A Case-Based Approach Delineating the Use of Pharmacologic Agents for the Management of Postoperative Ileus

Robert MacLaren, PharmD, BSc (Pharm), FCCM, FCCPAssociate ProfessorSchool of Pharmacy

University of Colorado

Critical Care Pharmacy SpecialistUniversity of Colorado Hospital

Aurora, Colorado

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

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

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

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

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

Are laxatives evidence-based treatment options for POI?

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.

Laxatives and POI

Administration of bisacodyl improves bowel recovery – no data with other laxatives

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

• 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

Is there a role for metoclopramide or erythromycin for the prevention

or treatment of POI?

Prokinetic Agents for Management of Ileus

• Metoclopramide improves nausea but…

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120

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ility

(hou

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Metoclopramide Placebo Erythromycin

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.

Data do not support prokinetic therapy for treatment or prevention of ileus

Prokinetic Agents for Management of Ileus

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

Pharmacologic ClinicalDecreased 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

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.

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.

Naltrexone N-methylnaltrexone

+

CH3

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.

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.

Methylnaltrexone: Phase 2 Results MNTX n = 33Placebo n = 32

0

20

40

60

80

100

120

140

160

180

200

Full Liquids 1st BM GI Recovery DischargeEligible

Actual Discharge

Tim

e (h

ours

)

*

*

*

*P < 0.05Viscusi, E et al. Anesthesiology. 2005;103:A893.

Methylnaltrexone for POI: Phase 3 Studies

Segmental colectomy (N = 542); IV methylnaltrexone (12 or 24 mg) or placebo every 6 hours1

• Preliminary results2

– 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 hours3

• Study active but not recruitingVentral hernia repair; IV methylnaltrexone (12 or 24 mg) or placebo every 6 hours4

• 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.

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

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

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) 6, 12 GI-3 GI-2, DOW

3083Bowel resection or simple or radical hysterectomy 666 (615) 6, 12 GI-3 GI-2, DOW

3144 Bowel resection 654 (629) 12 GI-2 GI-3, DOW

0015 Bowel resection 738 (705) 6, 12 GI-3 GI-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 writtenAll 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

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 RecoveryGI-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

Alvimopan Phase 3 Studies – GI Recovery

0

20

40

60

80

100

120

140

Study 313 Study 302 Study 308 Study 314 Study 001

Tim

e to

GI-2

(hou

rs)

Placebo 6 mg Alvimopan 12 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

§

##

#

§

Alvimopan Phase 3 Studies – GI Recovery

Phase 3 results suggest alvimopan expedites GI recovery

Alvimopan Phase 3 Studies: Discharge Orders Written

-25

-20

-15

-10

-5

0Study 313 Study 302 Study 308 Study 314 Study 001

Red

uctio

n in

Tim

e to

Dis

char

ge O

rder

Writ

ten

Com

pare

d w

ith P

lace

bo (h

ours

)

6 mg Alvimopan 12 mg Alvimopan

P = 0.003

P < 0.001 P = 0.008P = 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.

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 mgAlvimopan 12 mg

2.52 1.5 10.50

In favor of alvimopanIn favor of placebo

P value

0.001< 0.001

< 0.001< 0.001

< 0.001< 0.001

< 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

Alvimopan POI-Related MorbidityBowel 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 POM Post-op NGTInsertion

Overall POIComplications

POI ComplicationsResulting in

Prolonged Stay

POI ComplicationsResulting in Readmission

Patie

nts

(%)

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

Treatment-Emergent Adverse Reaction

Bowel Resection Patients All Surgical PatientsPlacebo (N = 986)

%

Alvimopan (N = 999)

%

Placebo (N = 1365)

%

Alvimopan (N = 1650)

%Anemia 4.2 5.2 5.4 5.4Constipation 3.9 4.0 7.6 9.7Dyspepsia 4.6 7.0 4.8 5.9Flatulence 4.5 3.1 7.7 8.7Hypokalemia 8.5 9.5 7.5 6.9Back pain 1.7 3.3 2.6 3.4Urinary retention 2.1 3.2 2.3 3.5

Worldwide POI Safety Population

Available at: http://www.entereg.com/pdf/prescribing-information.pdf. Accessed March 2009.

Alvimopan SafetyTreatment-emergent adverse events reported in ≥ 3%

alvimopan-treated patients and for which the rate for alvimopan was ≥ 1% than placebo

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

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.

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.

Clinical Decision Analysis of PAMORA

No POI

POIProlonged POI- YES

Prolonged POI- NO POI-associated

complication- NO

POI-associated complication- YES

PAMRA

Placebo

Prolonged stayComplication-YES

Prolonged stayComplication-NO

Readmit-YES

Readmit-NO

Nosocomial infectionVTE

N/VNG tubeAntiemetics Aspiration?

Abd. distension Wound dehiscence?

Malnutrition InfectionLabsCentral lineRadiology

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.

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

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