V. as measured by the proportion of patients with a complete response in the 24 hours following the end of surgery. Study 2 also did not reach statistical significance with respect to the secondary end point ―no use of rescue medications for established emesis or nausea‖ in the 24 hours following the end of surgery. *Not superior based on a prespecified, fixed-sequence multiplicity strategy. Prevention of Emesis at 48 Hours Aprepitant superior to ondansetron • In Study 2, the secondary end point ―no emesis‖ in the 48 hours following the end of surgery showed that aprepitant was not superior to ondansetron I.V. after prespecified multiplicity adjustment. • Study 2 did not satisfy its primary hypothesis that aprepitant is superior to ondansetron I.V. as measured by the proportion of patients with a complete response (no emesis, no rescue medications) in the 24 hours following the end of surgery. Time to First Emesis Percentage of Patients Who Remained Emesis Free During the 48 Hours Following the End of Surgery • Use of aprepitant did not affect time to first use of rescue medication when compared with ondansetron. Aprepitant (EMEND®): Indications and Usage  APREPITANT, in combination with other antiemetic agents, is indicated for: — Prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. — Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.  APREPITANT is indicated for prevention of postoperative nausea and vomiting  40mg within 3 hours prior to induction of anesthesia Aprepitant (EMEND®) Drug Interactions • Corticosteroids: — Dexamethasone - 50% oral dose reduction in CINV studies with 125/80mg dose, no dosage reduction with single 40mg oral dose — Methylprednisolone - 25% IV dose reduction and 50% oral dose reduction in CINV with 125/80mg dose, no dosage reduction with single 40mg oral dose • Oral Contraceptives: alternative or back-up contraceptive methods should be used following a single 40mg oral dose for 1 month • Midazolam: Mild increases in serum levels of midazolam with single 40mg oral dose, no dosage reduction recommended • Warfarin: Significant decreases in INR’s Side Effect Profile Most Common Clinical Adverse Experiences in PONV Clinical Trials Aprepitant 40 mg (n=564) Ondansetron 4 mg I.V. (n=538) 7.6% 8.6% 8.4% Constipation Nausea Pruritus 8.5% 8.5% 7.6% Pyrexia Hypotension Headache 5.9% 5.7% 5.0% 10.6% 4.6% 6.5% • • • Most adverse experiences were mild to moderate. Bradycardia 4.4% 3.9% No serious drug-related adverse experiences were observed in studies of aprepitant 40 mg for prevention of PONV. Aprepitant is classified as a Pregnancy Category B drug. Summary and Conclusions (cont) • Understanding of emetic pathways continue to evolve • Involvement of different emetic neurotransmitter pathways may impact treatment strategies • The first new class of PONV therapy in more than 10 years – NK-1 receptor antagonist — Comparable rates of complete response vs traditional 5HT3 receptor antagonist activity (ondansetron 4 mg I.V.) — Significant reduction in emesis compared to traditional 5HT3 receptor antagonist (ondansetron 4mg I.V.) • Utilize multimodal and complementary techniques to optimize therapy University of Michigan Health Systems Football Saturdays – 100,000 Fans