1. ASHP Chapter Meeting Content
The Evolving Multimodal Management Plan for Postoperative Ileus: Improving Time to Bowel Recovery

2. Educational Learning Objectives
Describe the prevalence, pathophysiology, and defining criteria for postoperative ileus (POI)
Distinguish evidence-based therapeutic options for the management of POI
Describe how to implement a multimodal management plan in your institution for patients undergoing bowel resection procedures to improve time to bowel recovery

3. Postoperative Ileus (POI)
A temporary impairment of GI motility that occurs for a variable period after abdominal surgery
Kehlet H, Holte K. Am J Surg. 2001;182 (5A Suppl):3S-10S. Holte K, Kehlet H. Drugs. 2002;62:

4. Postoperative Ileus (POI)
Results in a functional inhibition of propulsive bowel activity, irrespective of pathogenetic mechanisms
Primary POI: such cessation occurring in the absence of any precipitating complication
Secondary POI: that occurring in the presence of a precipitating complication (infection, anastomotic leak, etc.)
Paralytic ileus: form of POI lasting > 5 days after open and > 3 days after laparoscopic colectomy
Livingston EH, Passaro EP Jr. Dig Dis Sci. 1990;35:
Delaney CP, et al. Clinical Consensus Update in General Surgery
Baig MK, Wexner SD. Postoperative ileus: a review. Dis Colon Rectum. 2004;47:
Livingston EH, Passaro EP Jr. Postoperative ileus. Dig Dis Sci. 1990;35:
Delaney C, Kehlet H, Senagore AJ, et al, for the Postoperative Ileus Management Council. Postoperative ileus: profiles, risk factors, and definitions—a framework for optimizing surgical outcomes in patients undergoing major abdominal and colorectal surgery. Ann Surg. In press. Available at: Accessed August 2, 2006.
Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg. 2003;138:
Longo WE, Virgo KS, Johnson FE, et al. Risk factors for morbidity and mortality after colectomy for colon cancer. Dis Colon Rectum. 2000;43:83-91. 4

5. There Are Numerous Risk Factors for POI
Resnick p751/ col1/para3/lines 1-5 (for surgical site)
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 Age, Gender, Race
Resnick p755/ col2/para2 (extent of bowel manipulation)
Senegore p483, cols 1-2, para 1 (Age, gender, race)
Resnick p759/ col2/para3/lines (operation time)
Woods, p 60, para 3
Senagore/pS4/t able1/bullet 5 (patient health)
Resnick p757/ col1/para1/ lines 6-8 (amount of opioids)
Resnick p 934/col 1/para 3/lines 6-9 (infection)
Resnick J, et al. Am J Gastroenterol. 1997;92:
Resnick J, et al. Am J Gastroenterol. 1997;92:
Senagore AJ. Am J Health-Syst Pharm. 2007;64(suppl 13):S3-S7.
Senagore AJ, et al. Surgery. 2007;142:
Woods MS. Perspect Colon Rectal Surg. 2000;12:57-76. 5 5

6. POI: Pathogenesis Is Multifactorial
Inhibitory Neural
Reflexes1,2
Stimulation of somatic and visceral fibers inhibits GI motility
Minimizing the effects of 1 or more of these factors could potentially shorten the duration of POI and reduce the incidence of morbidity
Inflammatory
Mediators1
Release of nitric oxide, vasoactive intestinal peptide, calcitonin gene-related peptide, substance P, and
prostaglandins contributes to POI
Opioids1-3
Endogenous
and exogenous opioids reduce propulsive activity in GI tract
Endogenous opioids = endorphins, enkephalins, and dynorphins.
1. Holte K, et al. Drugs. 2002;62:
2. Behm AJ, et al. Clin Gastroenterol Hepatol. 2003;1:71-80.
3. Bauer B, et al. Curr Opin Crit Care. 2002;8:
Holte K, Kehlet H. Postoperative ileus: progress towards effective management. Drugs. 2002;62:
Behm B, Stollman N. Postoperative ileus: etiologies and interventions. Clin Gastroenterol Hepatol. 2003;1:71-80.
Bauer AJ, Schwarz NT, Moore BA, Turler A, Kalff JC. Ileus in critical illness: mechanisms and management. Curr Opin Crit Care. 2002;8: 6

7. Origins of Postoperative Ileus
Neural regulation of the digestive tract involves both intrinsic and extrinsic control systems
Intrinsic control occurs via the enteric nervous system
Executes basic motility patterns
Responds to local and extrinsic events
Extrinsic control occurs via the autonomic nervous system
Integrates gut function into homeostatic balance of the organism
Alterations in the intrinsic or extrinsic control systems of the gut contribute to the pathogenesis of POI, as do several other mechanisms, pathways, and mediators
Goyal RK, Hirano I. N Engl J Med. 1996;334:
Goyal RK, Hirano I. The enteric nervous system. N Engl J Med. 1996;334: 7

8. Inflammatory Pathways of Postoperative Ileus
Anti-Inflammatory
HO-1 (CO/Biliverdin)
Intestinal
Surgery
Macrophages
Muscularis Externa
Inflammatory cytokines
Prostanoids
Adhesion molecules α -
adrenergic NO
iNOS
PMN
Sympathetic Efferents
Primary Afferents
NO (iNOS)
COX-2 (prostanoids)
PGs (COX – 2)
Motility
Cytokines (IL – 6)
ROIs and Proteases
Macrophage
Monocytes
(inhibition)
Mast Cells
iNOS
Vagal
“Barrier Function Disruption” α -
7 receptor
acetylcholine
JAK
/ STAT
Lumenal Colo-Lymphatic
Factors Activate Leukocytes
HO-1: heme oxygenase-1; NO: nitric oxide;
iNOS: inducible nitric oxide synthase; PGs: prostaglandins;
ROIs: reactive oxygen intermediates
Moore B, et al. Sem Col Rect Surg. 2005;16(4):

9. GI Effects of Opioids Pharmacologic Clinical
Decreased gastric motility
Increased GI reflux
Inhibition of small intestinal propulsion
Delayed absorption of medications
Inhibition of large intestinal propulsion
Straining, incomplete evacuation, bloating, abdominal distension
Increased amplitude of non-propulsive segmental contractions
Spasm, abdominal cramps and pain
Constriction of sphincter of Oddi
Biliary 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
Pappagallo M. Am J Surg. 2001;182 (suppl):11S-18S.
Vanegas G, et al. Cancer Nurs. 1998;21:
Kurz A, Sessler DI. Drugs. 2003;63:

10. Incidence of POI for Common Abdominal Surgeries
Procedure Description
Procedures, N
POI Cases, %
Abdominal hysterectomy
456,292
4.1
Large bowel resection
257,336
14.9
Small bowel resection
48,824
19.2
Appendectomy
175,964
6.2
Cholecystectomy
81,013
8.5
Nephroureterectomy
44,808
8.9
Other procedures
597,492
9.0
Total
1,661,729
HCFA Data (Medicare, ). Evaluating 161,000 major intestinal/colorectal resections from 150 US hospitals.
Delaney CP, et al. Clinical Consensus Update in General Surgery
Health Care Financing Administration, , Federal Register. Available at: Accessed April 2006.
Delaney C, Kehlet H, Senagore AJ, et al, for the Postoperative Ileus Management Council. Postoperative Ileus: profiles, risk factors, and definitions—a framework for optimizing surgical outcomes in patients undergoing major abdominal and colorectal surgery. Ann Surg. In press. Available at: Accessed August 2, 2006. 10

11. Consequences of Prolonged POI
Delayed passage of flatus and stool
Increased postoperative pain and cramping
Increased nausea and vomiting
Delay in resuming oral intake
Possible need for parenteral nutrition
Poor wound healing
Delay in postoperative mobilization
Increased risk of other postoperative complications
Deconditioning
Pulmonary complications
Other nosocomial infections
Prolonged hospitalization
Decreased patient satisfaction
Increased health care costs
Delaney CP, et al. Clinical Consensus Update in General Surgery
Delaney C, Kehlet H, Senagore AJ, et al, for the Postoperative Ileus Management Council. Postoperative ileus: Profiles, risk factors, and definitions—A Framework for optimizing surgical outcomes in patients undergoing major abdominal and colorectal surgery. Ann Surg. In press. Available at: Accessed August 2, 2006.
Bungard TJ, Kale-Pradhan PB. Prokinetic agents for the treatment of postoperative ileus in adults: a review of the literature. Pharmacotherapy. 1999;19:
Kehlet H, Holte K. Review of postoperative ileus. Am J Surg. 2001;182(suppl):3S-10S.
Behm B, Stollman N. Postoperative ileus: etiologies and interventions. Clin Gastroenterol Hepatol. 2003;1:71-80. 11

12. Hospital Discharge Associated With Recovery of GI Function25
GI-2 recovery
Hospital discharge 20 15
Patients (%) 10 5 1 2 3 4 5 6 7 8 9 10
Postoperative Day
GI-2 = Recovery of bowel movement and toleration of solid food
Delaney CP, et al. Am J Surg. 2006;191: 12

13. There Is an Overall Health Care Burden Associated With POI
Prolonged hospitalization
POI
Beds occupied for more time
Increased nursing time
Increased resource utilization
Schuster TG, Montie JE. Urology. 2002;59:
Holte K, Kehlet H. Br J Surg. 2000;87:
Chang SS, et al. J Urol. 2002;167:
Sarawate CA, et al. Gastroenterology. 2003;124(4S1):A-828.

14. Postoperative Ileus: Economic Consequences and LOS
Hospital Claims Database Analysis, open laparotomy pts
ICD-9 coded POI (560.1 = paralytic ileus; and = digestive system complications)
No Coded POI
(n = 175,992)
Coded POI
(n = 17,417)
Mean age (yrs)
50.8
59.8*
Mean OR time (hrs)
2.5 3*
Mean LOS (d)
5.4
10.6*
Opioid PCA (%)
31.3
41.8*
Opioid epidural (%)
2.8
3.7*
Mortality (%)
2.3
Mean total costs
$9,944
$16,303*
Severe or most severe illness (%)**
20.7
48.4*
* P < 0.05 vs no coded POI; ** Based on APR-DRG severity levels
Senagore A, et al. American Society of Colon and Rectal Surgeons 2005 Annual Meeting (abstract). S22, p.165.

15. Economic Burden of POI Associated With Abdominal Surgery
Coded POI
Without Coded POI
Total number of procedures (%)
142,026 (8.5%)
1,519,663 (91.5%)
Average length of stay (days)
11.5
5.5
Cost per hospital stay
$18,877
$9,460
Number of readmissions (%)
5,113 (3.6%)
304 (0.02%)
Cumulative costs for coded POI (total hospitalization + readmission cost) = $1,464,167,173
Data from Premier’s Perspective Comparative Database,160 Hospitals, 2002
Goldstein J, et al. P&T. 2007;32(2):82-90.

16. What Are Current Management Strategies for POI?

17. Preventive and Therapeutic Management Options for POI
Physical Options
Nasogastric tube
Early postoperative feeding
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:
Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg. 2003;138:
Baig MK, Wexner SD. Postoperative ileus: a review. Dis Colon Rectum. 2004;47: 17

18. Nasogastric (NG) Intubation and POI
Traditionally used at many institutions and is one of the mainstays of therapy along with IV hydration
There are no data to support any beneficial effect of NG tubes on postoperative ileus
Can delay feeding and thus recovery from POI
May contribute to problems such as atelectasis, pneumonia, and fever
Kehlet H, et al. Am J Surg. 2001;182(S):3-10.
Cheatam M, et al. Ann Surg. 1995;221:
Sagar P, et al. Br J Surg. 1992;79(11):

19. NG Tubes
NG tubes routinely inserted for gastric decompression until return of bowel function
Removal of NG intubation
Meta-analysis of 28 trials (n = 4194) of abdominal surgery
Accelerated bowel recovery by 0.52 days (95% CI, ; P < )
Earlier flatulence by 0.53 days (95% CI, ; P = )
Reduced vomiting (OR = % CI, ; P = 0.03)
Reduced pulmonary complications (RR = % CI, ; P = 0.01)
Shortened LOS by 1.21 days (95% CI, ; P < )
Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.
Nelson R, et al. Cochrane Database Syst Rev. 2007;CD

20. Rationale Why would NG tube removal improve outcomes?
Resumption of oral intake
Why would early oral or enteral feeding improve outcomes?
Counteracts catabolism
Improves immune function
Hastens wound healing

21. Early Oral or Enteral Feeding
Convention is restriction of enteral intake
Early oral or enteral feeding (within 24 hours)
Meta-analysis of 13 trials (n = 1173) of colorectal surgery
Less vomiting (RR = % CI, ; P = 0.04)
Shortened LOS by 0.89 days (95% CI, ; P = 0.01)
Reduced mortality (RR = % CI, ; P = 0.03)
Meta-analysis of three trials (n = 413) of abdominal gynecologic surgery
Reduced nausea (RR = % CI, ; P = 0.006)
Earlier bowel sounds by 0.50 days (95% CI )
Shortened time to intake of solid food by 1.47 days (95% CI, ; P = )
Shortened LOS by 0.73 days (95% CI, ; P = 0.07)
Andersen HK et al. Cochrane Database Syst Rev. 2006;CD
Charoenkwan K et al. Cochrane Database Syst Rev. 2007;CD

22. RCTs of Early Postoperative Feeding vs Traditional Feedingb
Early feeding
Traditional feeding (no oral intake until POI resolved)
140
120
100 80 60 40 20 * *
Duration of Ileus (h)
*P <.05 * C C D I D F D
Binderow et al. (1994)
Reissman et al. (1995)
Ortiz et al. (1996)
Schilder et al. (1997)
Stewart et al. (1998)
Pearl et al. (1998)
Cutillo et al. (1999)
*P < 0.05
D = defecation; F = flatus; C = combination score; I = ingest regular food
Holte K, Kehlet H. Br J Surg. 2000;87:
Holte K, Kehlet H. Postoperative ileus: A preventable event. Br J Surg. 2000;87: 22

23. Mobilization and Postoperative Ileus
Important in helping to prevent postoperative complications such as clots, atelectasis, or pneumonia
Ambulation thought to help increase blood flow to the GI and speed up recovery from POI
Lack of studies showing any effect of mobilization (alone) to stimulate bowel function and decrease duration of POI
Waldhausen J, et al. Ann Surg. 1990;212:

24. Effect of Surgical Technique
MOA: Reduced activation of inhibitory reflexes and local inflammation due to reduced surgical trauma
800
600
400
200 * * *
Cells/125 x Magnification *
Control
Laparotomy
Eventration
Running
Compression
Histogram of infiltrating polymorphonuclear neutrophils in muscularis whole mounts after different degrees of surgical manipulation. N = 5-7; *P < 0.05
MOA = mechanism of action
Holte K, Kehlet H. Br J Surg. 2000;87:
Kehlet H, Holte K. Am J Surg. 2001;182(5A suppl):3S-10S.
Holte K, Kehlet H. Postoperative ileus: A preventable event. Br J Surg ;87:
Kehlet H Holte K. Review of postoperative ileus. Am J Surg. 2001;182(5 A suppl):3S-10S. 24

25. RCT: Laparoscopy vs Open Surgery.
Laparoscopic
Open
120
100 80 60 40 20 *
Duration of Ileus (h) * * F D D F
Lacy et al.
(1995)
Schwenk et al.
(1998)
Milsom et al.
(1998)
Leung et al.
(2000)
*P < 0.05
D = defecation; F = flatus; RCT = randomized clinical trial
Holte K, Kehlet H. Br J Surg. 2000;87:
Kehlet H, Holte K. Am J Surg. 2001;182(5A suppl):3S-10S.
Holte K, Kehlet H. Postoperative ileus: A preventable event. Br J Surg. 2000;87:
Kehlet H, Holte K. Review of postoperative ileus. Am J Surg. 2001;182(5 A suppl):3S-10S. 25

26. Why Would Laparoscopic Surgery Improve Outcomes?
Smaller incisions
Less handling of intestine (particularly the colon) and less inflammation
Less pain = less opioid used
Earlier ambulation
Less exposure to air and endotoxin
Improved immune consequences
Fewer NG tubes and earlier diet

27. Anesthetic Choice and Route
Almost all intraoperative inhaled or i.v. anesthetics temporarily inhibit GI motility
Level of monitoring is important!
Epidural anesthesia/analgesia synergistically block inhibitory sympathetic reflexes, prevent the release of afferent pain neurotransmitters, and increase splanchnic blood flow
Epidural anesthetics dose-dependently block nociceptive and autonomic fibers first and motor and somatosensory fibers last
Epidural analgesia reduces opioid adverse effects
Use of local anesthesia and nerve blocks further reduce systemic exposure
Bonnet F, Marret E. Br J Anaesth. 2005;95:52-58.

28. Epidural vs PCA Administration of Opioids
Pain control
At rest
On mobilization
+++ ++
+/-
Adverse effects
Ileus
Nausea and vomiting
Sedation
Hypotension
Urinary retention
Workload
Shortening - +
Prolongation
Postop morbidity reduction
Cardiovascular (CV)
Respiratory
Bonnet F, Marret E. Br J Anaesth. 2005;95:52-58.
PCA: patient-controlled analgesia

29. Effect of Epidural Local Anesthetics vs Systemic Opioids on Postoperative Ileus* 50
100
150
200
Wallin
1986
Scheinin
1987
Ahn
1988
Wattwil
1989
Bredtman
1990
Riwar
1991
Liu
1995
Neudecker
1999
Length of POI (hours)
Epidural local
anesthetics
Systemic opioid
Holte K, Kehlet H. Br J Surg. 2000;87:

30. Opioid-Sparing Analgesia
Total Morphine (mg)
40 colectomy patients
Correlation between morphine PCA dose and first bowel sounds (P = 0.001), flatulence, (P = 0.003), and first bowel movement (shown, P = 0.002)
No correlation between incision length and morphine dose
350.0
300.0
250.0
200.0
150.0
100.0
50.0
R = 0.48 P = 0.002
ICD-9-CM coded POI correlates with systemic morphine (OR = 12.1;
95% CI, )
Hours to First Bowel Movement
Cali RL, et al. Dis Colon Rectum. 2000;43:
Goettsch WG, et al. Pharmacoepidemiol Drug Saf. 2007;16:

31. Opioid-Sparing Analgesia
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Reduce prostaglandin production
R, DB study of morphine PCA ± ketorolac in 79 colorectal surgeries showed 29% less morphine use, earlier first bowel movement (1.5 [ ] vs 1.7 [1-2.8] days, P < 0.05), and earlier ambulation (2.2 ± 1 vs 2.8 ± 1.2 days, P < 0.05) with NSAID use
Similar results in other surgeries and epidural route
Concerns: platelet inhibition (bleeding)
Cyclooxygenase-2 (COX-2) Inhibitors
Similar results as NSAIDs; safety?
Surveys indicate patients prefer inadequate pain relief over adequate analgesia with associated bowel dysfunction
Person B. Wexner S. Curr Probl Surg. 2006;43:6-65.
Chen JY. Acta Anaesthesiol Scand. 2005;49:

32. Prokinetic Agents Metoclopramide improves nausea but… 120 90 60 30
Placebo
Erythromycin
120 90
Hypomotility (hours) 60 30
Jepsen
(n = 55)
Cheape
(n = 93)
Tollesson
(n = 20)
Seta
(n = 32)
Chan
(n = 32)
Lightfoot
(n = 22)
Jepsen S, et al. Br J Surg. 1986;73:
Cheape JD, et al. Dis Colon Rectum. 1991;34:
Tollesson PO, et al. Eur J Surg. 1991;157:
Seta ML, et al. Pharmacotherapy. 2001;21:
Chan DC, et al. World J Gastroenterol. 2005;11:
Lightfoot AJ, et al. Urology. 2007;69:

33. 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
Alvimopan
Methylnaltrexone
Kurz A, Sessler DI. Drugs. 2003;63: Taguchi A, et al. N Engl J Med. 2001;345:
Kurz A, Sessler DI. Opioid-induced bowel dysfunction. Drugs. 2003;63:
Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med. 2001;345: 33

34. Naltrexone N-methylnaltrexone
Methylnaltrexone: A Novel, Quaternary -Opioid Receptor Antagonist
Naltrexone N-methylnaltrexone +
CH3
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.

35. 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 i.v.
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.
Delaney CP, Weese JL, Hyman NH, et al, for the Alvimopan Postoperative Ileus Study Group. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;48.

36. Methylnaltrexone Phase 2: Results Reported as Mean Time (hr)  S.E.
Endpoint
MNTX
(n = 33)
Placebo
(n = 32)
P-value*
Full liquids
70 ± 9
100 ± 19
0.05
1st BM
97 ± 6
120 ± 10
0.01
GI recovery
124 ± 9
151 ± 16
0.06
Discharge eligible
119 ± 7
149 ± 17
0.03
Actual discharge
140 ± 6
165 ± 16
0.09
*1-sided
Viscusi E, et al. Anesthesiology. 2005;103:A893.

37. Methylnaltrexone for POI: Phase 3 Studies
Segmental colectomy1,2 and ventral hernia repair3
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 endpoints4-6
1. Available at: Accessed March 2009.
2. Available at: Accessed March 2009.
3. Available at: Accessed March 2009.
4. Available at:
html. Accessed March 2009.
5. Available at: Accessed March 2009.
6. Available at: Accessed July 2009.

38. Alvimopan: A Novel, Quaternary -Opioid Receptor Antagonist
Moderately Large MW (461 Da)
Alpha vi mu opioid peripheral antagonist
Fentanyl
Schmidt WK. Am J Surg. 2001;182(5A suppl):27S-38S.

39. Alvimopan Peripherally acting µ-opioid receptor antagonist1
Highly selective for µ-opioid receptor over  and κ receptors1,2
Higher potency at µ-opioid receptor than morphine and methylnaltrexone2
Because of large molecular weight and polarity, does not readily cross the blood-brain barrier; thus, does not block central opioid receptors2
Phase 1, phase 2, and phase 3 trials have been completed3-8
FDA approval May 20089
Azodo IA, et al. Curr Opin Investig Drugs. 2002;3:
Schmidt WK. Am J Surg. 2001;182(5A suppl):27S-38S.
Taguchi A, et al. N Engl J Med. 2001;345:
Wolff BG, et al. Ann Surg. 2004;240:
Delaney CP, et al. Dis Colon Rectum. 2005;48:
Viscusi E, et al. Surg Endosc. 2006;20:67-70.
Ludwig K, et al. Arch Surg. 2008;143:
Buchler M, et al. Aliment Pharmacol Ther. 2008;28:
FDA approval available at: Accessed March 2009.
Azodo IA, Ehrenpreis ED. Alvimopan (Adolor/GlaxoSmithKline). Curr Opin Investig Drugs. 2002;3:
Pasternak GW. Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol. 1993;16:1-18.
Schmidt WK. Alvimopan (ADL ) is a novel peripheral opioid antagonist. Am J Surg. 2001;182(5A suppl):27S-38S.
Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med. 2001;345:
Wolff BG, Michelassi F, Gerkin TM, et al, for the Alvimopan Postoperative Ileus Study Group. Alvimopan, a novel, peripherally acting mu opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004;240:
Delaney CP, Weese JL, Hyman NH, et al, for the Alvimopan Postoperative Ileus Study Group. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;48: 39

40. Alvimopan for POI: Phase 3 Clinical Trial Summary
Study
Surgery
N (MITT)
Alvimopan Dose (mg)
Primary Endpoint
Secondary Endpoints
3131
Bowel resection or radical hysterectomy
510 (469)
6, 12
GI-3
GI-2, DOW
3022
Partial colectomy or simple or radical hysterectomy
451 (424)
3083
Bowel resection or simple or radical hysterectomy
666 (615)
3144
Bowel resection
654 (629) 12
GI-2
GI-3, DOW
0015
738 (705)
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
Wolff BG, et al. Ann Surg. 2004;240:
Delaney CP, et al. Dis Colon Rectum. 2005;48:
Viscusi E, et al. Surg Endosc. 2006;20:67-70.
Ludwig K, et al. Arch Surg. 2008;143:
Buchler M, et al. Aliment Pharmacol Ther. 28:

41. Alvimopan for POI: Phase 3 Trials
Men and women, ≥ 18 years old
Partial small or large bowel resection with primary anastomosis; total abdominal hysterectomy (in some studies)
General anesthesia
Standardized postoperative care
Pain Management
Analgesia via IV opioid patient-controlled analgesia (PCA) (US)
Opioids via IV or IM bolus or IV PCA (non-US)
Nasogastric (NG) tube out at end of surgery or early on postoperative day (POD) 1
Liquids offered, ambulation encouraged on POD 1
Solid food offered on POD 2
Exclusions: Opioids within 1-4 weeks, epidural opioids, local anesthetics, nonsteroidal antiinflammatory drugs (NSAIDs), or severe concomitant disease(s)

42. Alvimopan POI Phase 3 Study Design
Surgery
Randomization
Treatment-emergent adverse reactions:
Events occurring after first dose and ≤ 7 days after last dose of study drug or those present at baseline that increased in severity after start of study drug
Preop dose ≥ 30 min and < 5 hr
Alvimopan 12* mg BID
Screening
Placebo BID
≤ 7 PODs or discharge
–30 1 2 3 4 5 6 7 8 9 10 11 12 13 14
POD
* In some studies, a 6 mg dose of alvimopan was also evaluated

43. Alvimopan Phase 3 Study Endpoints
GI-3 (Primary endpoint studies 302, 308, 313, 001)
Later time of:
Upper GI recovery: time to tolerating solid food
Lower GI recovery: first to occur of passed flatus or bowel movement (BM)
GI-2 (Primary endpoint study 314)
Lower GI recovery: time to first BM
Time to discharge order (DCO) written

44. Alvimopan in Bowel Resection: Pooled Analysis (Studies 302, 308, 313)
Delaney CP, et al. Ann Surg. 2007;245: 44 44

45. Postoperative NGT insertion
Pooled Data From Phase III Studies of Alvimopan: Postoperative Morbidity Studies 302, 308, 313 15
12.2 12
Placebo
9.2
Alvimopan 6 mg 9
Alvimopan 12 mg *
6.8 *
6.8
Patients, %
6.7 6 ‡ †
3.9 † †
3.0 3
1.8
1.9
1.5
1.2
1.0
Postoperative NGT insertion
POI as an SAE
EPSBO or POI
as an SAE
Anastomotic leak
*P < 0.05; †P < 0.001; ‡P = 0.003
NGT = nasogastric tube; POI = postoperative ileus; SAE = serious adverse event; EPSBO = early postoperative small bowel obstruction
Delaney CP, et al. Ann Surg. 2007;245:
Delaney CP, Wolff BG, Viscusi ER, et al. Alvimopan, for postoperative ileus following bowel resection: A pooled analysis of Phase III studies. Ann Surg. In press. Available at: Accessed August 2, 2006.
Delaney CP, Weese JL, Hyman NH, et al, for the Alvimopan Postoperative Ileus Study Group. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;48:
Wolff BG, Michelassi F, Gerkin TM, et al, for the Alvimopan Postoperative Ileus Study Group. Alvimopan, a novel, peripherally acting mu opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004;240:
Viscusi ER, Goldstein S, Witkowski T, et al. Double-blind, randomized, placebo-controlled, phase III clinical trial of alvimopan for the management of postoperative ileus (POI) following major abdominal surgery (Study 14CL308) [Abstract No. S075]. Presented at the American Society of American Gastrointestinal and Endoscopic Surgeons, Hollywood, FL. April 14-17, 2005. 45

46. Prolonged hospital stay
Pooled Data From Phase III Studies of Alvimopan: Hospital Resource Use Studies 302, 308, 313 40
38.1 35
Placebo 30
Alvimopan 6 mg †
Alvimopan 12 mg
24.4 † 25
19.9
Patients, % 20 15
13.7 *
11.7 † ‡
8.6 10
7.0
7.3
7.7 5
Prolonged hospital stay
Readmission
DCO written ≥ 7 days
*P = 0.024; †P < 0.001; ‡P = 0.040
DCO = discharge order
Delaney CP, et al. Ann Surg. 2007;245:
Delaney CP, Wolff BG, Viscusi ER, et al. Alvimopan, for postoperative ileus following bowel resection: A pooled analysis of Phase III studies. Ann Surg. In press. Available at: Accessed August 2, 2006.
Delaney CP, Weese JL, Hyman NH, et al, for the Alvimopan Postoperative Ileus Study Group. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;48:
Wolff BG, Michelassi F, Gerkin TM, et al, for the Alvimopan Postoperative Ileus Study Group. Alvimopan, a novel, peripherally acting mu opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004;240:
Viscusi ER, Goldstein S, Witkowski T, et al. Double-blind, randomized, placebo-controlled, phase III clinical trial of alvimopan for the management of postoperative ileus (POI) following major abdominal surgery (Study 14CL308) [Abstract No. S075]. Presented at the American Society of American Gastrointestinal and Endoscopic Surgeons, Hollywood, FL. April 14-17, 2005. 46

47. GI Tract Recovery in Patients Following Bowel Resection: Alvimopan 12 mg Study 314
Endpoint
Alvimopan
(n = 317)
Placebo
(n = 312)
P-value
GI-2 (hr)
92.0
111.8
---
GI-2 hazard ratio
1.53 (1.29, 1.82)
< 0.001
LOS (days)
5.2
6.2
POI-related morbidity (%)
6.9
14.4
0.003
3 Most Common Treatment-Emergent Adverse Events
– Nausea (placebo 66.2% vs alvimopan 57.8%; P = 0.003)
– Vomiting (placebo 24.6% vs alvimopan 14.0%; P < 0.001)
– Abdominal distention (placebo 20.3% vs alvimopan 17.6%; P = 0.42)
Ludwig K, et al. Arch Surg. 2008;143:

48. Time to GI-2: Combined Data From 5 Alvimopan Studies (Bowel Resection)
1.0
Alvimopan 12 mg
Placebo
0.9
0.8
0.7
0.6
Estimated Probability of
Achieving GI-2 Recovery
0.5
0.4
0.3
0.2
0.1
0.0 24 48 72 96
120
144
168
192
216
240
264
Hours After End of Surgery
Wolff BG, et al. Ann Surg. 2004;240:
Delaney CP, et al. Dis Colon Rectum. 2005;48:
Viscusi E, et al. Surg Endosc. 2006;20:67-70.
Ludwig K, et al. Arch Surg. 2008;143:
Buchler M, et al. Aliment Pharmacol Ther. 28:
Available at: Accessed March 2009.

49. 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

50. Alvimopan for Opioid-induced Bowel Dysfunction (OBD)
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: and
Accessed March 2009.

51. 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: Accessed March 2009.

52. Multimodal/Fast Track Management

53. 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?
NG tube
removal
Opioid sparing
Laxatives, prokinetics
POI (the role of
the pharmacist)
Laparoscopic surgery
Epidural anesthetics
Early feeding,
fluid
management
Mobilization?
Mattei P. World J Surg. 2006;30:
Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.

54. Multimodal Approach: Preoperative Components
Education
Stabilize coexisting diseases
Optimize comfort (minimize anxiety)
Ensure hydration, electrolytes, normothermia
Appropriate use of prophylactic therapy (nausea, ileus, pain, antibiotic)
White PF, et al. Anesth Analg. 2007;104:

55. Multimodal Approach: Intraoperative Components
Anesthesia to optimize surgery and recovery
Local anesthesia/analgesia (or thoracic epidural) if possible
Laparoscopic surgery if possible (gentle handling of tissue)
White PF, et al. Anesth Analg. 2007;104:

56. Multimodal Approach: Postoperative Components
Remove NG tube
Laxative, start oral feedings early
Minimize opioids
Ambulate
Discharge criteria
White PF, et al. Anesth Analg. 2007;104:

57. Fast-Track Example (Colectomy)
Day
Standard
Fast-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 1
Admit 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 2
Epidural or PCA, laxative, mashed food, out of bed
Remove epidural, plan discharge
POD 3
Transition to oral opioids (limit epidural and systemic opioids), out of bed
Oral opioids or NSAIDs, fully mobilize, discharge
POD 7
Extract staples, discharge pending orders
Outpatient clinic, extract staples
SICU = surgical intensive care unit
PACU = postanesthetic care unit
Raue W, et al. Surg Endosc. 2004;18:

58. Multimodal Outcomes Expedited gastrointestinal recovery
Earlier oral nutrition
Fewer complications
Shortened hospital LOS
Fewer readmissions
Cost minimization
Greater patient satisfaction?
Best results with epidural anesthesia/ analgesia
Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.
White PF, et al. Anesth Analg. 2007;104:
Raue W, et al. Surg Endosc. 2004;18:

59. Costs of POI? Implementation of multimodal pathways
Decreased length of hospital stay
Decreased incidence of prolonged hospital stay
Decreased readmission
Decreased need for supportive care
Decreased personnel use
Decreased laboratory tests
Decreased radiological studies
Increased hospital bed availability
Leslie JB. Alvimopan: A peripherally acting mu-opioid receptor (PAM-OR) antagonist. Drugs Today. 2007;43(9): 59

60. Role of the Pharmacist Medication protocol Comfort (minimize anxiety)
Appropriate hydration, electrolytes, normothermia
Appropriate use of prophylactic therapy (nausea, ileus, pain, antibiotic)
Postoperative analgesia (with opioid minimization) and pain assessment
Laxatives
Gannon RH. Am J Health-Syst Pharm. 2007;64(20Suppl 13):S8-12.

61. Role of the Pharmacist (cont)
Stabilize coexisting diseases
Advocate diet
Promote mobilization
Team member and education of team
Discharge planning
Patient education and compliance assessment
Gannon RH. Am J Health-Syst Pharm. 2007;64(20Suppl 13):S8-12.

62. 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:

63. POI: Summary
POI affects between 4% and 20% of abdominal surgical patients annually and has a detrimental effect on clinical outcomes and costs of care
Accelerating recovery of GI function improves clinical outcomes, enhances patient comfort, and shortens hospital length of stay
Treatment options for POI include both pharmacologic and nonpharmacologic approaches 63

64. POI: Summary (cont)
Laparoscopy, NSAIDs, and peripheral opioid-receptor antagonists show promise in reducing the incidence of POI
Thoracic epidurals with local anesthetics may help to reduce POI without adversely affecting pain relief
NSAIDs may reduce the requirement for opioids
Peripheral opioid-receptor antagonists appear to reduce the adverse GI side effects of opioids while preserving their analgesic benefits
There is an evolving consensus that a multimodal approach using both nonpharmacologic and pharmacologic options is the most consistent and effective strategy for managing POI 64