Pathogenesis of POI Is Multifactorial

1
Pathogenesis of POI Is Multifactorial
Sympathetic Nervous System Inhibitory neural
reflexes
Neuropeptide and Hormonal Factors Calcitonin
gene-related peptide, endogenous opioid peptides,
corticotropin-releasing hormone
Enteric Nervous System Nitric oxide Vasoactive
intestinal peptideSubstance P
Multiple Pathways
Inflammatory Mediators Macrophage and neutrophil
infiltration, IL-1, tumor necrosis factor, IL-6
Pharmacologic Exogenous opioids
IL interleukin Luckey A, et al. Arch Surg.
2003138206-214. Holte K, Kehlet H. Drugs.
200262(18)2603-2615. Person B, Wexner S. Curr
Probl Surg. 20064312-65.
2
There Are Numerous Risk Factors for POI
Extent ofBowel Manipulation
Surgical Site
POI Is Expected to Affect AlmostEvery Patient
Who Undergoes Abdominal Surgery
Operation Time
PatientFactors
PatientHealth
Amount of Opioids
Systemic Infections
Resnick J, et al. Am J Gastroenterol.
199792751-762. Resnick J, et al. Am J
Gastroenterol. 199792934-940. Senagore AJ. Am J
Health-Syst Pharm. 200764(suppl 13)S3-S7.
Senagore AJ, et al. Surgery. 2007142478-486.
3
POI and Abdominal Surgery
25
20
15
Coded POI ()
10
5
0
Abdominal Hysterectomy
Large Bowel Resection
Small Bowel Resection
Chole- cystectomy
Nephro- ureterectomy
Other Procedures
Appendectomy
Cystectomy
Based on HCFA Data 1999-2000 for all surgeries
except cystectomy cystectomy data from Chang et
al, 2002
Delaney C, et al. Clinical Consensus Update in
General Surgery. 2006. Chang S, et al. J Urol.
20021672012-2016.
4
Clinical and Economic Impact of POI

• DELAYED RECOVERY
• Increased postoperative pain
• Increased nausea and vomiting
• Increased risk of aspiration
• Prolonged time to regular diet
• Delayed wound healing
• Increased risk of malnutrition/catabolism
• Prolonged time to mobilization
• Increased pulmonary complications

• PROLONGED HOSPITALIZATION
• Increased health care costs

Cumulative costs for coded POI (total
hospitalization readmission cost)
1,464,167,173
Kehlet H, Holte K. Am J Surg. 2001182(5A
suppl)3S-10S. Person B, Wexner S. Curr Probl
Surg. 20064312-65. Goldstein J, et al. PT.
200732(2)82-90.
5
Preventive and Therapeutic Management Options
for POI

• Physical Options
• Nasogastric tube
• Early postoperative feeding
• Sham feeding, gum chewing
• Early ambulation
• Surgical Technique
• Laparoscopy
• Psychological Perioperative Information

• Anesthesia and Analgesia
• Epidural
• NSAIDs
• Pharmacologic
• Prokinetic agents
• Opioid (PAMOR) antagonists
• Other agents
• Perioperative Care Plan(s)
• Multimodal clinical pathways
• Fluid/sodium restriction?

PAMOR peripherally acting µ-opioid receptor
antagonist Luckey A, et al. Arch Surg.
2003138206-214. Person B, Wexner S. Curr Probl
Surg. 20064312-65.
6
Management Options for POI
Nelson R, et al. Cochrane Database Syst Rev.
2007(3)CD004929. Holte K, Kehlet H. Br J
Surgery. 2000871480-1493. Andersen H, et al.
Cochrane Database Syst Rev. 2006(4)CD004080. Cha
roenkwan K, et al. Cochrane Database Syst Rev.
2007(4)CD004508.
Lewis S, et al. J Gastrointest Surg.
200913569-575. Noble E, et al. Int J Surg.
20097100-105. Waldhausen J, et al. Ann Surg.
1990212671-677. Zutshi M, et al. Colorectal
Dis. 20046477-480. Schwenk W, et al. Cochrane
Database Rev. 2005(3)CD003145.
7
Management Options for POI
Person B, Wexner S. Curr Probl Surg.
20064312-65. Chen JY, et al. Acta Anaesthesiol
Scand. 200549546-551. Luckey A, et al. Arch
Surg. 2003138206-214. Becker G, Blum H. Lancet.
2009373(9670)1198-1206.
8
POI Peripheral Opioid Antagonism

• Most patients require opioids
• Opioids inhibit GI propulsive motility and
  secretion the GI effects of opioids are mediated
  primarily by µ-opioid receptors within the bowel
• Naloxone and naltrexone reduce opioid bowel
  dysfunction but can reverse analgesia in higher
  doses
• An ideal POI treatment is a peripheral opioid
  receptor antagonist that reverses GI side effects
  without compromising postoperative analgesia
• Alvimopan
• Methylnaltrexone

Kurz A, Sessler DI. Drugs. 200363649-671.Taguch
i A, et al. N Engl J Med. 2001345935-940. Becker
G, Blum H. Lancet. 2009373(9670)1198-1206.
9
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 http//www.clinicaltrials.gov/ct2
/show/NCT00387309. Accessed March 2009. 2.
Available at http//www.clinicaltrials.gov/ct2/sh
ow/NCT00401375. Accessed March 2009. 3. Available
at http//www.clinicaltrials.gov/ct2/show/NCT0052
8970. Accessed March 2009. 4. Available at
http//www.wyeth.com/news/archive?navdisplaynavT
o/wyeth_html/ home/news/pressreleases/200
8/1205322072160.html. Accessed March 2009. 5.
Available at http//www.progenics.com/releasedeta
il.cfm?ReleaseID311785. Accessed March 2009. 6.
Available at http//www.progenics.com/releasedeta
il.cfm?ReleaseID370543. Accessed July 2009.
10
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
0
Bowel Resection, Hysterectomy Study 313
Bowel Resection Study 314
Bowel Resection, Hysterectomy Study 302
Bowel Resection, Hysterectomy Study 308
Bowel Resection Study 001
Wolff BG, et al. Ann Surg. 2004240728-735. Delan
ey CP, et al. Dis Colon Rectum.
2005481114-1125. Viscusi E, et al. Surg
Endosc. 20062067-70. Ludwig K, et al. Arch
Surg. 20081431098-1105. Büchler M, et al.
Aliment Pharmacol Ther. 28312-325.
P lt 0.001 P lt 0.01 P lt 0.02
11
Pooled Data From Phase III Studies of Alvimopan
Hospital Resource Use Studies 302, 308, 313
38.1
40
35
Placebo

Alvimopan 6 mg
30
Alvimopan 12 mg
24.4

25
19.9
Patients,
20
13.7
15
11.7



8.6
10
7.7
7.3
7.0
5
0
Prolonged hospital stay
Readmission
DCO written 7 days
P 0.024 P lt 0.001 P 0.040 DCO
discharge order Delaney CP, et al. Ann Surg.
2007245355-363.
12
Alvimopan Safety
Worldwide POI Safety Population
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 http//www.entereg.com/pdf/prescribi
ng-information.pdf. Accessed March
2009. Available at http//www.fda.gov/bbs/topics/
NEWS/2008/NEW01838.html http//www.gsk.com/media/
pressreleases/2007/2007_04_09_GSK1012.htm.
Accessed March 2009. E.A.S.E. Entereg Access
Support and Education. Available at
http//www.entereg.com/pdf/prescribing-information
.pdf. Accessed March 2009.
13
Alvimopan for POI Formulary Considerations

• E.A.S.E. Program
• Distribution Program for ENTEREG (alvimopan)
• Alvimopan is available only to hospitals that
  enroll in the E.A.S.E. Program. To enroll in the
  E.A.S.E. Program, the hospital must acknowledge
  that hospital staff who prescribe, dispense, or
  administer alvimopan have been provided the
  educational materials on
• Limiting the use of alvimopan to short-term,
  inpatient use
• Patients will not receive more than 15 doses of
  alvimopan
• Alvimopan will not be dispensed to patients
  after they have been discharged from the
  hospital
• Hospital will not transfer alvimopan to
  unregistered hospitals

E.A.S.E. Entereg Access Support and Education.
Available at http//www.entereg.com/pdf/prescribi
ng-information.pdf. Accessed March 2009.
14
What Is Fast-Track Recovery?

• An interdisciplinary multimodal concept to
  accelerate postoperative convalescence and reduce
  general morbidity (including POI) by
  simultaneously applying several interventions
• What are the
• appropriate
• choices in
• constructing
• fast-track,
• multimodal
• protocols?

NG tube removal
Opioid sparing
Laparoscopicsurgery
Laxatives, prokinetics
Early/sham feeding, Optimal fluid management
Epidural anesthetics
Mobilization?
such as gum chewing
Mattei P. Rombeau J. World J Surg.
2006301382-1391. Person B, Wexner S. Curr
Probl Surg. 2006436-65.
15
Fast-Track Example (Colectomy)
SICU surgical intensive care unit PACU
postanesthetic care unit
Not all centers admit patients to the SICU under
standard care
Raue W, et al. Surg Endosc. 2004181463-1468.
16
The Future

• Identification of risk factors for POI
• Patient-centered care
• Hydration and electrolytes
• Opioid regimen and opioid-sparing therapies
• Anxiolytic and anti-emetic therapies
• Pharmacologic modification of the stress
  response
• Multidisciplinary PACUs
• Clinical pathways
• Outreach services for rehabilitation

White PF, et al. Anesth Analg. 20071041380-1396.