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

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slide1

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

Robert MacLaren, PharmD, BSc (Pharm), FCCM, FCCP

Associate Professor

School of Pharmacy

University of Colorado

Critical Care Pharmacy Specialist

University of Colorado Hospital

Aurora, Colorado

faculty disclosure
Faculty Disclosure

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.

educational learning objectives
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
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
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
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

laxatives and neostigmine
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.

slide9

Laxatives and POI

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

case progression days 1 2 postsurgery
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
case progression day 3 postsurgery
Case Progression Day 3 Postsurgery
  • 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
prokinetic agents for management of ileus
Prokinetic Agents for Management of Ileus

Metoclopramide improves nausea but…

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

slide14

Prokinetic Agents for Management of Ileus

Data do not support prokinetic therapy

for treatment or prevention of ileus

slide16

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
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

NaltrexoneN-methylnaltrexone
  • 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
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

200

180

160

*

140

120

*

MNTX n = 33

100

Time (hours)

*

Placebo n = 32

80

60

40

20

0

Full Liquids

1st BM

GI Recovery

Discharge

Actual

Eligible

Discharge

Methylnaltrexone: Phase 2 Results

*P < 0.05

Viscusi, E et al. Anesthesiology. 2005;103:A893.

methylnaltrexone for poi phase 3 studies
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 recruiting

Ventral 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 results22
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

alvimopan a novel quaternary opioid receptor antagonist

Fentanyl

Alvimopan: A Novel, Quaternary-Opioid Receptor Antagonist

Moderately Large MW (461 Da)

Alpha vimu opioid peripheral antagonist

  • 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

Schmidt WK. Am J Surg. 2001;182(5A suppl):27S-38S.

alvimopan for poi phase 3 clinical trial summary
Alvimopan for POI - Phase 3 Clinical Trial Summary

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

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;240:728-735.
  • 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 poi phase 3 study design
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

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

alvimopan phase 3 studies gi recovery
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

Study 313

Study 302

Study 308

Study 314

Study 001

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

Studies 313, 302, 308 include bowel resection and hysterectomy;

Studies 314, 001 bowel resection only

alvimopan phase 3 studies gi recovery27
Alvimopan Phase 3 Studies – GI Recovery

Phase 3 results suggest alvimopan

expedites GI recovery

alvimopan phase 3 studies discharge orders written
Alvimopan Phase 3 Studies: Discharge Orders Written

Study 313

Study 302

Study 308

Study 314

Study 001

0

-5

-10

Reduction in Time to Discharge Order Written

Compared with Placebo (hours)

P = 0.008

P < 0.001

-15

P = 0.015

P < 0.001

-20

P = 0.003

6 mg Alvimopan

12 mg Alvimopan

-25

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.

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

alvimopan bowel resection pooled analysis
Alvimopan Bowel Resection Pooled Analysis

P value

1.28

0.001

< 0.001

GI-3

1.38

Alvimopan 6 mg

Alvimopan 12 mg

1.34

GI-2

< 0.001

< 0.001

1.46

1.37

< 0.001

< 0.001

Ready for HD

1.48

1.36

< 0.001

< 0.001

DOW

1.43

0

0.5

1

1.5

2

2.5

In favor of placebo

In favor of alvimopan

Possible dose response relationship 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;245:355-363.

Studies 302, 308, 313

alvimopan poi related morbidity bowel resection pooled analysis
Alvimopan POI-Related MorbidityBowel Resection Pooled Analysis‡

Similar pain scores and opioid usage in all studies

18

16

Placebo n = 695

14

Alvimopan 12 mg n = 714

12

10

*

Patients (%)

*

8

6

*

4

*

2

0

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;204:609-616.

slide31

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

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

alvimopan for poi summary
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
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
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
Clinical Decision Analysis of PAMORA

Placebo

No POI

Readmission costs

Prolonged

POI- NO

POI-associated

complication-

NO

POI

PAMRA

Prolonged

POI- YES

Prolonged stay

Complication-

NO

POI-associated

complication-

YES

Readmit-

NO

Prolonged stay

Complication-

YES

Readmit-

YES

NG tube

Antiemetics

Aspiration?

N/V

Wound dehiscence?

Abd. distension

Infection

Labs

Central line

Radiology

Nosocomial infection

VTE

Malnutrition

TPN

  • 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

Side effects?

Bell TJ. Am J Health-Syst Pharm. 2009;66:1362-1368.

case summary
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
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