Transcript Postoperative Ileus (POI)

Focus on Pharmacologic Approaches
Michael D. Kraft, PharmD, BCNSP
Clinical Associate Professor
University of Michigan College of Pharmacy
Clinical Coordinator
University of Michigan Health System
Department of Pharmacy Services
Ann Arbor, Michigan
Faculty Disclosure
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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.
Michael D. Kraft, PharmD, BCNSP, is a member of the speakers bureau
and has received honorarium from Cubist Pharmaceuticals.
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
GI Recovery Patient Case
• 58-year-old female, past medical history of hypertension,
constipation-predominant IBS, diverticulosis and
diverticulitis; presented to the ED with worsening left lower
quadrant abdominal pain x ~5 days, decreased PO intake
• She states she has had discomfort off and on for several
days (similar to previous episode of diverticulitis) then with
onset of nausea and vomiting x 24 hours, denies fevers
• Past medical history: hypertension, constipationpredominant IBS, diverticulosis and diverticulitis (managed
with PO antibiotics)
• Past surgical history: colonoscopy with biopsy (2009,
negative for Crohn’s disease or cancer)
GI Recovery Patient Case
• Family history: N/C; no hx/o IBD, IBS, colon cancer
• Social history
– Drinks socially ~1 or 2 times per month
– Does not smoke or use illicit drugs
• Medications
– Aspirin 81 mg PO daily
– Metoprolol 75 mg PO twice daily
– Polyethylene glycol 17 gm PO BID prn constipation (states she
uses it 4–5 days/week)
• Allergies and intolerances
– NKDA
GI Recovery Patient Case
• Hospital day 1
– CT with contrast revealed possible diverticulitis
– Started on empiric piperacillin/tazobactam 3.375g IV q
6 hours
– NG tube was placed and she was made NPO
– Abdomen tender on exam, slightly distended
– WBC = 12.3 cells x 103/µL
– BUN/SCr = 14 mg/dL/0.9 mg/dL
– Other labs WNL
CT = computed tomography
NG = nasogastric
NPO = nothing by mouth
WBC = white blood cell
WNL = within normal limits
GI Recovery Patient Case
• Hospital day 2
– Patient continued to have increased pain
– WBC increased to 14.6 cells x 103/µL
– Decision made to take her to the OR for exploratory
laparotomy, left hemicolectomy with primary
anastomosis
• Postoperatively
–
–
–
–
D5 ½ NS + 20 mEq/L KCl at 100 mL/hr
Morphine 2–4 mg IV q 4–6 hours prn pain
Heparin 5000 units SQ q 8 hours
Piperacillin/tazobactam 3.375g IV q6h x 24 hours
WBC = white blood cell
GI Recovery Patient Case
• Hospital day 3, postoperative day 1
– Patient c/o severe pain not controlled with intermittent morphine 
morphine PCA initiated (demand dose = 1mg, lockout = 8 min, 4
hour limit = 40 mg, no basal dose)
– Patient c/o mild nausea w/ morphine  NG tube left in place (output
~150 mL q 8 hrs), NPO
– Limited ambulation, IS
• Hospital day 4, postoperative day 2
– Nausea improved  NG tube removed, attempted sips of clear
liquids
– Encouraged ambulation (patient not very willing to ambulate due to
pain)
NG = nasogastric
PCA = patient-controlled analgesia
NPO = nothing by mouth
IS = incentive spirometry
GI Recovery Patient Case
• What could have been done preoperatively and
immediately postoperatively to improve GI
recovery after bowel resection surgery?
• What preventative/pre-emptive measures could
have been taken?
• Specifically, what pharmacologic treatment options
are available for the prevention and treatment of
postoperative ileus?
Postoperative Ileus
Management Council
Definition of POI
“Transient cessation of coordinated bowel motility after
surgical intervention, which prevents effective transit of
intestinal contents or tolerance of oral intake”
Duration of POI
“The time from surgical intervention until passage of flatus
or stool and until initiation of adequate oral intake that is
tolerated and maintains hydration during 24 hours”
Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006.
Intestinal Segment Recovery
After Surgery
• Average time to resolution of POI after major
abdominal surgery
– Small intestine ~12–24 hours
– Stomach ~24–48 hours
– Colon ~48–120 hours
Prolonged POI: > 5 days
Luckey A, et al. Arch Surg. 2003;138:206-214.
Livingston EH, Passaro EP Jr. Dig Dis Sci. 1990;35:121-132.
Delaney CP, et al. Clinical Consensus Update in General Surgery. 2006.
Pathophysiology of POI:
Multifactorial
• The major causes of POI
– Surgical trauma and manipulation of the bowel
– Physiologic/metabolic stress (inhibitory inflammatory
and acute-phase mediators)
– Stimulation of GI opioid receptors by endogenous
opioid peptides and exogenous (pharmacologic)
opioids
– Has been reported after non-abdominal surgeries as
well (eg, hysterectomy, knee, thoracic)
Kehlet H, Holte K. Am J Surg. 2001;182(5A Suppl):3S-10S.
Holte K, Kehlet H. Drugs. 2002;62:2603-2615.
Luckey A, et al. Arch Surg. 2003;138:206-214.
Behm B, et al. Clin Gastroenterol Hepatol. 2003;1:71-80
GI Recovery Patient Case
Question
This patient has been treated postoperatively with
IV morphine for pain. Which of the following best
characterizes the expected effect of this pain
management strategy on gastrointestinal function?
A.
B.
C.
D.
Acceleration of gastric emptying
Stimulation of motility
Inhibitory effect on motility; bowel dysfunction
No effect on the GI tract
C. Inhibitory effect on motility; bowel dysfunction
The gastrointestinal effects of opioids include
inhibition of enteric nerve activity, inhibition of
propulsive motor activity, and inhibition of
secretory activity, all of which contribute to “bowel
dysfunction” and POI
Opioid-Induced Adverse Effects
•
•
•
•
•
Nausea
Vomiting
Sedation
Hypotension
Respiratory Depression
•
•
•
•
Sweating
Urinary retention
Pruritus
Gastrointestinal effects
– Opioid-induced bowel
dysfunction (OBD)
– Ileus and constipation
“Bowel dysfunction” considered the most common, and often the most
debilitating by patients on chronic opioids
For more information on opioid-induced bowel dysfunction click on the following link:
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Drugs%22%5BJour%5D+AND+63%5Bvolume%5D+AND+649%5Bpag
e%5D+AND+2003%5Bpdat%5D&cmd=detailssearch
Kurz A, Sessler DI. Drugs. 2003;63:649-671.
Schug SA, et al. J Pain Symptom Manage. 1992;7:259-266.
Walsh TD. J Pain Symptom Manage. 1990;5:362-367.
Symptoms of POI
•
•
•
•
•
Abdominal distention/bloating
Pain
Nausea/vomiting
Inability to pass stools
Inability to tolerate a solid diet
Kehlet H, Holte K. Am J Surg. 2001;182 (5A Suppl):3S-0S.
Holte K, Kehlet H. Drugs. 2002;62:2603-2615.
There Is an Overall Healthcare Burden
Associated with POI
POI
Prolonged hospitalization
Beds
occupied for
more time
Increased
resource
utilization
Schuster TG, Montie JE. Urology. 2002;59:465-471.
Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.
Chang SS, et al. J Urol. 2002;167:208-211.
Sarawate CA, et al. Gastroenterology. 2003;124:A-828.
Increased
nursing time
Financial Impact of POI After Colectomy
“Practical” Definition of POI
• Retrospective review, 186 colectomy patients
• Primary POI: > 3 emesis and return to NPO and/or reinsertion of NGT
• Secondary POI: POI associated with intraabdominal complication
Outcome
n = 186
Primary POI
38 (20.4 %)*
Secondary POI
7 (3.8%)
LOS
(Primary POI vs. Secondary POI vs. non-POI)
8.9 d vs. 7 d vs. 4 d*
Total mean cost for admission
(Primary POI vs Secondary POI vs. w/out POI)
$15,914 vs. $17,311 vs.
$8.316*
*P < 0.05, ANOVA
For more information on the economic impact of POI, click on the following link:
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Journal+of+the+American+College+of+Surge
ons%22%5BJour%5D+AND+210%5Bvolume%5D+AND+228%5Bpage%5D+AND+2010%5B
pdat%5D&cmd=detailssearch
Asgeirsson T, et al. J Am Coll Surg. 2010;210:228-231.
NGT = nasogastric tube
Preventive and Therapeutic
Management Options for POI
• Preoperative
– Counseling, psychological
information/preparation
– Glucose-containing fluids
– Anxiolytics?
• Intraoperative
– Laparoscopic/minimally-invasive
surgical technique
– Fluid management/avoiding fluid
overload
• Postoperative
–
–
–
–
Early NG removal
Early postoperative feeding
Early ambulation
Fluid/sodium/potassium/
magnesium/phosphorus
optimization
– Gum chewing/sham feeding?
– Avoid medications that reduce
gastrointestinal (GI) motility
• Pharmacologic Management
− Epidural, NSAIDs/opioid-sparing
− Laxatives? Prokinetics?
− Peripherally-acting mu-opioid receptor antagonists
Luckey A, et al. Arch Surg. 2003;138:206-214.
Mattei P, et al. World J Surg. 2006;30:1382-1391.
Person B, et al. Curr Probl Surg. 2006;43:12-65.
“Multimodal
clinical
pathways”
Epidural Anesthetics/Analgesics
Epidural Thoracic Anesthetics
• Epidural anesthesia with local anesthetics-suppression of
inhibitory neural responses
• Randomized trials demonstrate decreased POI duration
compared with systemic opioids
– Epidural local anesthetic (epi-LA) better than systemic or epidural
opioid
– 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
Holte K, Kehlet H. Br J Surg. 2000;87:1480-1493.
Jorgensen H, et al. Cochrane Database Syst Rev. 2001;CD001893.
Epidural Anesthetic vs
Parenteral Opioids
•
Meta-analysis of 16 trials (n = 806) of colorectal surgery
patients
– Reduced postop pain by 15-18/100 (95% CI, 10-26; P < 0.001)
– Earlier bowel function by ~1.6 days (95% CI, 0.84-2.3; P < 0.001)
– Also observed:
 Increased hypotension (OR = 13.5, 95% CI: 4-57.7; P < 0.001)
 Pruritus (OR = 4.8, 95% CI: 1.3-17; P = 0.02)
 Urinary retention (OR = 4.3, 95% CI: 1.2-15.9; P = 0.03)
•
Cochrane Review: Epidural anesthesia reduces time to GI
recovery
 By 37 hour (19-56) vs systemic opioids
 By 24 hour (10-39) vs epidural opioids
Marret E, et al. Br J Surg. 2007;94:665-673.
Jorgensen H, et al. Cochrane Database Syst Rev. 2001;CD001893.
Opioid-Sparing Regimens
GI Recovery Patient Case
Question
If a non-steroidal anti-inflammatory drug (NSAID) was
incorporated into the postoperative pain management plan
for this patient, could benefits be expected with regard to
gastrointestinal function?
A. Yes
B. No
C. I’m not sure
A. Yes
Use of NSAIDs (such as ketorolac) is an opioidsparing strategy, which is associated with earlier
return of bowel function compared with morphineonly analgesia
Opioid-Sparing Analgesia
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
– Randomized, double-blind study of morphine PCA ± ketorolac in 79
colorectal surgeries showed 29% less morphine use, earlier first
bowel movement (1.5 [0.7-1.9] 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), not adequate as sole agent
to control moderate-severe postoperative pain
• Cyclooxygenase-2 (COX-2) Inhibitors
– Similar results as NSAIDs
– Safety?
For more information on the use of NSAIDs as an opioid sparing strategy, click on the following link:
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Acta+anaesthesiologica+Scandinavica%22%5BJour%5D+AND+49%5Bvolu
me%5D+AND+546%5Bpage%5D+AND+2005%5Bpdat%5D&cmd=detailssearch
Person B, Wexner S. Curr Probl Surg. 2006;43:12-65.
Chen JY. Acta Anaesthesiol Scand. 2005;49:546-551.
GI Recovery Patient Case (continued)
• Hospital day 6, postoperative day 3
– Developed nausea  returned to NPO status
– Continued morphine PCA for analgesia
– Bowel sounds hypoactive/absent, mild abdominal
distention, no flatus or BM, “await return of bowel
function”
• Hospital day 8, postoperative day 5
– Worsening nausea, emesis x 2  diagnosed with ileus
– NG tube replaced (~400 mL per 8-hr shift), PN initiated
– Ambulation/activity encouraged
PN = parenteral nutrition
GI Recovery Patient Case
Question
What pharmacologic options would be effective for
the treatment of postoperative ileus at this point?
A. Metoclopramide
B. Erythromycin
C. A or B
D. None of the above
D. None of the above
The evidence does not support a role for either
metoclopramide or erythromycin for reduction of
POI
Prokinetics and Laxatives
Metoclopramide for POI
Recovery of
Bowel Function (hrs)
Metoclopramide
Placebo
120
90
60
30
0
• Metoclopramide may improve nausea but…studies demonstrate no
benefit for reduction of POI
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.
Bungard TJ, Kale-Pradham PB. Pharmacotherapy. 1999;19:416-423.
Off-label discussion –
not FDA-approved for
this indication
Erythromycin and POI
• Thought to act as motilin agonist
– Stimulates MMC and postprandial activity
– Highest quantity of motilin receptors found in gastric antrum and
proximal duodenum
• Few studies have assessed efficacy for reduction of POI
and recovery of bowel function after intestinal surgery
• No studies demonstrate difference between
erythromycin and placebo for reduction of POI
Bonacini M, et al. Am J Gastroenterol. 1993;88:208-211.
Smith AJ, et al. Dis Colon Rectum. 2000;43:333-337.
Lightfoor AJ, et al. Urology. 2007;69:611-615.
Baig MK, Wexner SD. Dis Colon Rectum. 2004;47:516-526.
Bungard TJ, Kale-Pradham PB. Pharmacotherapy. 1999;19:416-423.
Off-label discussion –
not FDA-approved for
this indication
Laxatives
• Double-blind, RCT, 20 patients undergoing elective
colectomy for cancer
– NG removed at end of surgery, morphine for analgesia, early
ambulation
– No PO diet until POD #5 (per protocol, regardless of BM)
– Bisacodyl vs. placebo suppositories, given on POD #3 if no
spontaneous defecation, repeated in 12 hours if no response
– POD #3: all 10 bisacodyl patients defecated vs. 2 placebo patients
(P < 0.001)
 Placebo patients: 5/10 defecated on POD #4, 3/10 on POD #5
– LOS: 8.5 ± 2.7 d vs. 10.4 ± 5.3 d (bisacodyl vs placebo, P = 0.325)
– Patients in control received ~twice as much morphine, but no clear
correlation between amount of morphine and time to defecation
POD = postoperative day
Wiriyakosol S, et al. Asian J Surg. 2007;30:167-171.
Off-label discussion –
not FDA-approved for
this indication
Laxatives
• Double-blind, RCT, 169 patients undergoing elective colon
resection (open or laparoscopic), multimodal care pathway
– Randomized to bisacodyl 10 mg PO or placebo (same capsule)
twice daily on day 1 prior to surgery until POD #3
– NGT removed at end of operation; all patients offered epidural for
analgesia (x 5-days postop); systemic opioids used as second-line;
PO intake started POD #1
– Mean time to composite endpoint (1st flatus, 1st defecation, 1st solid
food) ~0.6 d shorter in favor of bisacodyl (P = 0.007), primarily due
to reduction in time to defecation (~1.2 d shorter, P = 0.001)
– No difference in secondary endpoints including LOS
• Bisacodyl may have a role in reducing POI, further data
needed to determine optimal timing and dose
Zingg U, et al. Int J Colorectal Dis. 2008;23:1175-1183.
Off-label discussion –
not FDA-approved for
this indication
Peripherally-Acting mu-Opioid
Receptor Antagonists
GI Recovery Patient Case
Question
Methylnaltrexone and alvimopan are peripherally acting
mu-opioid receptor antagonists. Evidence from phase 3
studies has demonstrated enhanced gastrointestinal
recovery following colorectal surgery for patients treated
with:
A. Methylnaltrexone
B. Alvimopan
C. Both methylnaltrexone and alvimopan
B. Alvimopan
Methylnaltrexone is FDA-approved for chronic opioidinduced constipation in patients receiving palliative care,
but benefits for POI were not demonstrated in phase 3
clinical trials.
Data from multiple phase 3 trials demonstrated that
compared with placebo, patients undergoing bowel
resection treated with alvimopan had accelerated return of
bowel function and reduced length of stay. Alvimopan is
FDA-approved for accelerating gastrointestinal recovery
following partial large or small bowel resection surgery
Methylnaltrexone
• Peripherally-acting mu-opioid receptor antagonist,
approved for treatment of chronic opioid-induced
constipation in patients with advanced illness receiving
palliative care when response to laxative therapy has not
been sufficient
FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021964s009lbl.pdf. Accessed September 2012.
Methylnaltrexone
• Evaluated for treatment/reduction of POI
– Patients undergoing segmental colectomy and ventral hernia repair
– 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 endpoints in
any of the phase III trials
For more information about methylnaltrexone and POI, click the following link:
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Diseases+of+the+colon+and+rectum%22%5BJour%5D+AND+54%5B
volume%5D+AND+570%5Bpage%5D+AND+2011%5Bpdat%5D&cmd=detailssearch
http://www.clinicaltrials.gov/ct2/show/NCT00387309. Accessed September 2012.
http://www.clinicaltrials.gov/ct2/show/NCT00401375. Accessed September 2012.
http://www.clinicaltrials.gov/ct2/show/NCT00528970. Accessed September 2012.
http://www.progenics.com/releasedetail.cfm?ReleaseID=370543. Accessed
September 2012.
Yu CS, et al. Dis Colon Rectum. 2011;54:570-578.
Off-label discussion –
not FDA-approved for
this indication
Alvimopan
Alvimopan
• Peripherally acting µ-opioid receptor antagonist, highly selective for
µ-opioid receptor
• Does not readily cross the blood-brain barrier or block central opioid
receptors
• Bioavailability ~6%, metabolized by intestinal flora, primarily biliary
(~65%) and renal (35%) elimination, terminal half-life ~14 hours
• P-glycoprotein substrate
– Not affected by mild-moderate P-gp inhibitors; strong inhibitors?
– Not apparent inhibitor or inducer of P450 isoenzymes
• Phase I, phase II, and phase III trials completed
• FDA approval May 2008
Azodo IA, et al. Curr Opin Investig Drugs. 2002;3:1496-1501.
Schmidt WK. Am J Surg. 2001;182(5A suppl):27S-38S.
Taguchi A, et al. N Engl J Med. 2001;345:935-940.
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.
Buchler M, et al. Aliment Pharmacol Ther. 2008;28:312-325.
FDA approval available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed September 2012.
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
3083
Bowel 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 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.
Buchler M, et al. Aliment Pharmacol Ther. 2008;28:312-325.
Alvimopan POI Phase 3 Study Design
Placebo BID
Randomization
Alvimopan 6 mg BID
Treatment until discharge or up to 7 days, maximum 15 doses
Alvimopan 12 mg BID*
Pre-op dose
≥ 30 min and < 5 hrs
before surgery
Surgery
*FDA-approved dose
Endpoints: GI-2, GI-3,
Time to discharge order written,
safety
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 for POI: Phase 3 Trials
• Men and women, ≥ 18 years old
• All patients received standardized postoperative care
–
–
–
–
Analgesia via opioid patient-controlled analgesia (PCA)
Nasogastric (NG) tube out at end of surgery or POD #1
Liquids offered, ambulation encouraged on POD 1
Solid food offered on POD 2
• Exclusions: opioids > 3 doses within 1 week of surgery,
epidural opioids, local anesthetics, nonsteroidal
antiinflammatory drugs (NSAIDs), or severe concomitant
disease(s)
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.
Buchler M, et al. Aliment Pharmacol Ther. 2008;28:312-325.
Alvimopan North American Phase 3 Studies:
140
GI Recovery
Placebo
Time to GI-2 (hours)
120
12 mg Alvimopan
§
*
100
*
*P < 0.001; §P < 0.02
80
60
40
20
0
Study 308
Viscusi, et al
Study 302
Delaney, et al
Study 313
Wolff, et al
Study 314
Ludwig, et al
Studies 313, 302, 308: bowel resection and hysterectomy;
Study 314: bowel resection only
Wolff BG, et al. Ann Surg. 2004;240:728-735.
Delaney CP, et al. Dis Colon Rectum. 2005;48:1114-1125. MITT Populations
Viscusi E, et al. Surg Endosc. 2006;20:67-70.
Ludwig K, et al. Arch Surg. 2008;143:1098-1105.
Alvimopan North American Phase 3 Studies:
Discharge Orders Written
Reduction in Time to Discharge Order Written
Compared with Placebo (hours)
Study 308
Viscusi, et al
Study 302
Delaney, et al
Study 313
Wolff, et al
Study 314
Ludwig, et al
0
12 mg Alvimopan
-5
-10
-15
P = 0.01
P < 0.001
-20
P = 0.003
-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.
Studies 313, 302, 308: bowel resection and hysterectomy;
Study 314: bowel resection only
MITT Populations
18
Alvimopan POI-Related Morbidity
Bowel Resection Pooled Analysis‡
POM: postoperative morbidity; NGT: nasogastric tube; POI: postoperative ileus
16
Placebo N = 695
Alvimopan 12 mg N = 714
Patients (%)
14
12
*P ≤ 0.001
‡Studies 302, 308, 313, 314
10
8
*
*
6
4
*
2
*
0
Overall POM
Post-op NGT
Insertion
Overall POI
Complications
POI Complications
Resulting in
Prolonged Stay
POI Complications
Resulting in
Readmission
To read more about this study, click on the following link:
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Journal+of+the+American+College+of+Surgeons%22%5BJour%5D+AND+204%5Bvolume%5D+AND+609
%5Bpage%5D+AND+2007%5Bpdat%5D&cmd=detailssearch
Wolff B, et al. J Am Coll Surg. 2007;204:609-616.
Alvimopan for POI: Pooled Analysis
• Pooled analysis of patients from 4 Phase III North American
trials
– Only bowel resection patients
– Only alvimopan 12 mg (n = 714) or placebo (n = 695)
Alvimopan
Placebo
Mean time to GI-2
102.0 hrs
121.8 hrs
Mean time to D/C order written
124.9 hrs
142.9 hrs
Mean LOS*
6.6 ± 3.8 d
7.6 ± 4.2 d
Pts w/ prolonged LOS
134 (19%)
239 (34%)
 FDA-approved
dose and indication
*Calculated from calendar day of surgery to calendar day of D/C order written
For more information on this analysis, click on the following link: http://www.ncbi.nlm.nih.gov/pubmed?term=%22American+journal+of+healthsystem+pharmacy+%3A+AJHP+%3A+official+journal+of+the+American+Society+of+HealthSystem+Pharmacists%22%5BJour%5D+AND+66%5Bvolume%5D+AND+1362%5Bpage%5D+AND+2009%5Bpdat%5D&cmd=detailssearch
Bell TJ, et al. Am J Health-Syst Pharm. 2009;66:1362-1368.
Alvimopan Safety
Treatment-emergent Adverse Events Reported in ≥ 3% of
Alvimopan Patients & Rate for Alvimopan ≥ 1% than Placebo
Worldwide POI Safety Population
TreatmentEmergent Adverse
Reaction
Bowel Resection Patients
Placebo
Alvimopan
(N = 986)
(N = 999)
%
%
All Surgical Patients
Placebo
Alvimopan
(N = 1365)
(N = 1650)
%
%
Anemia
4.2
5.2
5.4
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
*Nausea: alvimopan 12 mg = 56%, placebo = 65% (P < 0.001)
*Vomiting: alvimopan 12 mg = 19%, placebo = 27% (P < 0.001)
Entereg. www.accessdata.fda.gov/drugsatfda_docs/label/2009/021775s004lbl.pdf. Accessed September 2012.
*Bell TJ, et al. Am J Health-Syst Pharm. 2009;66:1362-1368.
Alvimopan for POI:
Potential Cost Considerations
• Mean doses of alvimopan = 8.9
• Total hospital costs estimated from Premier’s Perspective
Comparative Database, and from US Census Bureau data
(2004- adjusted to 2007 dollars)
• Alvimopan cost estimated at $62.50 per dose (First Data
Bank as of June 2008)
Alvimopan
Placebo
Total hospital costs-Premier’s^
$14,798
$15,677
Total hospital costs-Census data^
$11,329
$12,306
^P < 0.05
Bell TJ, et al. Am J Health-Syst Pharm. 2009;66:1362-1368.
Alvimopan Study 014
Safety Concerns
Alvimopan Safety:
Adverse CV Events in Opioid-induced
Bowel Dysfunction (OBD) Study
• 12-month study of alvimopan 0.5 mg or placebo twice daily, patients
taking chronic opioids for chronic non-cancer pain
• More reports of myocardial infarction (MI) in patients treated with
alvimopan (7 [1.3%]) vs. placebo (0)
– Serious CV adverse events in patients at high risk for CV disease
– MI 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 up to 15 total doses)
– Causal relationship between alvimopan and MI has not been established
– POI studies: majority of patients (~95%) evaluated only to ~2 weeks
– Ongoing monitoring of patients receiving alvimopan essential
– FDA required Risk Evaluation and Mitigation Strategy (REMS)
http://www.gsk.com/media/pressreleases/2007/2007_04_09_GSK1012.htm. Accessed September 2012
http://www.fda.gov/ohrms/DOCKETS/ac/08/briefing/2008-4336b1-02-Adolor.pdf. Accessed September 2012.
Alvimopan REMS Program
• E.A.S.E.™ Program
– Distribution Program for alvimopan
– Alvimopan only available to hospitals that perform bowel
resection surgery and that enroll in E.A.S.E. Program
– Hospital must acknowledge:
 Staff who prescribe, dispense, or administer alvimopan have been
provided the educational materials
 Hospital has systems, order sets, protocols, or other measures in
place to limit the use of alvimopan to short-term, inpatient use, and
patients will not receive more than 15 doses
 Alvimopan will not be dispensed to patients after they have been
discharged from the hospital and will not be transferred to hospitals
that are not registered
E.A.S.E.: Entereg Access Support and Education. http://www.entereg.com/content/e_a_s_e_program/.
Accessed September 2012
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
Alvimopan for POI Summary
• Alvimopan must be started PREOPERATIVELY (1 dose),
continued postoperatively for maximum of 15 total doses,
patients receiving systemic opioids for analgesia
• Hospitals must enroll in REMS program, ongoing
monitoring essential
• Potential overall cost benefit if length of stay reduced
GI Recovery Patient Case (continued)
• Hospital day 10, postoperative day 7
–
–
–
–
Nausea and vomiting improved
NG output decreased, distention improved
Morphine PCA changed to intermittent morphine IV
Given bisacodyl 10 mg suppository x 1 (no response)
• Hospital day 11, postoperative day 8
–
–
–
–
–
NG removed
+ flatus
Initiated clear liquid diet
Initiate polyethylene glycol 17g PO twice a day
Repeat bisacodyl suppository (with small BM)
GI Recovery Patient Case (continued)
• Hospital day 12, postoperative day 9
– Advanced to full liquid diet in morning, then regular
diet in afternoon, wean PN off
• Hospital day 13, postoperative day 10
–
–
–
–
–
–
Good PO intake + bowel movement
Incision clean, no distention
Minimal pain
No nausea/vomiting
Labs WNL
D/C home
D/C = discharge
Summary: Pharmacologic Therapies
With Proven Benefit
• Epidural anesthesia/analgesia
• Minimization of opioid administration (opioidsparing)
• Alvimopan (started preoperatively, continued
postoperatively)
Summary: Pharmacologic Therapies
With NO Proven Benefit
• Prokinetic agents (erythromycin, metoclopramide)
Summary: Pharmacologic Therapies
That May Be Beneficial
• Laxatives (bisacodyl)
Best Option to Enhance GI Recovery
After Bowel Resection Surgery:
“Fast-Track Recovery” or
“Multimodal Treatment” Approach
Interdisciplinary, multimodal concept to accelerate
postoperative recovery and reduce general morbidity
(including POI) by simultaneously applying several
interventions
Mattei P. World J Surg. 2006;30:1382-1391.
Person B, Wexner S. Curr Probl Surg. 2006;43:6-65.
Multimodal Approach:
Preoperative Components
•
•
•
•
Education: health care team AND patients
Stabilize coexisting diseases
Optimize comfort (minimize anxiety)
Ensure appropriate hydration, correct electrolyte
abnormalities, normothermia
• Appropriate use of prophylactic therapy (antiemetics,
analgesics, antibiotics, possibly alvimopan if appropriate)
White PF, et al. Anesth Analg. 2007;104:1380-1396.
Kehlet H, et al. Br J Surg. 1999;86:227-230.
Delaney CP, et al. Br J Surg. 2001;88:1533-1538.
Delaney C, et al. Dis Col Rect. 2003;46:851-859.
Person B, et al. Curr Probl Surg. 2006;43:12-65.
Multimodal Components:
Intraoperative Components
• Anesthesia to optimize surgery and recovery
• Local anesthesia/analgesia (or thoracic epidural)
if possible
• Laparoscopic/minimally-invasive surgery if
possible
White PF, et al. Anesth Analg. 2007;104:1380-1396.
Kehlet H, et al. Br J Surg. 1999;86:227-230.
Delaney CP, et al. Br J Surg. 2001;88:1533-1538.
Delaney C, et al. Dis Col Rect. 2003;46:851-859.
Person B, et al. Curr Probl Surg. 2006;43:12-65.
Multimodal Approach:
Postoperative Components
•
•
•
•
Early NG tube removal
Fluid and electrolyte management
Laxative/bowel regimen, start oral feeding early
Minimize opioids, possibly alvimopan if
appropriate and started prior to surgery
• Ambulation
• Discharge criteria
White PF, et al. Anesth Analg. 2007;104:1380-1396.
Kehlet H, et al. Br J Surg. 1999;86:227-230.
Delaney CP, et al. Br J Surg. 2001;88:1533-1538.
Delaney C, et al. Dis Col Rect. 2003;46:851-859.
Person B, et al. Curr Probl Surg. 2006;43:12-65.
Engage the Multidisciplinary Team
•
•
•
•
•
•
Surgeons
Anesthesiologists
Physician assistants, nurse practitioners
Med-surgical nurses
Hospital pharmacists
Rehabilitation personnel
Potential Future Pharmacologic Therapies for POI*
*None of the following agents have been approved by the
FDA for this indication, therefore all discussions are off-label
Potential Future Therapies for POI?
Prokinetic agents: 5-HT4 agonists
• Prucalopride*: High affinity and selectivity for 5-HT4 receptor
– Evaluated in randomized, placebo-controlled, multicenter phase 3 trial x 12
weeks
– Total 620 patients with severe chronic constipation
– Prucalopride 2 mg and 4 mg daily significantly improved frequency of BMs,
as well as satisfaction with treatment, severity of symptoms, & QOL; no
significant effect on QTc
• Mosapride*: 5-HT4 agonist, available in Japan
– Evaluated for POI in 40 patients after hand-assist laparoscopic colectomy
– Mosapride 15 mg PO q8h vs placebo, all received multimodal care
– Mosapride significantly reduced time to first BM (48.5 vs. 69.3 hours,
P = 0.0149) and LOS (6.7 v. 8.4, P = 0.0398)
– No QT prolongation reported
*No current or ongoing US studies for POI
Camilleri M, et al. N Engl J Med. 2008;358:2344-2354.
Narita K, et al. Dis Colon Rectum. 2008;51:1692-1695.
www.clinicaltrials.gov. Accessed September 2012.
Potential Future Therapies for POI?
• Ghrelin agonists: hormone involved in regulation of appetite
and GI motility
– Studies of ghrelin agonists in rat model of surgical and morphineinduced ileus
 RC-11391
 TZP-101 (ulimorelin)2
 Ipamorelin3
– Effects may be more pronounced in stomach vs small intestine
– Phase 2 trial of ipamorelin for POI completed,4 another ongoing5
– Phase 2 study of TZP-101 (ulimorelin) for POI completed6
1.
2.
3.
4.
5.
6.
Poitras P, et al. Peptides. 2005;26:1598-601
Fraser GL, et al. Eur J Pharmacol. 2009;604:132-137
Venkova K, et al. J Pharmacol Exp Ther. 2009;329:1110-1116.
NCT00672074. http://www.clinicaltrials.gov. Accessed September 2012.
NCT01280344. http://www.clinicaltrials.gov. Accessed September 2012.
Popescu I, et al. Dis Colon Rectum. 2010;53:126-134.
Potential Future Therapies for POI?
• Prokinetic agents: Motilin agonists (atilmotin)
– Peptide analogue (IV dosage form)
– Accelerated gastric emptying at 30 min, no effect on
colonic filling or colonic transit
– No trials recruiting or completed currently found
– Others may be in development: BM-591348
(synthetic), KOS-2187 (non-peptide)
– SK-896 evaluated in dog model of POI
Park MI, et al. Neurogastroenterol Motil. 2006;18:28-36.
Furuta Y, et al. Biological Pharmaceutical Bulletin. 2002;25:1063-1071.
www.clinicaltrials.gov. Accessed August 2012.
Summary and Final Thoughts
• Limited pharmacologic options for prevention/treatment of POI
• Alvimopan may be of overall benefit if :
– Started preoperatively (30 min–5 hours) x 1 dose
– Patient receiving systemic opioids for analgesia
– Length of stay can be reduced
• Early ambulation and early PO intake may not reduce POI,
but should be encouraged given other benefits
• Multimodal approach may be best overall
• Future potential treatment options must be evaluated