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

2. Educational Activity 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 Management Council
Definition of POI
Transient cessation of coordinated bowel motility after surgical intervention, which prevents effective transit of intestinal contents and/or tolerance of oral intake
Delaney CP, et al. Clinical Consensus Update in General Surgery

4. Primary POI: Response by Different Intestinal Segments
Average time to resolution of POI after major abdominal surgery1-3
Small intestine: 0-24 hours
Stomach: hours
Colon: hours
Following intestinal surgery, inhibition of small intestine motility can last from 0 to 24 hours.1,2 The stomach typically takes 24 to 48 hours to regain function, while the colon tends to recover within 48 to 120 hours.1,2 Prolonged ileus may result in bacterial overgrowth and translocation, which potentially lead to sepsis.3
Luckey A, et al. Arch Surg. 2003;138:
Livingston EH, Passaro EP Jr. Dig Dis Sci. 1990;35:
Delaney CP, et al. Clinical Consensus Update in General Surgery
Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg. 2003;138:
Livingston EH, Passaro EP Jr. Postoperative ileus. Dig Dis Sci. 1990;35:
Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs. 2003;63: 4

5. Pathophysiology of POI: Multifactorial
The major causes of POI
Surgical trauma and manipulation of the bowel
Other surgeries such as hysterectomy, knee, thoracic
Stress
Stimulation of GI opioid receptors by endogenous and exogenous opioids
POI has been generally regarded as a usual and inevitable response to surgery
Kehlet H, Holte K. Am J Surg. 2001;182 (5A Suppl):3S–10S.
Holte K, Kehlet H. Drugs. 2002;62:

6. Pathogenesis of POI Is Multifactorial
Luckey p207/col1/para 2/lines 8-10
Sympathetic Nervous System1,2 Inhibitory neural reflexes
Behm p72/col1/para3/ lines 1-3
Behm p72/col2/para2/ lines 4-8
Luckey p207/Table 1
Behm p71/col2/para1/ line 1
Enteric Nervous System2
Nitric oxide
Vasoactive intestinal peptide Substance P
Neuropeptide and Hormonal Factors1,2 Calcitonin gene-related peptide, endogenous opioid peptides, corticotropin-releasing factor
Luckey p207/Table 1
Multiple Pathways
Behm p71/col2/para1/ line 1
Behm p72/ col1/para4; col2/para1/ lines 7-10
Inflammatory Mediators1,2 Macrophage and neutrophil infiltration, IL-1, IL-6
Pharmacologic2
Exogenous opioids
IL = interleukin
1. Luckey A, et al. Arch Surg. 2003;138:
2. Behm B, et al. Clin Gastroenterol Hepatol. 2003;1:71-80. 6 6

7. Effect of Surgical Manipulation
Leukocyte infiltration into intestinal mucosa
Intestinal contractility
0.2
0.4
0.6
0.8 1
0.1 10
100
300
Bethanechol uM
Contractility
Control
Laparotomy
Eventration
Running
Compression
* P < 0.05
800 * *
600 *
400 *
200
Control
Running
Compression
Eventration
Laparo...
Kalff J, et al. Ann Surg. 1998;228:

8. Inhibitory Effects of Opioids on Bowel Function
Endogenous Opioids
Released in response to surgical trauma/ manipulation
Higher degrees of surgical trauma/manipulation → Greater inflammation → Greater gut paralysis
Exogenous Opioids
Commonly administered for postoperative pain
Relationship between amount of opioid administered and time to return of bowel function
Brix-Christensen V, et al. Int J Cardiol. 1997;62:
Yoshida S, et al. Surg Endosc. 2000;14:
Kalff JC, et al. Ann Surg. 1998;228:
Cali R, et al. Dis Colon Rectum. 2000;43:

9. Risk Factors for Postoperative Ileus
Abdominal surgery
Surgical technique
Prolonged opioid analgesia
Preexisting gastrointestinal disease
Physiological stress from surgery
Physical inactivity pre/post surgery
Senagore A. Am J Health-Syst Pharm. 2007;64(S13):S3-7.

10. Clinical Impact of POI 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
Prolonged hospitalization
Increased health care costs
Delayed recovery
Kehlet H, Holte K. Am J Surg. 2001;182(5A suppl):3S-10S.
Leslie JB. Ann Pharmacother. 2005; 39:
Behm B, Stollman N. Clin Gastroenterol Hepatol. 2003;1:71-80.

11. How Long Can POI Last?
Figure from Steinbrook RA. Contemp Surg. 2005; March(suppl):4-7.
Wolff B, et al. Ann Surg. 2004;240:

12. POI and Abdominal Surgery25 20 15
Coded POI (%) 10 5
Abdominal
Hysterectomy
Large Bowel
Resection
Small Bowel
Resection
Chole-
cystectomy
Nephro-
ureterectomy
Other
Procedures
Appendectomy
HCFA Data
Delaney C, et al. Clinical Consensus Update in General Surgery

13. Economic Burden of POI Nasogastric (NG) intubation IV hydration
Additional nursing care
Lab tests
Increased hospital days
Livingston E, Passaro E Jr. Dig Dis Sci. 1990;35:
Collins TC, et al. Ann Surg. 1999;230:
Sarawate CA, et al. Gastroenterology. 2003;124:A-828.

14. Postoperative Ileus: Economic Consequences and Length of Stay (LOS)
Prolonged POI at an Academic Medical Center (ICD-9 codes and 997.4)
Total of 83 patients (total abdominal hysterectomy & hemicolectomy)
Incidence of PPOI
Avg time to Dx (d)
Avg time from Dx to D/C (d)
Avg LOS vs no PPOI (d)
Increase in total average costs
(vs no PPOI)
TAH
(n = 43)
18.2%
3.1
3.8
6.9 vs 3.7
$4,512 HC
(n = 40)
24.5%
2.5
15.6
16.6 vs 8.6
$12,416
Salvador CG, et al. P&T. 2005;30:

15. Indications for Readmission
33%
23%
24%
20%
Surgical site septic
complications (SSSC)
Ileus/small bowel
obstruction (SBO)
Medical
complications
Other
Kariv Y, et al. Am J Surg. 2006;191: 15 15

16. Factors Associated With Readmission Cause
Indication for RD
First-admission factor
OR (95% CI)
SSSC
Bowel perforation
Re-operation
12.8 (0.98, 167.2)
16.9 (1.05, 272.6)
Medical complications
Functional capacity
COPD
Postoperative fever
Postoperative ileus
Stoma at discharge
3.58 (2.28, 10.0)
11.0 (1.39, 87.4)
5.6 (1.78, 17.5)
3.33 (1.08, 10.3)
3.15 (0.98, 10.1)
Ileus/SBO
Prior PE/DVT
Prior abdominal surgery
11.8 (1.48, 93.3)
2.6 (1.12, 6.02)
RD = readmission within 30 days of discharge
SSSC: surgical site septic complications; SBO: small bowel obstruction
Kariv Y, et al. Am J Surg. 2006;191: 16 16

17. Options to Reduce LOS Change discharge criteria
Change postoperative care plans
Altered surgical technique
Laparoscopy vs Open
Different incisions
Enhance postoperative recovery
Better analgesia
“Anti-ileus” adjuncts
Early ambulation

18. Current Management Strategies for Postoperative Ileus

19. 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?
Various treatment modalities have been used in the management of postoperative ileus (POI). Chief among them are “physical” options, such as nasogastric intubation, early postoperative enteral feeding, and early ambulation. Even preoperative suggestion training has been studied. Modifying the surgical approach to limit bowel and tissue trauma with expanded use of laparoscopic techniques and specialized stapling systems has also been employed to reduce the incidence and duration of POI.1
In addition, anesthetic drugs and techniques have been evaluated for their potential value in preventing prolonged ileus. These have included the omission or limitation of use of certain drugs such as opiates and the addition of prokinetic agents to hasten the return of normal bowel motility and function.1
Perhaps the most effective strategy has been a multimodal approach using a well-planned perioperative care plan combining various individual therapies.1,2
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: 19

20. Management Options for POI
Nonpharmacologic Options
Management
Potential Mechanism
Comments
NG tube
Gastric/small bowel decompression
Helps symptoms of POI, but no evidence NG tubes reduce duration of POI; may increase pulmonary postoperative complications
Early feeding
Stimulates GI motility by eliciting reflex response and stimulating release of hormonal factors
Appears safe, well tolerated; some, but not all, studies suggest decrease in POI
Early ambulation
Possible mechanical stimulation; possible stimulation of intestinal function
No significant change in duration of POI, but may decrease other postoperative complications
Laparoscopic surgery
Decreased opiate requirements, decreased pain, less abdominal wall trauma, less intestinal manipulation
Most studies find decreased duration of POI
Among the nonpharmacologic interventions that have been utilized in the treatment of postoperative ileus (POI) are1-3:
− Nasogastric suction, which has long been advocated for the relief of POI but has not been found to be effective; indeed, it may contribute to further morbidity
− Early enteral feeding, which may have modest efficacy and is well tolerated
Holte K, Kehlet H. Drugs. 2002;62: Behm B, Stollman N. Clin Gastroenterol Hepatol. 2003;1: Luckey A, et al. Arch Surg. 2003;138:
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.
Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg. 2003;138: 20

21. Prophylactic Nasogastric Decompression Following Abdominal Surgery
Meta-analysis
33 Studies, N = 5,240 patients
Patients without routine NG tube use had:
Earlier return of bowel function (P < )
Decrease in pulmonary complications (P = 0.01)
Trend toward increase risk of wound infection (P = 0.22)
Shorter length of stay
No difference in anastomotic leak between patients with vs without NG tubes (P = 0.70)
“Routine nasogastric decompression does not accomplish any of its intended goals and should be abandoned in favor of selective use of the nasogastric tube”
Nelson R, et al. Cochrane Database Syst Rev. 2007;Jul 18;(3):CD

22. Early Oral/Enteral Nutrition Within 24 Hours of Intestinal Surgery
Meta-analysis of 13 clinical trials, N = 1,173 patients
Mortality – reduced with early post-op feeding
RR (95% CI): 0.41 (0.18, 0.93)
Data suggestive of reduced
Wound Infections – RR (95% CI): 0.77 (0.48, 1.22)
Pneumonia - RR (95% CI): 0.76 (0.36, 1.58)
Length of Stay - RR (95% CI): (-0.66, -0.54)
Anastomotic Dehiscence – little evidence of benefit or harm
RR (95% CI): 0.69 (0.36, 1.32)
Overall conclusion: no benefit for restricting postoperative oral/enteral nutrition
Lewis S, et al. J Gastrointest Surg. 2009;13:

23. Mobilization and Postoperative Ileus
Important in helping to prevent postoperative complications, ie, 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. Controlled Rehabilitation with Early Ambulation and Diet (CREAD) Laparotomy & Intestinal Resection
Compared with traditional postoperative care:
CREAD patients spent less total time in the hospital following surgery (5.4 vs 7.1 days, P = 0.02)
Patients < 70 years had greater benefits than overall study group
No adverse effect on patient satisfaction, pain scores, complications, or readmission rates
Increased surgeon experience with CREAD associated with improved outcome
N = 31 CREAD patients
N = 33 traditional postop care patients
Delaney C, et al. Dis Col Rect. 2003;46:

25. Surgical Technique - Laparoscopy
Duration of ileus is shortened after less invasive surgery
Progression to a solid diet and discharge is faster
Several studies have shown favorable results
Possible rationale
Reduced surgical trauma leads to less sympathetic activation and inflammation
Smaller incisions, less pain (therefore less opiate use)
Earlier ambulation, earlier tolerance of feeding, less NGT use
Holte K, Kehlet H. Drugs. 2002;62:
Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.

26. RCT: Laparoscopy vs Open Surgery.
Laparoscopic
Open
120
100 80 60 40 20 *
Duration of Ileus (h) * *
Using laparoscopic procedures as opposed to open procedures reduces the inflammatory response (ie, less leukocytosis and interleukin-6 and fewer acute phase proteins) and reduces postoperative ileum (POI). This figure describes the results of 4 studies in which defecation or flatus was used to signify the resolution of POI. In 3 of these studies, statistically significant (P<.05) decreases were found in the duration of POI with the use of laparoscopic procedures.1 The general consensus is toward the use of these less invasive procedures. These procedures have come into favor, not only because of their potential for decreasing the duration of POI, but also because of the association with earlier food intake and reduced use of nasogastric intubation.
Comparison of laparoscopic and open surgical procedures has generally shown a decreased duration of POI after laparoscopic procedures.2 However, there may be an inherent bias in how aggressively the patients are fed and to what degree the postoperative nausea is tolerated without altering the patient’s diet after laparoscopic procedures; thus, retrospective comparisons with conventional open surgical procedures need to be reviewed with caution. 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; RCTs = randomized clinical trials.
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. 26

27. Intraoperative Measures: Laparoscopic Surgery
Meta-analysis of 22 trials (n = 2965) of colorectal surgery
Reduced blood loss of 71.8 mL (95% CI, mL; P = )
Reduced postoperative pain by 9.3/100 (95% CI, ; P < )
Earlier flatulence by 1 day (95% CI, ; P < )
Earlier bowel movement by 0.9 days (95% CI, ; P < )
Lessened ileus (RR = % CI, ; P = 0.003)
Reduced wound infections (RR = % CI, ; P = 0.002)
Shortened hospital length of stay (LOS) by 1.5 days (95% CI, ; P < )
Schwenk W, et al. Cochrane Database Syst Rev. 2005;CD

28. Management Options for POI
Pharmacologic Options
Treatment or Prevention
Potential Mechanism
Comments
Epidural anesthesia with only local anesthetics
Inhibits sympathetic reflex at cord level; opioid-sparing analgesia
Several RCTs suggest benefit in preventing POI; most effective when inserted at thoracic level
NSAIDs
Opiate-sparing analgesia, inhibits COX-mediated prostaglandin synthesis
Probable benefit; COX-2 selective medications need further evaluation
Metoclopramide
Dopamine antagonist, cholinergic agonist
Majority of RCTs suggest no benefit
Peripherally selective mu-receptor antagonists
Block enteric mu-receptors and minimize opiate effects on GI function, without impacting CNS-mediated analgesia
Clinical trials with alvimopan demonstrate reduced duration of POI, time to discharge order written
To date, pharmacologic agents have had little to no effectiveness in minimizing or preventing postoperative ileus (POI).1-3
Prokinetic agents, such as metoclopramide, which target inhibitory neural reflexes, have not been found effective in POI.
Thoracic epidural anesthesia has modest efficacy in preventing POI. It inhibits afferent input from the wound, which, in turn, blocks inhibitory neural reflexes. Epidural anesthesia must be delivered at the thoracic level to be effective.
Holte K, Kehlet H. Drugs. 2002;62: Behm B, Stollman N. Clin Gastroenterol Hepatol. 2003;1: Luckey A, et al. Arch Surg. 2003;138:
Becker G, Blum H. Lancet. 2009;373(9670):
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.
Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg 2003;138: 28

29. Epidural Thoracic Anesthetics
Epidural (epi) anesthesia with local anesthetics (LA)
Suppression of inhibitory neural responses
Randomized trials demonstrate decreased POI duration compared with systemic opioids
epi-LA vs systemic opioid =  POI
epi-LA vs epi-opioid =  POI
epi-LA/opioid vs systemic opioid =  POI (less than epi-LA)
Location of catheter important: thoracic application more effective than lumbar or low-thoracic
Jorgensen H, et al. Br J Anaesthesia. 2001;87:
Steinbrook R. Anesth Analg.1998;86:
Holte K, Kehlet H. Br J Surg. 2000;87:
Jorgensen H, et al. Cochrane Database Syst Rev. 2001;(1):CD

30. Epidural Analgesia and Duration of Postoperative Ileus
Study
Surgery
Earlier Gas
Earlier Stool
*P-value
Hjortso et al, 1985
Major abdominal No NS
Wallin et al, 1986
Scheinin et al, 1987
Colonic
---
Yes
< 0.05
Ahn et al, 1988
Colorectal
< 0.001
Bredtmann et al, 1990
Jayr et al, 1993
Morimoto et al, 1995
Proctocolectomy/IPAA
< 0.01
Liu et al, 1995
< 0.005
Scott et al, 1996
Bradshaw et al, 1998
Welch et al, 1998
Gastrointestinal
Neudecker et al, 1999
Laparoscopic sigmoidectomy
Carli et al, 2001
Carli et al, 2002
Steinberg et al, 2002
< 0.002
*Compared with systemic analgesic regimens;
IPAA: ileal pouch anal anastomosis
Adapted from Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.

31. Opioid-Sparing Analgesia
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Reduce prostaglandin production
Randomized, double-blind 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. Effect of Metoclopramide on POI
120
100 80 60 40 20
Duration of Ileus (h)
Jepsen et al.
(1986)
Cheape et al.
(1991)
Tollesson et al.
Metoclopramide
Placebo F I D
At this point, incorporation of prokinetic agents into a multimodal approach can not be recommended. Several clinical studies were undertaken to investigate whether metoclopramide altered the course of postoperative ileus (POI) by acting as a dopamine antagonist as well as by direct and indirect effects on cholinergic and serotenergic receptors throughout the gastrointestinal tract.1-4 Although these studies used a variety of endpoints (time to flatus, time to tolerance of regular food, and time to defecation),2-4 none demonstrated a significant benefit from metoclopramide therapy, and one study actually reported a metoclopramide-associated delay to resolution of POI.2
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:
Holte K, Kehlet H. Br J Surg. 2000;87:
D = defecation; F = flatus; I = ingestion of solid food
Holte K, Kehlet H. Postoperative ileus: A preventable event. Br J Surg ;87:
Jepsen S, Klaerke A, Nielsen PH, et al. Negative effect of Metoclopramide in postoperative adynamic ileus. A prospective, randomized, double blind study. Br J Surg :73:
Cheape JD, Wexner SD, James K, et al. Does metoclopramide reduce the length of ileus after colorectal surgery? A prospective randomized trial. Dis Colon Rectum ;34:
Tollesson PO, Cassuto J, Faxen A, et al. Lack of effect of metoclopramide on colonic motility after cholecystectomy. Eur J Surg ;157: 32

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
It is now accepted that blocking opioids is a sound therapeutic strategy for postoperative ileus (POI).
− Traditional opioid antagonists such as naloxone and naltrexone are able to improve opioid bowel dysfunction, but they cross the blood-brain barrier and reverse opioid-induced centrally mediated analgesia1
− An ideal agent to treat POI would be a peripheral opioid receptor antagonist that would reverse the adverse gastrointestinal effects of opioids without compromising opioid-induced centrally mediated analgesia2
− 2 peripheral opioid receptor antagonists are currently being evaluated: alvimopan and 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 Results20 40 60 80
100
120
140
160
180
200
Full Liquids
1st BM
GI Recovery
Discharge
Eligible
Actual
Time (hours) *
MNTX N = 33
Placebo N = 32
*P < 0.05
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 I, phase II, and phase III trials have been completed3-8
FDA approval May 20089
Alvimopan is a peripherally acting μ-opioid receptor antagonist.1 To review, μ-opioid receptors are receptors for β-endorphins, enkephalins, and endomorphins. The μ1-opioid receptors are thought to be mainly responsible for analgesia and euphoria, and μ2 opioid receptors are believed responsible for respiratory depression and gastrointestinal effects.2
Because of its large molecular weight and its polarity, alvimopan does not readily cross the blood-brain barrier and thus does not block central opioid receptors.1,3 It is highly selective for the μ-opioid receptor, demonstrating a greater affinity for this receptor over δ and  receptors.1,3
Alvimopan has a higher potency at the μ-opioid receptor than does morphine or methylnaltrexone and a longer duration of action than methylnaltrexone. It also has a high therapeutic index and a favorable side-effect profile. Side effects, which were seen only at higher doses, were limited to abdominal pain, flatulence, and diarrhea.3
Following positive alvimopan phase I and phase II4 trials, phase III trials5,6 have been completed.
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 POI Phase 3 Study Design
Placebo BID
Alvimopan 6 mg BID
Randomization
Treatment until discharge or up to 7 days
Alvimopan 12 mg BID
Pre-op dose
≥ 30 min and < 5 hrs before surgery
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)
Endpoints: GI-2, GI-3,
Time to discharge order written,
safety
Surgery
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

42. Alvimopan Phase 3 Studies – GI Recovery
140
Placebo
6 mg Alvimopan
12 mg Alvimopan
120 # * # #
100 * * 80
Time to GI-2 (hours) 60 40 20
Study 313
Study 302
Study 308
Study 314
Study 001
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:
*P < 0.001; #P < 0.01; §P < 0.02;
Studies 313, 302, 308 include bowel resection and hysterectomy;
Studies 314, 001 bowel resection only

43. Alvimopan Phase 3 Studies: Discharge Orders Written
Study 313
Study 302
Study 308
Study 314
Study 001 -5
-10
Reduction in Time to Discharge Order Written
Compared with Placebo
(hours)
-15
P < 0.001
P = 0.008
P = 0.015
P < 0.001
-20
P = 0.003
6 mg Alvimopan
12 mg Alvimopan
-25
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

44. Alvimopan Bowel Resection Pooled Analysis
P value
1.28
0.001
< 0.001
GI-3
1.38
Alvimopan 6 mg
Alvimopan 12 mg
GI-2
1.34
< 0.001
1.46
1.37
< 0.001
Ready for HD
1.48
< 0.001
1.36
DOW
1.43
0.5 1
1.5 2
2.5
In favor of placebo
In favor of alvimopan
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
Delaney C, et al. Ann Surg. 2007;245:
Studies 302, 308, 313

45. Alvimopan POI-Related Morbidity Bowel Resection Pooled Analysis‡18 16
Placebo N = 695 14
Alvimopan 12 mg N = 714 12 10
Patients (%) * 8 * 6 * 4 * 2
Overall POM
Post-op NGT
Overall POI
POI Complications
Resulting in
Prolonged Stay
POI Complications
Resulting in
Readmission
Insertion
Complications
POM: postoperative morbidity; NGT: nasogastric tube; POI: postoperative ileus
*P ≤ 0.001
‡Studies 302, 308, 313, 314
Wolff B, et al. J Am Coll Surg. 2007;204:

46. Alvimopan Safety Treatment-emergent Adverse Events Reported in ≥ 3%
Alvimopan-treated Patients and for Which the Rate for Alvimopan
was ≥ 1% than Placebo
Worldwide POI Safety Population
Treatment-Emergent Adverse Reaction
Bowel Resection Patients
All Surgical Patients
Placebo
(N = 986) %
Alvimopan
(N = 999)
(N = 1365)
Alvimopan (N = 1650)
Anemia
4.2
5.2
5.4
Constipation
3.9
4.0
7.6
9.7
Dyspepsia
4.6
7.0
4.8
5.9
Flatulence
4.5
3.1
7.7
8.7
Hypokalemia
8.5
9.5
7.5
6.9
Back pain
1.7
3.3
2.6
3.4
Urinary retention
2.1
3.2
2.3
3.5
Available at: Accessed March 2009. 46 46

47. 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

48. 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: Accessed March 2009.

49. 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.

50. Multimodal/Fast Track Management for Postoperative Ileus

51. 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
Laparoscopic surgery
Laxatives,
prokinetics
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.

52. Engage the Multidisciplinary Team
Surgeons
Anesthesiologists
Med-surgical nurses
Hospital pharmacists
Rehabilitation personnel

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

54. 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:

55. 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:

56. 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:

57. 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:

58. Economic Burden of POI (2002 Premier’s Perspective Database)
No coded POI (N = 175,992) 15
Coded POI (N = 17,417) 25 *
10.6 * 20 10
16.3
Mean Duration of Hospital Stay (days)
Mean Hospital Costs per Patient × $1,000 15
5.4
9.9 10 5 5
*P < 0.05 for coded POI vs no coded POI
Senagore A, et al. American Society of Colon and Rectal Surgeons 2005 Annual Meeting (abstract). S22, p.165. 58

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
All patients (placebo and alvimopan groups) in the alvimopan phase 3 trials were managed with a standardized accelerated postoperative care pathway intended to facilitate GI recovery. This pathway included removal of the nasogastric tube, if used, by noon on postoperative day (POD) 1; a liquid diet and ambulation were encouraged on POD 1, and a solid diet was encouraged on POD 2.
A theoretical model estimating the cost of postoperative ileus (POI) and the potential economic influence of alvimopan on the health care system is shown on the slide. Overall per-patient hospital costs are the result of both resource and personnel costs per patient during the treatment period. An increased length of stay, prolonged stay, or readmission will increase the overall duration of treatment and, thus, increase overall hospital costs. Additionally, hospital resource costs are based on the types of treatments a patient receives. An increase in the number of treatments used to manage POI (ie, multimodal pathways including use of laxatives, opioid-sparing analgesia, antiemetics, or nasogastric tube insertion) may also increase overall hospital costs.
Leslie JB. Alvimopan: A peripherally acting mu-opioid receptor (PAM-OR) antagonist. Drugs Today. 2007;43(9): 59

60. Time to Change the Way We Think About POI!
Classic view: Postoperative ileus is an inevitable response to major surgery that prolongs hospitalization and causes significantly diminished patient quality of life
New view: Surgeons can participate in the proactive prevention and treatment of postoperative ileus to help facilitate hospital discharge, lower hospitalization costs, and improve patient outcomes

61. Summary Postoperative ileus has a multifactorial pathophysiology
Neurogenic, inflammatory, hormonal, pharmacologic components
Selective nasogastric tube use, laparoscopic surgery, epidural anesthesia/analgesia, and opioid sparing techniques help to reduce the duration of POI
Peripheral opioid receptor antagonism is a promising approach for accelerating GI recovery in patients following bowel resection
Accelerating recovery of GI function improves clinical outcomes, enhances patient comfort, and reduces hospital length of stay
A multimodal approach incorporating nonpharmacologic and pharmacologic options is an effective strategy for managing POI