1. A Case-Based Approach Delineating the Use of Pharmacologic Agents for the Management of Postoperative Ileus Robert MacLaren, PharmD, BSc (Pharm), FCCM, FCCP Associate Professor School of Pharmacy University of Colorado Critical Care Pharmacy Specialist University of Colorado Hospital Aurora, Colorado

2. It is the policy of The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty, activity planners, content reviewers, and staff participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a person with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The France Foundation has identified and resolved any and all conflicts of interest prior to the release of this activity. Dr. MacLaren has received grants/research support from Hospira. Faculty Disclosure

3. Educational Learning Objectives Describe the importance of improving time to gastrointestinal recovery that occurs postsurgery and consider how this affects length of hospital stay and overall quality of patient care Evaluate the evidence for therapeutic options that may improve gastrointestinal recovery postsurgery and integrate these efforts toward supporting overall surgical quality measures Describe how interprofessional collaboration surrounding gastrointestinal surgery can result in better alignment with current surgical quality measures and formulate strategies to integrate this into current practice

4. Patient Case Goals Evaluate the evidence regarding the use of laxatives, prokinetic agents (metoclopramide and erythromycin), and peripherally acting mu-opioid receptor antagonists (PAMORA) for the management of postoperative ileus (POI) Describe the clinical application of these pharmacologic agents with respect to managing POI and improving time to bowel recovery Given a case scenario, implement therapeutic strategies using pharmacologic agents to improve time to bowel recovery and patient outcomes

5. Patient Case QQ is a 57-year-old male (5’11”, 85 kg) who is undergoing an urgent open laparotomy for a partial colectomy secondary to stage IIB adenocarcinoma His physical exam is normal, vital signs are within normal limits, and all laboratory values are within normal limits except hemoglobin = 9.5 g/dL and hematocrit = 30.1 (values of both one week prior at a clinic visit were 14.5 g/dL and 45, respectively) The anemia is believed related to the colon cancer as his stools are guaiac-positive His past medical history is significant for coronary artery disease and hypertension (metoprolol 50 mg PO bid, ASA 325 mg PO daily); coronary artery bypass grafting was performed 5 years ago QQ does not smoke, rarely drinks alcohol, and his mother died of colon cancer

6. Patient Case (cont) Preoperatively, QQ is given lorazepam 1 mg po and clindamycin 900 mg iv x 1 Intraoperatively, QQ is sedated with fentanyl, propofol, and sevoflurane During surgery, a low anterior resection is performed (excision of the tumor, 10 cm of colon, and regional lymphadenectomy) with colorectal anastomosis Estimated blood loss is minimal and QQ remains hemodynamically stable during the three-hour surgery QQ is extubated in the PACU, the nasogastric tube is removed, and he is transferred to the step-down unit for monitoring Transfer orders include bisacodyl 10 mg po tid, morphine by patient- controlled analgesia (PCA) with basal of 1 mg/hr, scheduled NSAID IV or PO if tolerated, sips of clear fluid as tolerated, ambulate as tolerated PACU: post-anesthesia care unit

7. Are laxatives evidence-based treatment options for POI?

8. Laxatives and Neostigmine Randomized study of 20 colectomy cases of bisacodyl 10 mg PR q 12 hours (2 doses) vs placebo suppositories starting three days after surgery –By POD 3, all 10 patients taking bisacodyl defecated vs 2 of 10 patients taking placebo (P < 0.001) –LOS: 8.5 ± 2.7 vs 10.4 ± 5.3 days Randomized study of 200 colorectal resections of bisacodyl 10 mg po bid vs placebo beginning before surgery –Time to defecation: 3 vs 4 days (P = 0.001) –Similar hospital length of stays and pain scores Neostigmine enhances colonic motility but not well studied and many adverse events Wiriyakosol S, et al. Asian J Surg. 2007;30:167-172. Zingg U, et al. Int J Colorectal Dis. 2008;23:1175-83.

9. Laxatives and POI Administration of bisacodyl improves bowel recovery – no data with other laxatives

10. Case Progression Days 1-2 Postsurgery Day one postsurgery –QQ received morphine 2 mg/hr by PCA, pain scores are 3-5/10 –He started sips of fluids and a soft diet Day two postsurgery –QQ transitioned to a pain regimen that includes an oral opioid, pain scores are 1-2/10 –Full diet ordered and he eats lunch but not much dinner –QQ is able to ambulate 100 yards twice

11. Day three postsurgery –QQ refuses breakfast, complains of nausea, abdominal pain (pain scores are 3-5/10), and cramping –No bowel movement or flatus to date –On exam, his abdomen is distended with infrequent bowel sounds –Labs are within normal limits, CT scan of the abdomen is unremarkable –An ileus is suspected and the care team discusses the use of prokinetic agents Case Progression Day 3 Postsurgery

12. Is there a role for metoclopramide or erythromycin for the prevention or treatment of POI?

13. Prokinetic Agents for Management of Ileus Metoclopramide improves nausea but… Jepsen S, et al. Br J Surg. 1986;73:290-291; Cheape JD, et al. Dis Colon Rectum. 1991;34:437-441; Tollesson PO, et al. Eur J Surg. 1991;157:355-358; Seta ML, et al. Pharmacotherapy. 2001;21:1181-1186; Chan DC, et al. World J Gastroenterol. 2005;11:4776-4781; Lightfoot AJ, et al. Urology. 2007;69:611-15; Bonacini M, et al. Am J Gastronterol. 1993;88:208-211; Smith AJ, et al. Dis Colon Rectum. 2000;43:333-337.

14. Data do not support prokinetic therapy for treatment or prevention of ileus Prokinetic Agents for Management of Ileus

15. QQ has an ileus – could something have been done to prevent it from occurring?

16. PharmacologicClinical Decreased gastric motilityIncreased GI reflux Inhibition of small intestinal propulsionDelayed absorption of medications Inhibition of large intestinal propulsionStraining, incomplete evacuation, bloating, abdominal distension Increased amplitude of non-propulsive segmental contractions Spasm, abdominal cramps, and pain Constriction of sphincter of OddiBiliary colic, epigastric discomfort Increased anal sphincter tone, impaired reflex relaxation with rectal distension Impaired ability to evacuate bowel Diminished gastric, biliary, pancreatic and intestinal secretions. Increased absorption of water from bowel contents Hard, dry stool GI Effects of Opioids: Establishing the Role for Peripherally Acting Mu-opioid Receptor Antagonists Pappagallo M. Am J Surg. 2001;182 (suppl):11S-18S. Vanegas G, et al. Cancer Nurs. 1998;21:289-297. Kurz A, Sessler DI. Drugs. 2003;63:649-671.

17. POI: Peripheral Opioid Antagonism Most patients require opioids Opioids inhibit GI propulsive motility and secretion; the GI effects of opioids are mediated primary by µ-opioid receptors within the bowel Naloxone and naltrexone reduce opioid bowel dysfunction but reverse analgesia An ideal POI treatment is a peripheral opioid receptor antagonist that reverses GI side effects without compromising postoperative analgesia –Methylnaltrexone –Alvimopan Kurz A, Sessler DI. Drugs. 2003;63:649-671. Taguchi A, et al. N Engl J Med. 2001;345:935-940.

18. Naltrexone N-methylnaltrexone + CH 3 Methylnaltrexone: A Novel, Quaternary  -Opioid Receptor Antagonist Poorly lipid soluble, does not penetrate the BBB, not demethylated to significant extent in humans Does not antagonize the central (analgesic) effects of opioids or precipitate withdrawal Foss JF. Am J Surg. 2001;182 (5ASuppl):19S-26S.

19. Methylnaltrexone: MNTX 203 Methods Phase 2 study for reduction of postoperative bowel dysfunction Randomized, double-blind, placebo-controlled 65 patients undergoing segmental colectomy MNTX 0.3 mg/kg or placebo iv –First dose within 90 min of end of surgery, then every 6 hr –Up to 24 hr after GI recovery, max of 7 days GI recovery: tolerated solid food plus bowel movement (BM) Viscusi E, et al. Anesthesiology. 2005;103:A893.

20. Methylnaltrexone: Phase 2 Results MNTX n = 33 Placebo n = 32 0 20 40 60 80 100 120 140 160 180 200 Full Liquids1st BMGI RecoveryDischarge Eligible Actual Discharge Time (hours) * * * *P < 0.05 Viscusi, E et al. Anesthesiology. 2005;103:A893.

21. Methylnaltrexone for POI: Phase 3 Studies Segmental colectomy (N = 542); IV methylnaltrexone (12 or 24 mg) or placebo every 6 hours 1 Preliminary results 2 –Study did not achieve the primary endpoint of a reduction in time to recovery of GI function for methylnaltrexone treatment compared with placebo –No improvement in time to hospital discharge eligibility compared with placebo Segmental colectomy; IV methylnaltrexone (12 or 24 mg) or placebo every 6 hours 3 Study active but not recruiting Ventral hernia repair; IV methylnaltrexone (12 or 24 mg) or placebo every 6 hours 4 Study completed but results pending Similar pain scores and opioid usage in all studies 1. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00387309. Accessed April 2010. 2. Available at: http://www.wyeth.com/irj/portal/news/archive?nav=display&navTo=/wyeth_html/home/news/pressreleases/2008/1205322072160. html. Accessed April 2010. 3. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00401375. Accessed April 2010. 4. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00528970. Accessed April 2010.

22. Methylnaltrexone: Phase 2 Results Phase 2 results suggest methylnaltrexone expedites GI recovery but phase 3 results either pending or do not support hastened GI recovery

23. Fentanyl Alpha vi mu opioid peripheral antagonist Alvimopan: A Novel, Quaternary  -Opioid Receptor Antagonist Moderately Large MW (461 Da) Schmidt WK. Am J Surg. 2001;182(5A suppl):27S-38S. Zwitterion and MW result in poor solubility, minimal absorption, and poor BBB penetration Does not antagonize the central (analgesic) effects of opioids or precipitate withdrawal

24. Alvimopan for POI - Phase 3 Clinical Trial Summary StudySurgeryN (MITT) Alvimopan Dose (mg) Primary Endpoint Secondary Endpoints 313 1 Bowel resection or radical hysterectomy 510 (469)6, 12GI-3GI-2, DOW 302 2 Partial colectomy or simple or radical hysterectomy 451 (424)6, 12GI-3GI-2, DOW 308 3 Bowel resection or simple or radical hysterectomy 666 (615)6, 12GI-3GI-2, DOW 314 4 Bowel resection654 (629)12GI-2GI-3, DOW 001 5 Bowel resection738 (705)6, 12GI-3GI-2, DOW GI-3: later time of first tolerated solid food and time for first flatus or bowel movement; GI-2: later time of first tolerated solid food and time for bowel movement; DOW: time to discharge order written All studies conducted in North America except 001, which was conducted in Europe and New Zealand 1.Wolff BG, et al. Ann Surg. 2004;240:728-735. 2.Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. 3.Viscusi E, et al. Surg Endosc. 2006;20:67-70. 4.Ludwig K, et al. Arch Surg. 2008;143:1098-1105. 5.Büchler M, et al. Aliment Pharmacol Ther. 2008;28:312-325. All North American studies (studies beginning with “3”) only enrolled subjects requiring open laparotomy, systemic exposure of opioids, and did not provide NSAID use for analgesia

25. Alvimopan POI Phase 3 Study Design Surgery Randomization Placebo BID Alvimopan 6 mg BID Pre-op dose ≥ 30 min and < 5 hrs before surgery Endpoints: GI-2, GI-3, Time to discharge order written, safety Treatment until discharge or up to 7 days Upper and Lower GI Recovery GI-3: later time of first tolerated solid food and time for first flatus or bowel movement; GI-2: later time of first tolerated solid food and time for bowel movement Alvimopan 12 mg BID

26. Alvimopan Phase 3 Studies – GI Recovery 0 20 40 60 80 100 120 140 Study 313Study 302Study 308Study 314Study 001 Time to GI-2 (hours) Placebo6 mg Alvimopan12 mg Alvimopan Studies 313, 302, 308 include bowel resection and hysterectomy; Studies 314, 001 bowel resection only 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. 2008;28:312-325. * * * *P < 0.001; # P < 0.01; § P < 0.02 vs placebo § # # # §

27. Alvimopan Phase 3 Studies – GI Recovery Phase 3 results suggest alvimopan expedites GI recovery

28. Alvimopan Phase 3 Studies: Discharge Orders Written -25 -20 -15 -10 -5 0 Study 313Study 302Study 308Study 314Study 001 Reduction in Time to Discharge Order Written Compared with Placebo (hours) 6 mg Alvimopan12 mg Alvimopan P = 0.003 P < 0.001 P = 0.008 P = 0.015 P < 0.001 Studies 313, 302, 308 include bowel resection and hysterectomy; Studies 314, 001 bowel resection only All studies conducted in North America except 001, which was conducted in Europe and New Zealand 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. 2008;28:312-325.

29. Alvimopan Bowel Resection Pooled Analysis Delaney C, et al. Ann Surg. 2007;245:355-363.Studies 302, 308, 313 GI-3 GI-2 Ready for HD DOW Alvimopan 6 mg Alvimopan 12 mg 2.52 1.5 10.50 In favor of alvimopanIn favor of placebo P value 0.001 < 0.001 1.28 1.38 1.34 1.46 1.37 1.48 1.36 1.43 GI-3: later time of first tolerated solid food and time for first flatus or bowel movement; GI-2: later time of first tolerated solid food and time for bowel movement; HD: ready for hospital discharge based on GI recovery; DOW: discharge order written Possible dose response relationship of alvimopan

30. Alvimopan POI-Related Morbidity Bowel Resection Pooled Analysis ‡ Wolff B, et al. J Am Coll Surg. 2007;204:609-616. *P ≤ 0.001 ‡ Studies 302, 308, 313, 314 0 2 4 6 8 10 12 14 16 18 Overall POMPost-op NGT Insertion Overall POI Complications POI Complications Resulting in Prolonged Stay POI Complications Resulting in Readmission Patients (%) Placebo n = 695 Alvimopan 12 mg n = 714 * * * * POM: postoperative morbidity; NGT: nasogastric tube; POI: postoperative ileus Similar pain scores and opioid usage in all studies

31. Treatment- Emergent Adverse Reaction Bowel Resection PatientsAll Surgical Patients Placebo (N = 986) % Alvimopan (N = 999) % Placebo (N = 1365) % Alvimopan (N = 1650) % Anemia4.25.25.4 Constipation3.94.07.69.7 Dyspepsia4.67.04.85.9 Flatulence4.53.17.78.7 Hypokalemia8.59.57.56.9 Back pain1.73.32.63.4 Urinary retention2.13.22.33.5 Worldwide POI Safety Population Available at: http://www.entereg.com/pdf/prescribing-information.pdf. Accessed March 2009. Alvimopan Safety Treatment-emergent adverse events reported in ≥ 3% alvimopan-treated patients and for which the rate for alvimopan was ≥ 1% than placebo

32. Alvimopan for POI Summary Treatment of patients undergoing bowel resection with alvimopan compared with placebo –Accelerated return of bowel function –Reduced the time to discharge order written –Reduced postoperative ileus-related morbidity Alvimopan did not reverse postoperative analgesia Alvimopan was well tolerated; adverse events were similar between placebo and alvimopan treatment groups FDA approval May 2008 for accelerating GI recovery following bowel resection with primary anastomosis Questionable application with laparoscopic surgical procedures, epidural analgesia, and concurrent use of NSAIDs

33. QQ has Coronary Artery Disease: Is Alvimopan Safe? 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 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 2010.

34. 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.

35. Clinical Decision Analysis of PAMORA No POI POI Prolonged POI- YES Prolonged POI- NO POI-associated complication- NO POI-associated complication- YES PAMRA Placebo Prolonged stay Complication- YES Prolonged stay Complication- NO Readmit- YES Readmit- NO Nosocomial infection VTE N/V NG tube Antiemetics Aspiration? Abd. distension Wound dehiscence? Malnutrition Infection Labs Central line Radiology TPN Readmission costs Side effects? Post-hoc analysis of studies suggest alvimopan saves $977 per treated patient ($11,329 vs. $12,306, P < 0.05) assuming 8.9 doses per patient Bell TJ. Am J Health-Syst Pharm. 2009;66:1362-1368.

36. Case Summary Postsurgery day 3: ondansetron 4 mg PO tid is started Postsurgery day 4: total parenteral nutrition (TPN) is started Postsurgery days 4-7: QQ chews gum and takes sips of water but remains nauseated with “stomach cramps” –He ambulates 100 yards twice daily –The oral opioid is stopped Postsurgery day 7: QQ is able to tolerate a liquid diet, flatus is present Postsurgery day 8: QQ is no longer nauseated, the cramps are gone, and he tolerates a full diet Postsurgery day 9: QQ passes a stool Postsurgery day 10: QQ is discharged

37. Summary Scheduled bisacodyl may reduce POI and accelerate GI recovery –10 mg PO bid within three days of surgery –Whether a similar beneficial effect is observed with other laxatives is unknown The prokinetic agents, metoclopramide and erythromycin, do NOT have a role in the management of POI Peripheral opioid receptor antagonism is a promising approach for reducing POI and accelerating GI recovery in patients following bowel resection –Phase III studies with methylnaltrexone either show no benefit or results are unavailable –Phase III studies with alvimopan show it safely accelerates return of bowel function, decreases the time to discharge order written, and reduces POI-related morbidity without altering pain perceptions and analgesic requirements –Limitations of studies with alvimopan include infrequent laparoscopic surgical procedures, mostly systemic opioid-based analgesia, and limited use of NSAIDs Further investigations need to delineate GI response with alvimopan in these subtypes as well as other types of abdominal surgeries A multimodal approach for managing POI should consider incorporating bisacodyl and alvimopan as management strategies