Alvimopan for Postoperative Ileus

Heather R. Bream-Rouwenhorst; Matthew A. Cantrell

Disclosures

Am J Health Syst Pharm. 2009;66(14):1267-1277. 

In This Article

Abstract and Introduction

Abstract

Purpose. The efficacy, safety, pharmacology, pharmacokinetics, drug–drug interactions, and administration of alvimopan for postoperative ileus are reviewed.
Summary. Alvimopan is a selective µ-opioid receptor antagonist with no central nervous system activity. When orally administered after partial small- or large-bowel resection in patients with primary anastomosis, alvimopan shortened the return of bowel function and time to discharge by approximately one day without compromising analgesia. Alvimopan was not shown to be beneficial on these same outcomes after hysterectomy and has not been studied in other surgical populations. Alvimopan is generally well tolerated, with the frequency of adverse events being similar to placebo when used postoperatively for one week or less. Long-term studies of alvimopan in opioid-induced bowel dysfunction have shown an association with adverse cardiovascular outcomes, neoplasms, and fractures. Because of these concerns, the Entereg Access Support and Education program was developed. The recommended dosage of alvimopan is 12 mg administered with a sip of water 30 minutes to five hours before surgery, followed by 12 mg twice daily beginning the day after surgery for a maximum of seven days, 15 total doses, or until discharge. There is a limited amount of pharmacoeconomic analysis concerning alvimopan.
Conclusion. Alvimopan, a peripherally acting µ-opioid receptor antagonist, is a novel agent for the treatment of postoperative ileus. It appears to decrease the duration of postoperative ileus and hospitalization by approximately one day, theoretically offsetting its acquisition costs. Unresolved long-term safety issues, a limited indication, and its restricted-access program are likely to hinder its widespread use in the surgical population.

Introduction

Postoperative ileus is a temporary impairment in gastrointestinal (GI) motility. Though considered an inevitable complication of abdominal and pelvic surgeries, postoperative ileus may also occur after nonabdominal surgeries, such as thoracic and orthopedic procedures. The duration of ileus depends on the part of the GI tract affected; recovery times for the small intestine and stomach are generally 0–24 and 24–48 hours, respectively, while the colon may take 48–72 hours to recover.[1,2] Although its etiology is multifactorial, postoperative ileus occurs largely as a result of surgical trauma and bowel manipulation, with laparotomy being a more likely cause than laparoscopic procedures.[3–5]

The pathophysiology of postoperative ileus includes activation of inhibitory sympathetic neural reflexes, resulting in decreased GI motility and inflammation directly proportional to the magnitude of bowel manipulation during surgery.[4,5] Inflammatory mediators, numerous neurotransmitters, and endogenous opioid peptides also play a role. Nitric oxide release as a result of local inflammation may be a key first step in causing gut paralysis; however, other inhibitory neurotransmitters, including vasoactive intestinal peptide and substance P, may also contribute.[1,6] Other overt causes of postoperative ileus include the use of inhaled anesthetics (e.g., halothane), which may directly inhibit GI motility, and opioid analgesics used for postoperative pain control.[7,8]

As a result of postoperative ileus, normally synchronized GI contractions become uncoordinated, resulting in bowel distention, absent bowel sounds, and an inability to pass flatus and stool.[1] Patients often suffer abdominal pain, nausea, and vomiting. In severe cases, postoperative ileus may contribute to aspiration; furthermore, due to decreased oral intake, patients may become catabolic, increasing the risk of complications.[2,9] While postoperative ileus is often a transient complication of surgery, recovery may take three to five days or even longer in some instances, often making postoperative ileus the rate-limiting step in recovery.[2,10,11] The associated costs of postoperative ileus are clinically important to both patients and payers, as the condition has been shown to more than double inpatient hospitalization costs and significantly increase the length of hospital stay.[12]

Treatment for postoperative ileus is supportive and includes i.v. hydration, electrolyte replacement, and gastric decompression via nasogastric tubes, if necessary.[13] Clinical trials evaluating the use of prokinetic agents, such as metoclopramide, and motilin agonists, such as erythromycin, have not found the drugs to have a significant effect on postoperative ileus.[14] Although endpoints in clinical trials vary, a patient may be considered fully recovered when solid oral intake is tolerated and bowel function becomes normal.[2]

Postoperative pain control nearly always includes opioid analgesia, which contributes to the development of postoperative ileus. The three main subtypes of opioid receptors include µ, κ, and δ. Although all opioid receptors are involved in analgesia, the µ-receptor is the primary receptor targeted for the pharmacologic treatment of pain.[15] All opioid receptors belong to the same 7-transmembrane G-protein-coupled receptor family and retain selectivity for specific ligands; however, there is overlap among the three classes with respect to their pharmacologic binding profiles.[16] Opiate receptors are distributed throughout the GI tract and assist in GI motility, secretion, and transportation of electrolytes. Localization of these receptors in the GI tract near interneurons, secretomotor neurons, and the interstitial cells of Cajal—the pacemaker cells for GI motility—aids in carrying out these aforementioned biological functions[17] (Figure 1). Despite opioids' beneficial effects for acute pain, the drugs decrease gastric motility, inhibit propulsion of the small and large intestine, delay transit time, cause constipation, and increase fluid absorption from bowel contents.[13,18] Thus, the GI effects of opioids, coupled with the effects of surgical procedures, place patients at further risk of postoperative ileus. The development and recent approval by the Food and Drug Administration (FDA) of labeling for alvimopan (Entereg marketed by Adolor and GlaxoSmithKline), a peripheral µ-opioid receptor antagonist, may represent an advance in the treatment of postoperative ileus.

Figure 1.

Inhibition of opioid activity by alvimopan. Opioid agonists stimulate the 7-transmembrane G-protein-coupled µ-opioid receptor on the postsynaptic neuron (top panel). This initiates steps that reduce the release of neurotransmitters (e.g., glutamate, acetylcholine, norepinephrine, serotonin, substance P) and promote the efflux of potassium, which leads to hyperpolarization and hence reduced cellular excitability. In the central nervous system (top panel), these actions reduce the transmission of pain, whereas in the gastrointestinal (GI) tract, stimulation of μ-opioid receptors causes changes in gut motility and water secretion and absorption that may result in constipation and contribute to the development of postoperative ileus. In the GI tract, alvimopan blocks the binding of opioid agonists to the μ-opioid receptor and helps prevent constipation (bottom panel). Because alvimopan is largely unable to cross the blood-brain barrier, it does not block μ-opioid receptors in the central nervous system or interfere with centrally mediated opioid analgesia. Illustration by Taina Litwak, CMI.

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