1. Sympathetic Nervous System Inhibitory neural reflexes Neuropeptide and Hormonal Factors Calcitonin gene-related peptide, endogenous opioid peptides, corticotropin-releasing hormone Pharmacologic Exogenous opioids Multiple Pathways Enteric Nervous System Nitric oxide Vasoactive intestinal peptide Substance P Inflammatory Mediators Macrophage and neutrophil infiltration, IL-1, tumor necrosis factor, IL-6 IL = interleukin Luckey A, et al. Arch Surg. 2003;138:206-214. Holte K, Kehlet H. Drugs. 2002;62(18):2603-2615. Person B, Wexner S. Curr Probl Surg. 2006;43:12-65. Pathogenesis of POI Is Multifactorial

2. There Are Numerous Risk Factors for POI POI Is Expected to Affect Almost Every Patient Who Undergoes Abdominal Surgery Surgical Site Extent of Bowel Manipulation Operation Time Patient Health Systemic Infections Amount of Opioids Patient Factors Resnick J, et al. Am J Gastroenterol. 1997;92:751-762. Resnick J, et al. Am J Gastroenterol. 1997;92:934-940. Senagore AJ. Am J Health-Syst Pharm. 2007;64(suppl 13):S3-S7. Senagore AJ, et al. Surgery. 2007;142:478-486.

3. POI and Abdominal Surgery 0 5 10 15 20 25 Abdominal Hysterectomy Large Bowel Resection Small Bowel Resection Appendectomy Chole- cystectomy Nephro- ureterectomy Coded POI (%) Delaney C, et al. Clinical Consensus Update in General Surgery. 2006. Chang S, et al. J Urol. 2002;167:2012-2016. Based on HCFA Data 1999-2000 for all surgeries except cystectomy; cystectomy data from Chang et al, 2002 Cystectomy Other Procedures

4. Clinical and Economic Impact of POI DELAYED RECOVERY Increased postoperative pain Increased nausea and vomiting –Increased risk of aspiration Prolonged time to regular diet –Delayed wound healing –Increased risk of malnutrition/catabolism Prolonged time to mobilization –Increased pulmonary complications Kehlet H, Holte K. Am J Surg. 2001;182(5A suppl):3S-10S. Person B, Wexner S. Curr Probl Surg. 2006;43:12-65. Goldstein J, et al. P&T. 2007;32(2):82-90. Coded POIWithout Coded POI Total number of procedures (%) 142,026 (8.5%)1,519,663 (91.5%) Average length of stay (days) 11.55.5 Cost per hospital stay $18,877$9,460 Number of readmissions (%) 5,113 (3.6%)304 (0.02%) PROLONGED HOSPITALIZATION Increased health care costs Cumulative costs for coded POI (total hospitalization + readmission cost) = $1,464,167,173

5. Preventive and Therapeutic Management Options for POI Physical Options –Nasogastric tube –Early postoperative feeding –Sham feeding, gum chewing –Early ambulation Surgical Technique –Laparoscopy Psychological Perioperative Information Anesthesia and Analgesia –Epidural –NSAIDs Pharmacologic –Prokinetic agents –Opioid (PAMOR) antagonists –Other agents Perioperative Care Plan(s) –Multimodal clinical pathways –Fluid/sodium restriction? PAMOR = peripherally acting µ-opioid receptor antagonist Luckey A, et al. Arch Surg. 2003;138:206-214. Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.

6. Management Options for POI Nonpharmacologic Options ManagementPotential MechanismImpact on Bowel Function, Length of Stay NG tube Gastric/small bowel decompression Removal of NG tube associated with earlier return of bowel function, reduction in pulmonary complications, shorter length of stay Early feeding (including sham feeding) Stimulates GI motility by eliciting reflex response and stimulating release of hormonal factors Some studies report a reduction in POI with early feeding, meta- analyses suggest a modest (non- significant) reduction in length of stay Early ambulation Possible mechanical stimulation; possible stimulation of intestinal function No effect on duration of POI; beneficial for prevention of lower extremity thromboembolism Laparoscopic surgery Decreased opiate requirements, decreased pain, less abdominal wall trauma, less intestinal manipulation Earlier passage of flatus, earlier bowel movement, shortened length of stay Nelson R, et al. Cochrane Database Syst Rev. 2007;(3):CD004929. Holte K, Kehlet H. Br J Surgery. 2000;87:1480-1493. Andersen H, et al. Cochrane Database Syst Rev. 2006;(4):CD004080. Charoenkwan K, et al. Cochrane Database Syst Rev. 2007;(4):CD004508. Lewis S, et al. J Gastrointest Surg. 2009;13:569-575. Noble E, et al. Int J Surg. 2009;7:100-105. Waldhausen J, et al. Ann Surg. 1990;212:671-677. Zutshi M, et al. Colorectal Dis. 2004;6:477-480. Schwenk W, et al. Cochrane Database Rev. 2005;(3):CD003145.

7. Management Options for POI Pharmacologic Options Treatment or Prevention Potential Mechanism Impact on Bowel Function, Length of Stay Epidural (thoracic) anesthesia/analgesia Inhibits sympathetic reflex at cord level; opioid-sparing analgesia Earlier bowel movement, reduced duration of POI compared with systemic analgesic regimens NSAIDs Opiate-sparing analgesia, inhibits COX-mediated prostaglandin synthesis Earlier bowel movement, earlier ambulation, no change in length of stay compared with morphine PCA Metoclopramide Dopamine antagonist, cholinergic agonist, prokinetic agent No benefit on the duration of POI Erythromycin Motilin receptor agonist, prokinetic effect No benefit on the duration of POI LaxativesHelp to induce bowel movement Limited data from small nonrandomized study suggests benefit; additional study required Peripherally selective mu-receptor antagonists Block enteric mu-receptors and minimize opioid effects on GI function, without impacting CNS- mediated analgesia Clinical trials with alvimopan demonstrated reduced time to recovery of GI function, reduced time to discharge order written compared with placebo Person B, Wexner S. Curr Probl Surg. 2006;43:12-65. Chen JY, et al. Acta Anaesthesiol Scand. 2005;49:546-551. Luckey A, et al. Arch Surg. 2003;138:206-214. Becker G, Blum H. Lancet. 2009;373(9670):1198-1206.

8. POI: Peripheral Opioid Antagonism Most patients require opioids Opioids inhibit GI propulsive motility and secretion; the GI effects of opioids are mediated primarily by µ-opioid receptors within the bowel Naloxone and naltrexone reduce opioid bowel dysfunction but can reverse analgesia in higher doses An ideal POI treatment is a peripheral opioid receptor antagonist that reverses GI side effects without compromising postoperative analgesia –Alvimopan –Methylnaltrexone Kurz A, Sessler DI. Drugs. 2003;63:649-671. Taguchi A, et al. N Engl J Med. 2001;345:935-940. Becker G, Blum H. Lancet. 2009;373(9670):1198-1206.

9. Methylnaltrexone for POI: Phase 3 Studies Segmental colectomy 1,2 and ventral hernia repair 3  Treatment: IV methylnaltrexone (12 or 24 mg) or placebo every 6 hours  Primary endpoint: Reduction in time to recovery of GI function compared with placebo  Results: Treatment did not achieve primary or secondary endpoints 4-6 1. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00387309. Accessed March 2009. 2. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00401375. Accessed March 2009. 3. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00528970. Accessed March 2009. 4. Available at: http://www.wyeth.com/news/archive?nav=display&navTo=/wyeth_html/ home/news/pressreleases/2008/1205322072160.html. Accessed March 2009. 5. Available at: http://www.progenics.com/releasedetail.cfm?ReleaseID=311785. Accessed March 2009. 6. Available at: http://www.progenics.com/releasedetail.cfm?ReleaseID=370543. Accessed July 2009.

10. Alvimopan Phase 3 Studies – GI Recovery Wolff BG, et al. Ann Surg. 2004;240:728-735. Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. Viscusi E, et al. Surg Endosc. 2006;20:67-70. Ludwig K, et al. Arch Surg. 2008;143:1098-1105. Büchler M, et al. Aliment Pharmacol Ther. 28:312-325. *P < 0.001; # P < 0.01; § P < 0.02; 0 20 40 60 80 100 120 140 Bowel Resection, Hysterectomy Study 313 Bowel Resection Study 314 Time to GI-2 (hours) Placebo6 mg Alvimopan12 mg Alvimopan * * * § # # # § Bowel Resection, Hysterectomy Study 302 Bowel Resection, Hysterectomy Study 308 Bowel Resection Study 001

11. Pooled Data From Phase III Studies of Alvimopan: Hospital Resource Use Studies 302, 308, 313 *P = 0.024; † P < 0.001; ‡ P = 0.040 DCO = discharge order Delaney CP, et al. Ann Surg. 2007;245:355-363. Prolonged hospital stayReadmissionDCO written ≥ 7 days Placebo Alvimopan 6 mg Alvimopan 12 mg Patients, % ‡ * † † † 13.7 11.7 38.1 8.6 7.3 24.4 7.0 7.7 19.9 0 5 10 15 20 25 30 35 40

12. Treatment- Emergent Adverse Reaction Bowel Resection PatientsAll Surgical Patients Placebo (N = 986) % Alvimopan (N = 999) % Placebo (N = 1365) % Alvimopan (N = 1650) % Anemia 4.25.25.4 Constipation 3.94.07.69.7 Dyspepsia 4.67.04.85.9 Flatulence 4.53.17.78.7 Hypokalemia 8.59.57.56.9 Worldwide POI Safety Population Available at: http://www.entereg.com/pdf/prescribing-information.pdf. Accessed March 2009. Available at: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01838.html; http://www.gsk.com/media/pressreleases/2007/2007_04_09_GSK1012.htm. Accessed March 2009. E.A.S.E.: Entereg Access Support and Education. Available at: http://www.entereg.com/pdf/prescribing-information.pdf. Accessed March 2009. Alvimopan Safety 12-month study in patients taking opioids for chronic non-cancer pain (alvimopan (0.5 mg) or placebo BID) More reports of myocardial infarction in patients treated with alvimopan (1.3%) compared with placebo (0) Serious cardiovascular adverse events in patients at high risk for cardiovascular disease Myocardial infarction did not appear to be linked to duration of dosing Not observed in other alvimopan studies, including POI studies in patients undergoing bowel resection (12 mg dose BID for up to 7 days) Causal relationship between alvimopan and myocardial infarction has not been established Alvimopan for Opioid-induced Bowel Dysfunction (OBD)

13. Alvimopan for POI: Formulary Considerations E.A.S.E.™ Program Distribution Program for ENTEREG ® (alvimopan) Alvimopan is available only to hospitals that enroll in the E.A.S.E. Program. To enroll in the E.A.S.E. Program, the hospital must acknowledge that hospital staff who prescribe, dispense, or administer alvimopan have been provided the educational materials on: – Limiting the use of alvimopan to short-term, inpatient use – Patients will not receive more than 15 doses of alvimopan – Alvimopan will not be dispensed to patients after they have been discharged from the hospital – Hospital will not transfer alvimopan to unregistered hospitals E.A.S.E.: Entereg Access Support and Education. Available at: http://www.entereg.com/pdf/prescribing- information.pdf. Accessed March 2009.

14. What Is “Fast-Track Recovery”? “An interdisciplinary multimodal concept to accelerate postoperative convalescence and reduce general morbidity (including POI) by simultaneously applying several interventions” What are the appropriate choices in constructing fast-track, multimodal protocols? Opioid sparing Laparoscopic surgery Early/sham* feeding, Optimal fluid management Mobilization? Epidural anesthetics Laxatives, prokinetics NG tube removal Mattei P. Rombeau J. World J Surg. 2006;30:1382-1391. Person B, Wexner S. Curr Probl Surg. 2006;43:6-65. *such as gum chewing

15. Fast-Track Example (Colectomy) DayStandardFast-Track Pre- operative Consent, epidural (local anesthetic [LA] with opioid) Consent and educate, anti-emetic, anxiolytic, epidural (LA with opioid) Day of surgery Admit to SICU*, NG out with order, i.v. fluids to body weight, continuous epidural or PCA, anti-emetic, nothing by mouth, sitting Admit to floor post PACU, NG out with extubation, limit i.v. fluid, continuous epidural (limit systemic opioids), NSAID, laxative, mobilize to chair, short walk, soft foods POD 1Admit to floor, epidural or PCA, clear oral liquids and i.v. fluids, out of bed, remove drains and Foley Transition to oral opioids or NSAIDs (limit epidural and systemic opioids), regular diet, mobilize > 8 hr, walk twice daily, remove drains and Foley POD 2Epidural or PCA, laxative, mashed food, out of bed Remove epidural, plan discharge POD 3Transition to oral opioids (limit epidural and systemic opioids), out of bed Oral opioids or NSAIDs, fully mobilize, discharge POD 8Extract staples, discharge pending orders Outpatient clinic, extract staples Raue W, et al. Surg Endosc. 2004;18:1463-1468. SICU = surgical intensive care unit PACU = postanesthetic care unit *Not all centers admit patients to the SICU under standard care

16. The Future Identification of risk factors for POI Patient-centered care –Hydration and electrolytes –Opioid regimen and opioid-sparing therapies –Anxiolytic and anti-emetic therapies Pharmacologic modification of the “stress response” Multidisciplinary PACUs Clinical pathways Outreach services for rehabilitation White PF, et al. Anesth Analg. 2007;104:1380-1396.