Opioid-induced constipation (OIC) accounts from over 40% to 60% in patients without cancer receiving opioids. Laxatives must be started at the same time as the opioid to prevent OIC. Once the disorder is established, treatment involves both pharmacological and nonpharmacological therapies. OIC may present immediately when a patient takes the opioid, or it may present gradually during opioid therapy. In association with constipation, patients may also develop other GI side effects like nausea, vomiting, bloat, abdominal pain, and straining. Many patients who develop constipation following opioids stop the drug therapy because they simply cannot tolerate the adverse effects on the GI tract. Once constipation to opioids has developed, the relief with treatment is slow and does not always result in optimal relief from constipation.
Opioid drugs are known to inhibit gastric emptying and peristalsis in the GI tract which results in delayed absorption of medications and increased absorption of fluid. The lack of fluid in the intestine leads to hardening of stool and constipation. Most patients with OIC complain of straining and incomplete emptying of the rectum during defecation. Opioids also increase anal sphincter tone impairing the defecation reflex. Anal sphincter dysfunction is important to note in patients experiencing anal blockage. Moreover, opioids have been found to decrease emptying of pancreatic juice and bile leading to delayed digestion.
The three subclasses of opioid receptors include mu, delta, and kappa. All 3 receptors mediate their actions through coupling with G-protein receptors. In the GI tract, the mu and delta receptors predominate and are found in the myenteric and submucosal plexus. The opioid receptors stimulate the production of adenylate cyclase and inhibit the calcium channels, which in turn results in a decrease in neurotransmitter release. Tolerance to opioids not only develops to pain but also to the pharmacological effects on the GI tract. 
Typical symptoms of opioid-induced constipation include the following:
The physical may reveal mild abdominal distension, and the rectal exam may reveal stool impaction.
The Rome IV diagnostic criteria is widely used for the definition of functional constipation.
The Rome IV criteria include two of following for the last 3 months:
Additionally, the Bristol Stool Scale can be used to classify the form of feces into seven categories. Type 1 and 2 show hard stools while types 3 and 4 are normal. Individuals with loose stools (types 5 through 7) tend to have diarrhea.
Imaging is not routinely done when patients present with constipation. Physicians should look out for alarm symptoms including weight loss, positive fecal occult blood tests, iron deficiency anemia, and a family history of colon cancer.
Increasing dietary fiber, fluid intake, and physical exercise are the backbone to prevention therapy. All healthcare workers who prescribe opioids need to also consider prophylactic treatment for constipation. All types of laxatives can be used as initial therapy except for the bulk-forming laxatives. The annual estimated expenditure for laxatives in the United States is over 800 million dollars . The only laxatives that should be avoided are the bulk-forming laxatives, like psyllium. These laxatives increase the bulk of the stools, distend the colon, and augment peristalsis. Opioids prevent peristalsis of the increased bulk which worsens abdominal pain and can contribute to bowel obstruction.
The most common regime for OIC is a stimulant (senna/bisacodyl) with or without a stool softener (docusate), or daily administration of an osmotic laxative (polyethylene glycol). Stool softeners are ideal for preventing constipation; they do not work well for established cases of constipation. Another laxative included saline laxative such as magnesium citrate which has an onset of action from 30 to 180 minutes. For refractory cases of OIC, newer agents may be used with methylnaltrexone being the most superior.
Methylnaltrexone bromide is the first available peripherally acting opiate antagonist which is used to treat OIC. Methylnaltrexone (Relistor) does not cross the blood-brain barrier which doesn't induce symptoms of opioid withdrawal. Subcutaneous methylnaltrexone was found to be significantly better at reversing OIC than lubiprostone, naloxegol, and oral methylnaltrexone. Relistor should not be used in patients with peptic ulcer disease, diverticulosis, colon cancer, or obstruction.
Lubiprostone (Amitiza) is a type-2 chloride channel activator that increases secretion of fluid in the GI tract. These actions result in increased tone, enhanced peristalsis, and increased acceleration of the small bowel and colonic transit times. Studies show that lubiprostone can increase the overall frequency of bowel movements each week in patients with opioid-induced constipation. 
Other therapies include naloxegol, alvimopan, and naldemedine. Naloxegol and naldemedine are both approved for treatment of OIC in patients with non-cancer pain. Alvimopan has only been approved to treat recalcitrant cases of postoperative ileus. In the United States, lubiprostone is approved for treatment of OIC in patients with non-cancer pain and those with cancer.
Whenever an opiate is prescribed, the patient should be educated on the prevention of constipation. This means eating an adequate fiber in the diet, drinking ample water, exercising to encourage motility of the bowels, limiting intake of other painkillers, and using a laxative. Other alternatives instead of milk of magnesia include the use of docusate or polyethylene glycol. The changes in lifestyle should start at the same time as the opioid therapy and continue for the duration of treatment.
There are many fiber-rich foods that one can eat to treat constipation. Fruits like apples, bananas, prunes, pears, raspberries, and vegetables like string beans, broccoli, spinach, kale, squash, lentils, peas, and beans are often recommended. One can also eat almost any type of bran products (usually cereals) and nuts. When eating foods with fiber, it is important not to consume more than 25 to 30 grams per day otherwise it can lead to a bloating sensation.
Ways to prevent opioid-induced constipation is by working as an interprofessional team consisting of a nurse, pharmacist, gastroenterologist, and a pain consultant. It is important to manage pain with non-opioid drugs, and the patient must be educated about the adverse effects by the pharmacist and clinician including constipation. The nurse should encourage a diet high in fiber, ample water, and regular exercise. The pharmacist should recommend discontinuation of drugs which cause constipation and suggest other options. If opioids cannot be avoided, a laxative and high fiber diet should be started simultaneously, and the nurse should monitor the patient's bowel habits. The patient's pain should be periodically assessed, and the dose of narcotics decreased gradually. An interprofessional approach to patient education may help prevent this problem and improve outcomes. 
Unfortunately once OIC has developed, returning bowel function to the pre-opiate status is difficult. Even though many novel drug combinations have been developed, no long-term studies are available to determine their effectiveness. Almost all studies suggest that use of non-opiates should be the drugs of first choice to manage pain if one wants to avoid OIC. (Level V)
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