US Pharm. 2010;35(12):55-73.
Postoperative ileus (POI) may be defined as the impairment of gastrointestinal (GI) motility after intra-abdominal or nonabdominal surgery. It is characterized by bowel distention, lack of bowel sounds, accumulation of GI gas and fluid, and delayed passage of flatus and stool (TABLE 1).1
The reported incidence of POI ranges from 4% to 32%.2,3 A higher incidence is associated with abdominal and pelvic surgery, open laparotomy, longer surgery time, greater estimated blood loss, prolonged opioid use, and inhalational anesthesia.4,5 POI incidence varies by procedure, ranging from 4.1% for abdominal hysterectomy to 14.9% for large-bowel resection to 19.2% for small-bowel resection.6 The overall incidence is approximately 8.5%, but the true incidence of clinically significant POI is probably higher.
Risk factors for POI include type of surgery and preexisting factors such as GI disease and physical inactivity.4,5 Consequences of the condition include patient discomfort, decreased patient satisfaction, and complications such as pain and nausea.5
POI affects all segments of the GI tract. It usually is uncomplicated and resolves spontaneously within 2 to 3 days, although it may last 6 days or more. The return of bowel function is commonly identified by active bowel sounds, the passage of flatus, and/or a bowel movement. The most reliable markers of bowel-function return are having a bowel movement and being able to tolerate oral intake. An ileus that lasts more than 3 days is considered a paralytic, or adynamic, ileus.1,3
POI readmission rates are estimated to be as high as 5% after major abdominal surgery.2 The economic impact of ileus has been estimated to be $750 million to about $1 billion in the United States.1,3,7
The cause of ileus appears to be multifactorial (TABLE 2).1,6 POI may result from the use of postsurgical opioid pain relievers (e.g., morphine), which can slow or inhibit normal motility. Opioid analgesics relieve pain by blocking pain signals through stimulation of opioid receptors (mu receptors) located on the surface of the nerves that transmit these signals. Opioid analgesics bind to the mu receptors in the central nervous system (CNS) and the GI tract. The binding of opioid analgesics to mu receptors in the GI tract greatly slows intestinal motility, thereby disrupting normal GI function. The slowing of intestinal motility may cause significant discomfort and pain. The combination of both endogenous and exogenous opioids may contribute to the development and persistence of ileus. Increased doses of opioid analgesics are related to extended periods of POI.
The effects of anesthesia and antispasmodics on the colon may also cause POI. The large intestine is devoid of intercellular gap junctions, which makes the colon more susceptible to the inhibitory actions of anesthetics.2 In particular, halothane, enflurane, and atropine delay gastric emptying. Some studies have shown that thoracic epidurals with bupivacaine hydrochloride significantly reduce ileus versus systemic opioid therapy in patients undergoing abdominal surgical procedures.3 Epidurals with local anesthetics are believed to block inhibitory reflexes and have other beneficial effects.
Paralytic ileus may result from intraperitoneal or retroperitoneal inflammation (e.g., appendicitis, diverticulitis, perforated duodenal ulcer); retroperitoneal or intra-abdominal hematoma (e.g., ruptured abdominal aortic aneurysm, lumbar compression fracture); metabolic disturbances (e.g., hypokalemia); or medications (e.g., opioids, anticholinergics, calcium channel blockers, anesthetics).8 Ileus sometimes occurs in association with renal or thoracic disease (e.g., lower lobe pneumonitis, lower rib fracture, myocardial infarction).
In uncomplicated POI, GI motility is restored within hours after surgery. Gastric and small-intestine recovery is believed to occur first, followed by the return of colonic function. Uncomplicated POI is a self-limiting process.1,6 A delayed return to normal function is painful for the patient and costly for the health care system.
The GI tract, which includes the stomach and colon, is innervated by the enteric nervous system (ENS). Normal GI motility is a result of several intricate relationships involving hormones, the CNS, the ENS, smooth-muscle activity, and the state of the stomach (fed or fasting).
Motility takes place even in the fasting state. This contractile pattern of the bowel, occurring every 1 to 2 hours during a fasting state, is known as the migrating motor complex (MMC).3 The stomach is made of muscles that function to produce electrophysiologic actions. Colonic motility is irregular. The colon does not contain gap junctions and thus does not function as a single agent.3 One proposed mechanism of POI is that the MMC function is disrupted. See TABLE 3.
Although peritoneal entry increases the severity of POI, duration of surgery does not appear to affect severity. The primary cause of POI is surgery and concomitant opioid treatment. Secondarily, POI may be precipitated by other factors, such as hematoma or infection.2,5
Patients with POI may experience a painful and distended abdomen, vomiting, toxemia, and dehydration. Although the lumen is not occluded, peristalsis fails when the intestinal contents back up, resulting in watery diarrhea. Pain rarely has the classic colicky pattern present in mechanical obstruction.9 Bowel sounds are minimal or absent. Abdominal tenderness generally is present only when the cause of the ileus is inflammation.
Diagnosis of POI consists of clinical evaluation and, occasionally, x-ray.3 First, obstruction (mechanical or pseudo-) must be ruled out. Pseudo-obstructions involve the colon only, particularly the right colon. They are caused by trauma, extreme debilitation, or certain diseases of the intestinal vasculature and/or musculature. Mechanical obstructions may be caused by cancer, hernia, foreign-body ingestion, or other conditions.
An x-ray or CT scan may be used to differentiate the type of obstruction versus ileus. On CT scan, pseudo-obstructions are indicated by a large, isolated colon, whereas mechanical obstructions appear as enlarged bow-shaped loops of small intestine with steplike air-fluid levels. On x-ray, both obstruction and POI may show gas accumulation; in POI, gas accumulates mainly in the large intestine. Water-soluble contrast may be used to distinguish the type of ileus.1-4,6 Physical examination reveals a quiet abdomen in POI patients; patients with obstruction may still have some bowel sounds, either hypo- or hyperactive (pseudo-obstruction) or high-pitched (mechanical obstruction). The different obstructions may have similar presentations.
Several medications have been used for the treatment and prevention of POI, including FDA-approved drugs that have been used off-label.
Metoclopramide is a prokinetic agent that potentially could be used for POI management. It is used extensively as an antiemetic and as a means of nasoduodenal feeding-tube advancement.9,10 Metoclopramide works by accelerating gastric emptying and stimulates gastric, pyloric, and small-bowel motor activity, but it has little or no effect on the colon.
A prospective, randomized study assessed metoclopramide for reducing the length of ileus after colorectal surgery in 100 patients who underwent elective abdominal colorectal surgical procedures.9 Not all patients received metoclopramide. The drug was administered IV every 8 hours from the completion of surgery until a solid-food diet was tolerated. It was concluded that metoclopramide does not significantly alter the course of POI.
A double-blind, controlled study of 60 patients found that metoclopramide had a negative effect on the resolution of POI.10 It is important to keep in mind that metoclopramide may cause sedation, akathisia (feelings of motor restlessness), and other extrapyramidal reactions.7
Another drug that has been used for POI because of its mechanism of action in the GI tract is erythromycin, a macrolide antibiotic that acts at motilin receptors in the intestinal tract and promotes GI motility in disorders such as diabetic gastroparesis.11 Some data suggest that erythromycin stimulates gastric emptying postoperatively. Like metoclopromide, erythromycin lacks activity in the colon.
A prospective, double-blind, randomized, placebo-controlled study of 77 patients investigated whether erythromycin shortened the period of POI.12 Forty-one patients received 250 mg erythromycin IV every 8 hours for nine doses upon admission to the recovery room, and 36 patients received placebo. Outcome measures included time to first passage of flatus, first liquid meal, first bowel movement, and total length of hospital stay. There was no significant difference between the groups. It was concluded that erythromycin did not seem to alter clinical parameters of GI motility after abdominal surgery.
Interestingly, it has been suggested that the colon does not possess motilin receptors in the distal portion of the large intestine.13 This may explain the lack of benefit of erythromycin in POI. In general, prokinetic agents studied for the treatment of POI have yielded inconsistent and marginal results.
Propranolol, a nonspecific beta-receptor antagonist, has been investigated for the treatment of POI; however, it has demonstrated variable results.13 Despite promising results from a few trials, the effects of these agents have not been adequately studied, and therefore they are not used for the treatment of prolonged POI.
Neostigmine, an acetylcholinesterase inhibitor, has been used for the treatment of ileus because of its ability to facilitate the activity of acetylcholine and induce GI contractions, especially in the colon. However, clinical data showing a benefit in accelerating postoperative GI recovery are lacking.14
Neostigmine was evaluated in surgical patients and medical patients with critical illness-related colonic ileus.15 Patients had ileus secondary to coronary bypass grafting, ruptured abdominal aortic aneurysm, pneumonia, sepsis, or state of low cardiac output. Patients were given neostigmine or placebo in a blinded manner. Treatment was administered by continuous IV infusion of 0.4 to 0.8 mg/h over 24 hours. Patients who did not respond to therapy were crossed over to placebo. Overall, 19 of the 24 patients who received neostigmine successfully passed stools, and no patients receiving placebo had bowel movements. The only serious neostigmine-related adverse reaction was increased salivation. It should be kept in mind that this trial was performed in patients with critical illness-related ileus, not necessarily POI.
It should be noted that bradycardia is a side effect associated with neostigmine use owing to its cholinergic properties.15
Laxatives are a potential therapeutic option for treating POI, but no randomized, controlled trials have assessed their utility in this setting. One nonrandomized study of 20 consecutive patients given laxative agents postoperatively found a reduction in time to flatus and first bowel movement, as well as decreased length of hospitalization, compared with historical controls.16 However, larger, placebo-controlled trials should be performed before the use of laxatives becomes a routine part of postoperative patient care. Laxatives have been used with other therapies after abdominal surgery in multimodal rehabilitation studies, with promising results.17
Gum chewing is theorized to promote physiologic stimulation of the cephalic-vagal axis, thereby increasing bowel motility and GI stimulation without the complications associated with early water intake or postoperative feeding. A systematic review of randomized, controlled trials comparing gum chewing with standard care after elective intestinal surgery was performed.18 The main outcome measures were time to flatus and stool postoperatively and length of hospital stay, which were analyzed using random-effect models.
Nine eligible trials enrolling a total of 437 patients were identified.18 The intervention was well tolerated and complication rates were low. There was statistical evidence of heterogeneity for the three main outcomes. Pooled estimates showed a 14-hour reduction in time to flatus (95% CI, -20 to -8 hours; P = .001), a 23-hour reduction in time to bowel movement (95% CI, -32 to -15 hours; P <.001), and a 1.1-day reduction in length of hospital stay (95% CI, -1.9 to -0.2 days; P = .016). Because of insufficient data, a reduced rate of clinical complications or reduced cost could not be demonstrated.
NEW TREATMENT OPTIONS
In considering the optimal medication for treating POI, several characteristics should be present.7 First, the medication should be able to antagonize the inhibitory effects of all of the potential factors implicated in the pathophysiology of POI (neurogenic, inflammatory, hormonal, and pharmacologic mediators) selectively in the GI tract. Mu-opioid receptors in the GI tract mediate reduced motility in surgical patients receiving postoperative opioid analgesic therapy.7
The agent should not penetrate the blood-brain barrier (BBB), where antagonism of central opioid receptors would interfere with analgesia.7 It should also be free of agonist activity at mu-opioid receptors in GI smooth muscle.7
The drug should be available in oral and injectable dosage forms for flexibility of administration.7 Preferably, to minimize potential systemic adverse effects, oral dosage forms would not be systemically absorbed.7
The medication should be easy to administer, well tolerated, and inexpensive.7 In addition, it should not interact with other drugs or disease states.7
Methylnaltrexone bromide was approved in April 2008 for the treatment of opioid-induced constipation (OIC) in patients with advanced illness who are receiving palliative care, when response to laxative therapy has been insufficient.19 Methylnaltrexone (N-methylnaltrexone bromide) is a peripherally acting selective mu-opioid receptor antagonist. Unlike naloxone, it is a quaternary derivative of naltrexone. The addition of a methyl group at the amine in the naltrexone ring results in a compound with greater polarity and lower lipid solubility; thus, the drug is prevented from crossing the BBB. This allows it to block peripheral receptor opioid effects without altering central analgesic effects. Methylnaltrexone has been shown to antagonize morphine-induced inhibition of contraction in isolated guinea pig ileum and human intestine. Reduction in GI transit time has been observed in subjects with OIC and in healthy opioid-naïve subjects.
The efficacy and safety of methylnaltrexone were demonstrated in two randomized, double-blind, placebo-controlled studies, as well as in one single-blinded phase II study, which also showed that methylnaltrexone rapidly induced laxation.20-23 In the first two studies, patients received methylnaltrexone for methadone-induced constipation; the third study examined findings in patients with advanced illness and OIC.21-23 Patients had advanced terminal illness and limited life expectancy (most had a primary diagnosis of incurable cancer; other primary diagnoses included end-stage chronic obstructive pulmonary disease, cardiovascular disease/heart failure, or other advanced illness). Prior to screening, patients had OIC (<3 bowel movements in preceding week or no bowel movement for 2 days).
Methylnaltrexone-treated patients had a higher rate of laxation within 4 hours of the initial dose than placebo-treated patients (48% vs. 16%, 95% CI, 7%-49%; P <.0001).21-23 Methylnaltrexone-treated patients also had higher rates of laxation within 4 hours after at least two of the first four doses (52% vs. 9%; P <.0001). Stool consistency was not meaningfully improved in patients who had soft stool at baseline. No episodes of generalized opioid withdrawal or a form of gut hypermotility known as gut withdrawal syndrome was observed, and there was no evidence of antagonism of analgesia. There was no differential effect of age or gender on safety or efficacy. The effect on race could not be analyzed because the population was predominately Caucasian (88%).
Methylnaltrexone is administered as a subcutaneous injection.19 The usual schedule is one dose every other day as needed, but no more frequently than one dose in a 24-hour period. The recommended dose is 8 mg for patients weighing 38 kg to less than 62 kg (84-<136 lb.) or 12 mg for those weighing 62 kg to 114 kg (136-251 lb.). Patients whose weight falls outside these ranges should be dosed at 0.15 mg/kg. No dose adjustment is necessary in patients with mild-to-moderate renal impairment. In patients with creatinine clearance less than 30 mL/min, 50% of the calculated dose should be administered.
The injection site should be rotated between the upper arm, abdomen, and thigh.19 Methylnaltrexone should be stored at room temperature and protected from light. It has not been studied for use beyond 4 months, and it should be discontinued if opioids are discontinued.
Methylnaltrexone is pregnancy category B.19 No evidence of impaired fertility or fetal harm from methylnaltrexone has been observed in animal studies. Methylnaltrexone should be used during pregnancy only if clearly needed. Methylnaltrexone is excreted in the milk of lactating rats; whether it is excreted in human milk is not known. Caution is advised if methylnaltrexone is administered to a breastfeeding woman. Methylnaltrexone has not been studied in pediatric patients, end-stage renal disease (ESRD), or severe hepatic impairment.
Adverse reactions associated with methylnaltrexone include abdominal cramping, diarrhea, dizziness, flatulence, nausea, and soft stool.19 Abdominal cramping is moderate in some patients, but appears to lessen or be relieved after a bowel movement. Methylnaltrexone is a weak inhibitor of CYP450 2D6 in vitro; in vivo, however, it has not affected the metabolism of the CYP2D6 substrate dextromethorphan. In vitro, it has not inhibited CYP1A2, CYP2A6, CYP2C9, CYP2C19, or CYP3A4. The potential for drug interactions with agents that are actively secreted by the kidney has not been studied in humans. Methylnaltrexone is contraindicated in known or suspected mechanical bowel obstruction. Rare cases of GI perforation have been reported in patients with advanced illness. Use caution in patients with known or suspected lesions of the GI tract.19
Methylnaltrexone is available as single-dose vials containing 12 mg/0.6 mL in a seven-tray kit. The average wholesale price for a single 0.6-mL vial is $50.21
Alvimopan (formerly known as ADL 8-2698) is a quaternary mu-opioid receptor antagonist with a pharmacologic profile that differs from that of methylnaltrexone, particularly in binding affinity.24 It has considerably greater binding affinity for mu-opioid receptors than for delta- and kappa-opioid receptors. Alvimopan was approved in May 2008 for accelerating the time to upper-GI and lower-GI recovery following partial large-bowel or small-bowel resection with primary anastomoses. Through competitive binding to the GI mu receptor, alvimopan antagonizes the peripheral effects of opioids on GI motility and secretion without reversing the central analgesic effects of the opioid. The drug is highly selective for the mu-opioid receptor; it also has an active metabolite that has less affinity for the mu-opioid receptor than the parent compound does.
Alvimopan is an amide hydrolysis compound that is exclusively a product of intestinal-flora metabolism.24 Absorption peak concentration is noted approximately 2 hours following oral administration, with an absolute bioavailability of approximately 6%. No significant accumulation was noted after twice-daily dosing, and high-fat meals decreased the extent and rate of absorption.
Approval of alvimopan was based on the results of five (four in the U.S., one in Europe) multicenter, randomized, double-blind, parallel-group, placebo-controlled studies.19,22,23,25,26 The trials enrolled more than 2,000 adults undergoing partial large-bowel or small-bowel resection with primary anastomosis or total abdominal hysterectomy under general anesthesia. All five trials had these design features in common: Patients were randomized to receive alvimopan oral capsules or placebo; the initial dose was given preoperatively, with subsequent doses administered twice daily from postoperative day 1 until postoperative day 7 or hospital discharge; and patients taking chronic opioids before surgery and those scheduled to have laparoscopic surgery or epidural anesthesia were excluded.
In all studies, the primary efficacy endpoint was time to recovery of both upper and lower GI-tract motility following surgery. In the four POI studies, time to recovery of the upper and lower GI tracts was a three-component composite endpoint (GI-3).25-29 In the POI efficacy study, time to recovery of the upper and lower GI tracts was a two-component composite endpoint (GI-2).12 GI-3 was defined as time from the end of surgery to time of recovery of the upper GI tract (toleration of solid food) and lower GI tract (first flatus or bowel movement, whichever occurred first); GI-2 was defined as time from the end of surgery to time of recovery of the upper GI tract (toleration of solid food) and lower GI tract (first bowel movement).
Secondary efficacy endpoints included the following measurements of length of hospitalization: discharge order written, the time from the end of surgery to the time the hospital discharge order was written; and ready, the time from the end of surgery to the time the patient was ready for hospital discharge based solely on the recovery of GI function, as determined by the surgeon.25-29
In all five studies, treatment with alvimopan significantly accelerated the time to recovery of GI function versus placebo by 10.7 to 26.1 hours, as measured by a composite endpoint of toleration of solid food and first bowel movement.25-29 GI recovery began approximately 48 hours postoperatively. Patients randomized to alvimopan were discharged 13 to 21 hours sooner than those in the placebo group, and use of alvimopan did not reverse opioid analgesia. Adverse events reported with alvimopan (n = 1,650) versus placebo (n = 1,365) in nine studies in surgical patients included constipation (9.7% vs. 7.6%), flatulence (8.7% vs. 7.7%), hypokalemia (6.9% vs. 7.5%), dyspepsia (5.9% vs. 4.8%), anemia (both, 5.4%), urinary retention (3.5% vs. 2.3%), and back pain (3.4% vs. 2.6%).
Alvimopan is dosed as a 12-mg tablet administered 30 minutes to 5 hours prior to surgery followed by 12 mg twice daily for up to 7 days, for a maximum of 15 doses.24 Concomitant administration of alvimopan with inducers or inhibitors of CYP450 enzymes is unlikely to alter its metabolism because it is not a substrate of CYP enzymes, according to in vitro data. Coadministration of alvimopan does not appear to alter the pharmacokinetics of morphine or alvimopan's metabolite, morphine-6-glucuronide, when morphine is administered IV; dosage adjustments, therefore, are not necessary.
Alvimopan is classified as pregnancy category B.24 The drug is not recommended for patients with severe hepatic impairment or ESRD or for patients undergoing surgery to correct complete bowel obstruction. Alvimopan is contraindicated in patients who have been receiving therapeutic doses of opioids for more than 7 consecutive days.
The FDA mandated that the manufacturer of alvimopan develop a Risk Evaluation and Mitigation Strategy (REMS).30 Enrollment in the Entereg Access Support and Education (E.A.S.E.) Program is required to purchase the drug. Hospitals that perform bowel resection are eligible and must acknowledge that educational materials are distributed to health care professionals responsible for ordering, dispensing, or administering alvimopan; systems, order sets, protocols, or other measures are in place to limit use to 15 doses; the hospital will not dispense alvimopan for outpatient use; and the hospital will not transfer a patient taking alvimopan to a nonregistered hospital.
Pharmacists play an integral role in the management and monitoring of patients with POI. Their contributions are not only clinical, but also economic in nature. It is the pharmacist's responsibility to ensure optimum pharmaceutical care at the most reasonable cost. In monitoring the patient at risk for POI, it is necessary to review medication regimens to ensure that patients are not taking medications that may exacerbate POI. If it is discovered that a patient is currently on such a regimen, the pharmacist should ensure that all preventive measures are being utilized.
All patients receiving narcotics for pain control should be on a bowel regimen, which should be initiated as soon as possible. An effective bowel regimen should include a stimulant laxative and a stool softener. These agents may include senna, bisacodyl, and docusate sodium. Pharmacists should monitor for adverse drug events (ADEs) and frequently maintain and review ADE reports.
FDA approval of methylnaltrexone and alvimopan has prompted formulary committees to evaluate these agents for inclusion in the health care system.30 Since methylnaltrexone and alvimopan would likely have a financial impact on health systems, pharmacists are positioned to participate in formulary decision-making. Pharmacists and Pharmacy & Therapeutics committees must develop and implement criteria for patient selection that might restrict the use of these drugs to patients undergoing bowel resection or possibly other abdominal surgeries associated with a higher risk of POI (e.g., total abdominal hysterectomy). Alvimopan may be restricted to 15 doses, as per the package insert. Pharmacists will also play an integral role in the management of REMS and E.A.S.E.
A number of drugs have been used to treat POI. Methylnaltrexone and alvimopan are promising new agents that could become an important component of perioperative care for the treatment of POI after bowel resection and, potentially, other major abdominal surgeries. These therapies may also reduce the economic burden of POI on health systems.
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15. van der Spoel JI, Oudemans-van Straaten HM, Stoutenbeek CP, et al. Neostigmine resolves critical illness-related colonic ileus in intensive care patients with multiple organ failure--a prospective, double-blind, placebo-controlled trial. Intens Care Med. 2001;27:822-827.
16. Fanning J, Yu-Brekke S. Prospective trial of aggressive postoperative bowel stimulation following radical hysterectomy. Gynecol Oncol. 1999;73:412-414.
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18. Noble EJ, Harris R, Hosie KB, et al. Gum chewing reduces postoperative ileus? A systematic review and meta-analysis. Int J Surg. 2009;7:100-105.
19. Relistor (methylnaltrexone bromide) product information. Tarrytown, NY: Progenics Pharmaceuticals, Inc; September 2010.
20. Kraft MD. Methylnaltrexone, a new peripherally acting mu-opioid receptor antagonist being evaluated for the treatment of postoperative ileus. Expert Opin Investig Drugs. 2008;17:1365-1377.
21. Yuan CS, Foss JF. Oral methylnaltrexone for opioid-induced constipation. JAMA. 2000;284:1383-1384.
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23. Yuan CS, Foss JF, O'Connor M, et al. Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial. JAMA. 2000;283:367-372.
24. Entereg (alvimopan) product information. Exton, PA: Adolor Corp; November 2009.
25. Herzog TJ, Coleman RL, Guerrieri JP Jr, et al. A double-blind, randomized, placebo-controlled phase III study of the safety of alvimopan in patients who undergo simple total abdominal hysterectomy. Am J Obstet Gynecol. 2006;195:445-453.
26. Wolff BG, Viscusi ER, Delaney CP, et al. Patterns of gastrointestinal recovery after bowel resection and total abdominal hysterectomy: pooled results from the placebo arms of alvimopan phase III North American clinical trials. J Am Coll Surg. 2007;205:43-45.
27. Delaney CP, Weese JL, Hyman NH, et al. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;48:1114-1125.
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29. Wolff BG, Michelassi F, Gerkin TM, et al. 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;240:728-734.
30. Entereg.com. Learn about and enroll in the E.A.S.E.™ Program. http://entereg.com/content/e_
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