DRUGS THAT COAX THE GUT BACK TO WORK
Drugs that coax the gastrointestinal tract back to work have been tried for many years and have recently gained renewed enthusiasm. Their efficacy varies according to their target organ, with greater success in the stomach and colon than in the small bowel.
Cisapride (Propulsid) was an effective gastric prokinetic agent, as shown in several controlled trials. However, it was withdrawn from the US market in 2000 because of its propensity to cause cardiac arrhythmias.
Erythromycin is a macrolide antibiotic that is also a motilin receptor agonist. In patients who underwent antrectomy and vagotomy, it was shown to accelerate gastric emptying by roughly 40% as measured by solid-phase gastric emptying scintigraphy.35,36 In a randomized controlled trial in 118 patients who underwent pancreaticoduodenectomy, intravenous erythromycin reduced gastroparesis by 37% (measured by solid-phase gastric emptying study) and also reduced the need for nasogastric tube reinsertion.37 A major shortcoming is the development of tachyphylaxis, thought to be mediated by down-regulation of motilin receptors.
Metoclopramide (Reglan) is an antiemetic and prokinetic that acts as a dopamine D2 receptor antagonist and mixed serotonin 5-HT3 antagonist/5-HT4 agonist. Metoclopramide also stimulates gastric emptying, as shown in controlled trials in patients in intensive care units.38,39 The drug should not be used in patients with parkinsonism, in view of its antidopamine properties.
In 2009, the US Food and Drug Administration required that a black box warning be added to metoclopramide because of the risk of tardive dyskinesia with long-term use, and recommended that its use be limited to 3 weeks in the acute setting.40 Prescribers and patients need to decide if this risk is worth the potential benefit on a case-by-case basis.
Although erythromycin and metoclopramide are effective in managing gastroparesis, neither has been shown to be effective for small-bowel ileus.41,42 However, colonic ileus is highly responsive to drug therapy.
Neostigmine (Prostigmin) is a reversible acetylcholinesterase inhibitor that enhances the activity of the neurotransmitter acetylcholine at muscarinic receptors. It is the first-line treatment for colonic ileus.43 In three randomized, placebo-controlled trials,44–46 the success rates were 85% to 94% after the first dose.
Neostigmine is generally given either as an intravenous bolus dose of 2 to 2.5 mg or as an intravenous infusion over 24 hours. It must be given in a monitored setting, as both bradycardia and bronchospasm can occur. Patients should continue to be monitored clinically and with plain abdominal radiography after the drug is given, and they sometimes require a second or third dose.
In cases in which neostigmine fails, decompressive colonoscopy can be done as a second-line measure.
Alvimopan (Entereg), a peripherally acting, mu-opioid receptor antagonist, has come on the scene most recently. This agent first showed promise when it precipitated diarrhea in morphine-dependent mice.47 Early studies in humans focused on its ability to reverse the effect of opiates on gastrointestinal transit without interfering with their analgesic properties.48–50 Later investigations concentrated on its ability to reduce the duration of postoperative ileus after a variety of major abdominal surgical procedures.51,52
A pooled analysis of phase III studies of alvimopan focused on the subset of 1,212 patients who underwent bowel resections; it found a significant reduction in the time to gastrointestinal tract recovery and hospital discharge.53 A 12-mg dose was more beneficial than a 6-mg dose, especially in females and in older patients (over age 65).
Most recently, a multicenter, double-blind, placebo-controlled trial evaluated alvimopan as part of a standardized postoperative care plan in 654 patients undergoing partial small-bowel and large-bowel resection.54 The alvimopan group took less time to have their first bowel movements, pass flatus, and tolerate solid food. Patients randomized to alvimopan also had their discharge orders written an average of 1 day sooner than the placebo group. Importantly, opioid use was the same in both groups.
Alvimopan is given as a single oral dose of 12 mg 30 to 90 minutes before surgery and twice daily after surgery for up to 7 days, for a total of 15 doses. It is contraindicated in patients receiving therapeutic doses of opiates for more than 7 consecutive days immediately before surgery. Its use is currently limited to hospitals enrolled in the EASE (Entereg Access Support and Education) program.
Common adverse effects include constipation, dyspepsia, flatulence, and urinary retention. In a placebo-controlled 12-month study in patients treated with opiates for chronic pain, there were more reports of myocardial infarction in the alvimopan group.55 This finding has not been replicated in any other study. The need to give the drug preoperatively obviously necessitates identifying patients most at risk of postoperative ileus.
A multimodal approach to managing postoperative ileus seems likely to be the most effective model in the long run. This should involve using minimally invasive surgery when possible, pharmacotherapy, and accelerated standardized postoperative care.
Standardized postoperative care has been implemented for a variety of procedures and generally involves minimal (if any) use of nasogastric tubes, early enteral intake and ambulation, and specific discharge criteria such as passage of flatus or stool, adequate pain control, and tolerance of solid food.56–58 Compared with a “traditional” (nonstandardized) approach, standardized care has led to shorter hospital stays and lower costs with no impact on rates of morbidity or readmission.59,60 (However, one clearly cannot underestimate the role of patient expectations in the success of such postoperative care pathways.)
There are plenty of incentives for patients, physicians, health care organizations, and third-party payers to support this push. For patients, it means less time in the hospital and a quicker return to eating normally. Surgeons can expect more-satisfied patients and lower rates of hospital-acquired conditions. For hospitals and insurers, it means less use of resources for some patients, making resources available to those who need them more.