Physicians should consistently rule out opioid therapy as the cause of gastrointestinal symptoms, states a new clinical practice update published in the September 2017 issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.05.014 ).

About 4% of Americans receive long-term opioid therapy, primarily for musculoskeletal, postsurgical, or vascular pain, as well as nonsurgical abdominal pain, writes Michael Camilleri, MD, of Mayo Clinic in Rochester, Minn., and his associates. Because opioid receptors thickly populate the gastrointestinal tract, exogenous opioids can trigger a variety of gastrointestinal symptoms. Examples include achalasia, gastroparesis, nausea, postsurgical ileus, constipation, and narcotic bowel syndrome.

Selective opioid use also can improve gastrointestinal symptoms in some disorders. Acute morphine use lowers resting lower esophageal sphincter (LES) pressure in both healthy and achalasic patients and inhibits transient LES relaxations in patients with gastroesophageal reflux disease, the experts note. However, chronic opioid therapy can impair LES relaxation and is also associated with high amplitude/velocity and simultaneous esophageal waves, outflow obstruction at the esophagogastric junction, higher integrated relaxation pressure, and lower distal latency on esophageal pressure topography.

In the stomach, opioid use can cause gastroparesis, early satiety, and postprandial nausea and emesis, especially in the postoperative setting. Even novel opioid agents that are less likely to cause constipation can retard gastric emptying. For example, tapentadol, a mu-opioid agonist and norepinephrine reuptake inhibitor, delays emptying to the same extent as oxycodone. Tramadol also appears to slow overall orocecal transit. Although gastroparesis itself can cause nausea and emesis, opioids also directly stimulate the chemoreceptor trigger zone in the area postrema in the floor of the fourth ventricle. Options for preventive therapy include using a prokinetic, such as metoclopramide, prochlorperazine, or a 5-hydroxytryptamine3 antagonist, especially if patients are receiving opioids for postoperative pain control.

Exogenous opioids also can cause ileus, especially after abdominal surgery. These patients are already at risk of ileus because of surgical stress from bowel handling, secretion of inflammatory mediators and endogenous opioids, and fluctuating hormone and electrolyte levels. Postoperative analgesia with mu-opioids adds to the risk of ileus by increasing fluid absorption and inhibiting colonic motility.

Both postsurgical and nonsurgical opioid use also can trigger opioid-induced constipation (OIC), in which patients have less than three spontaneous bowel movements a week, harder stools, increased straining, and a feeling of incomplete evacuation. Patients may also report nausea, emesis, and gastroesophageal reflux. Even low-dose and short-term opioid therapy can lead to OIC. Symptoms and treatment response can be assessed with the bowel function index , in which patients rate ease of defecation, completeness of bowel evacuation, and severity of constipation over the past week on a scale of 0-100. Scores of 0-29 suggest no OIC. Patients who score above 30 despite over-the-counter laxatives are candidates for stepped-up treatments, including prolonged-release naloxone and oxycodone, the intestinal secretagogue lubiprostone, or peripherally acting mu-opioid receptor antagonists (PAMORAs), such as methylnaltrexone (12 mg subcutaneously) and naloxegol (12.5 mg or 25 mg per day orally). Additionally, tapentadol controls pain at lower doses than oxycodone and is less likely to cause constipation.

Narcotic bowel syndrome typically presents as moderate to severe daily abdominal pain lasting more than 3 months in patients on long-term opioids equating to a dosage of more than 100 mg morphine daily. Typically, patients report generalized, persistent, colicky abdominal pain that does not respond to dose escalation and worsens with dose tapering. Work-up is negative for differentials such as kidney stones or bowel obstruction. One epidemiological study estimated that 4% of patients on long-term opiates develop narcotic bowel syndrome, but the true prevalence may be higher according to the experts who authored this update. Mechanisms remain unclear but may include neuroplastic changes that favor the facilitation of pain signals rather than their inhibition, inflammation of spinal glial cells through activation of toll-like receptors, abnormal function of the N-methyl-D aspartate receptor at the level of the spinal cord, and central nociceptive abnormalities related to certain psychological traits or a history of trauma.

Treating narcotic bowel syndrome requires detoxification with appropriate nonopioid therapies for pain, anxiety, and withdrawal symptoms, including the use of clonidine. “This is best handled through specialists or centers with expertise in opiate dependence,” the experts stated. Patients who are able to stay off narcotics report improvements in pain, but the recidivism rate is about 50%.

The practice update also covers opioid therapy for gastrointestinal disorders. The PAMORA alvimopan shortens time to first postoperative stool without counteracting opioid analgesia during recovery. Alvimopan also has been found to hasten recovery of gastrointestinal function in patients with postoperative ileus after bowel resection. There is no evidence for using mu-opioid agonists for pain associated with irritable bowel syndrome (IBS), but the synthetic peripheral mu-opioid receptor agonist loperamide can improve stool consistency and urgency. A typical dose is 2 mg after each loose bowel movement or 2-4 mg before eating in cases of postprandial diarrhea. The mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist eluxadoline also can potentially improve stool consistency and urgency, global IBS symptoms, IBS symptom severity score, and quality of life. However, the FDA warns against using eluxadoline in patients who do not have a gallbladder because of the risk of severe outcomes – including death – related to sphincter of Oddi spasm and pancreatitis. Eluxadoline has been linked to at least two such fatalities in cholecystectomized patients. In each case, symptoms began after a single dose.

Dr. Camilleri is funded by the National Institutes of Health. He disclosed ties to AstraZeneca and Shionogi. The two coauthors disclosed ties to Forest Research Labs, Ironwood Pharmaceuticals, Prometheus, and Salix.