Opioids are widely used to treat pain from a variety of non-cancer and cancer causes. While these drugs do work well as analgesics, they also have powerful adverse effects. One of them is opioid-induced constipation (OIC). This disorder can present at any time after opioid treatment. Symptoms include nausea, vomiting, hard stools, straining, bloating, and abdominal pain. These gastrointestinal (GI) symptoms can have a major negative impact on the quality of life. 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. Several newer anti-opioid antagonists have been developed to block opiate actions in the GI tract but not to cross the blood-brain barrier. Overall, the treatment of OIC is not satisfactory, and it is important for healthcare workers to prevent the condition.
Opiates are widely used for the management of pain from a variety of causes, both malignant and non-malignant. Pain is one of the most common symptoms that cause patients to see healthcare workers. While a common reason to see a healthcare worker is acute pain, it is chronic pain that is more disabling for most patients. It is estimated that chronic pain affects anywhere from 10% to 15% of the population.
Over the past 2 decades, the use of opiates has markedly increased for a variety of reasons. Besides liberal prescribing methods by healthcare workers for mild to moderate pain, big pharma has also been heavily marketing these agents to physicians. Data indicates that healthcare providers prescribe potent narcotics to 1 out of every 5 patients who present with a pain complaint. The other reason why narcotics are so readily prescribed is that they are also rapidly effective in controlling moderate to severe pain. Moreover, there is a subset of patients who demand that they only find pain relief with opioids.
While the use of opioids to treat chronic pain has increased, what is also more evident from the empirical prescribing of opiates is that these drugs also possess many adverse effects that include tolerance, physical dependence, sedation, and respiratory depression (Szigethy et al., 2018). One very common side effect of all opioids that is often not discussed is constipation. The prevalence of OIC in patients with chronic non-cancer pain varies from 40% to 80%. The reasons for this variance is that many patients initially make no correlation between the drug and the altered bowel movement. In addition, many patients also seek home remedies before seeking medical help for fear of embarrassment. Opioid-induced constipation is probably the most common adverse effect of these agents and can significantly impact the quality of life (Webster, 2015).
OIC may present immediately when a patient takes the opioid, or it may present gradually over a few weeks. The vast majority of patients on opioids will complain of constipation at some point during the treatment. Constipation can occur immediately and can be pronounced. In association with constipation, patients may also develop other GI side effects like nausea, vomiting, bloat, abdominal pain, and straining. The longer patients take opioids, the intensity of constipation increases. Many patients who develop constipation following opioid use stop the drug therapy because they simply cannot tolerate the adverse effects on the GI tract. Following treatment of constipation, the compliance to opioids also increases. One should note that a significant number of healthcare workers never consider treating the OIC prophylactically. Once constipation to opioids has developed, the relief with treatment is slow, often takes time, and does not always result in optimal relief from constipation.
For decades, healthcare professionals have known that all opioids have some pharmacological effect on the GI tract. These drugs are known to inhibit gastric emptying and enhance the tone of the pylorus, which results in nausea, vomiting, and anorexia. Opioids are also known to inhibit 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. Other actions of the opioids include heightened tone of the anal sphincter, abnormal relaxation in response to distension of the rectum and enhanced amplitude of non-propulsive segmental contractions. These pharmacological actions result in an impaired ability to evacuate the bowel as well as abdominal cramps, pain, bloating and abdominal distension. Other adverse effects of opioids on the GI tract include decreased secretions from the stomach, biliary tree, pancreas, and intestine which also results in abnormal digestion of food.
The prevalence of OIC is high. Based on surveys of patients treated with opioids figures range from 21% to 90% depending on the type of opiate and length of usage. Individuals of any ages can be affected by OIC, and no race or ethnicity is immune. Among patients reporting OIC, close to 50% have a history of constipation which worsened with the opioid. The constipation was also more severe in patients taking multiple agents that affect the GI tract. Studies showed that patients who developed OIC were more likely to be older, female, and unemployed. In addition, many of these patients were more likely to be taking step 3 medications and for more than 6 months. Constipation in many patients started within days if initiating treatment with the opioid and progressively worsened. A significant number of these patients indicated that the treatment of OIC was not adequate, and the disorder affected their quality of life.
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. When stimulated these receptors induce membrane hyperpolarization via activation of the potassium channels. In addition, the opioid receptors also 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. From laboratory studies, it appears that tolerance to the effects of mu-action of opiates occurs in all parts of the GI system, except the colon. Because of a varying degree of tolerance, constipation persists, and with long-term opiate therapy, other GI symptoms appear to improve.
Opioid-induced constipation can also occur at both low and high doses and can present at any time once the treatment begins. The clinical features of OIC are similar to other causes of constipation, except that these patients do present with a history of opioid ingestion. Typical symptoms of opioid-induced constipation include the following:
On physical exam, the patient may appear apprehensive and anxious about not being able to go regularly to the bathroom. The physical may reveal mild abdominal distension, and the rectal exam may reveal stool impaction.
Because the symptoms of constipation are variable and non-specific, the Rome 111 criteria are used to define the severity of the disorder. The Rome III criteria include the following:
Diagnosis of Opioid-Induced Constipation
There is no universal method to make the diagnosis of opioid-induced constipation. In most cases, the diagnosis is made clinically based on the history of presentation that includes a change in bowel habits and alteration in defecation patterns after starting opiate treatment.  To objectively classify the problem, one or more of the following assessment tools may be used to quantify constipation:
There are several other similar tools used to assess constipation and choosing one depends on personal preference and experience.
Imaging is not always done when patients present with constipation. However, obtaining plain abdominal x-rays may reveal fecal impaction in the colon.
Difficulties in Diagnosis of OIC
Despite the fact that it is known that OIC is common, very few healthcare workers ever make a formal diagnosis and manage it. From the literature it appears that the barriers to making a diagnosis of OIC include the following:
Once the diagnosis of OIC is made, the treatment is either non-pharmacological or pharmacological. However, it is important to understand that it is best to prevent OIC in the first place. This means that all healthcare workers who prescribe opioids need to consider prophylactic treatment for constipation.
Over the years, experts in pain management have developed some guidelines for management of OIC. Even though laxatives are an essential component of any treatment regimen, there is no consensus on which laxative to use first. Except for the bulk-forming laxatives, all other types of laxatives can be used as initial therapy. There is no evidence to date indicating that one laxative is better than a laxative from another class. The following algorithm has been recommended for managing OIC.
It is vital that when healthcare workers prescribe opioids, they also prescribe a laxative at the same time. This helps prevent constipation and distressful GI tract symptoms. The laxative has to be continued for the duration of the opioid therapy. The traditional laxative often prescribed is milk of magnesia, 30 ml taken twice a day. The milk of magnesia has to be taken at least 2 hours after the opiate otherwise, as it can interfere with the absorption of the opiate. For most patients, this laxative works well, but it can be augmented with lactulose. At the same time, the patient should be encouraged to change lifestyle (see later).
Treatment of Established OIC
Once OIC has developed, the use of non-pharmacological remedies alone is not adequate to manage constipation. Most of these patients are old, debilitated, may have varying degrees of pain and are not able to exercise. Some patients may not even be able to eat a high fiber diet or drink ample water. Further, the chronic pain may limit all types physical activity. Even though there is no evidence that non-pharmacological therapy alone can be used to treat established OIC, nevertheless this therapy should be recommended as supplementary treatment and combined with pharmacological therapy.
Use of Pharmacological Therapy
Laxatives form the backbone of OIC therapy. The 2 types of laxatives recommended for treatment of OIC are the stool softeners or the intestinal stimulants. Patients can use any other laxative because there is no evidence that one laxative is better than the other. 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. However, opioids are known to prevent peristalsis of stools augmented with fiber. In addition, these laxatives also worsen the abdominal pain, cramps and bloating.
Treating OIC with Newer Opioid Antagonists
Methylnaltrexone bromide is the first available peripherally acting opiate antagonist which is used to treat OIC. To date, it has been used in managing patients receiving palliative care who have had a poor or inadequate response to the conventional laxatives. Methylnaltrexone is a selective antagonist at the mu receptor and does not cross the blood-brain barrier (BBB). As a result, the actions of the drug are limited to the GI tract. The one major benefit of this drug is that while it decreases OIC symptoms, it does not alter the centrally mediated opiate effects. Preliminary studies indicate that methylnaltrexone can antagonize the gastrointestinal effects of opiates; this results in increased gastric emptying and orocecal transit time. Studies also reveal that the drug can act as a rescue treatment in patients who have failed to respond to the traditional laxatives.
Reported adverse effects of the drug include flatulence, abdominal cramps, dizziness, nausea, and diarrhea. However, if the patient is known or suspected of having a mechanical bowel obstruction, the drug should not be used. In addition, it is not recommended that the drug should be prescribed to patients with peptic ulcer disease, diverticulosis, colon cancer or ileus as this may result in perforation of the bowel. 
Naloxone and Oxycodone
Preliminary studies have shown that a combination of naloxone and oxycodone may help prevent OIC. When administered orally, naloxone has low bioavailability due to its extensive breakdown in the liver. Therefore, orally administered naloxone may bind to the peripheral opioid receptors in the gastrointestinal tract and prevent the adverse effects of opiates and decrease the risk of OIC.
Several studies have shown that naloxone does not affect the analgesic effect of opiates when administered orally but at the same time prevent OIC. More important individuals prescribed the combination of naloxone and oxycodone also had fewer gastrointestinal symptoms and required fewer laxatives compared to patients who only took oxycodone. These benefits appear to be maintained in the long term.
However, the combination of naloxone and oxycodone is associated with adverse effects that include nausea, vomiting, diarrhea, constipation and abdominal cramps. Recently, concern has been raised that diversion of the oxycodone is a real possibility. Finally, this drug combination is not recommended in patients with moderate to severe liver dysfunction and should be used cautiously in patients with mild renal dysfunction. In addition, naloxone and oxycodone are contraindicated in pregnancy or women who are breastfeeding. There are several formulas of naloxone-oxycodone in the market, and in some cases, the pharmacist can prepare the desired ratio, depending on the type of response desired.
Lubiprostone is a derivative of prostaglandin E1 and is known to increase secretion of fluid in the GI tract. The drug is known to stimulate the cystic fibrosis transmembrane regulator and type-2 chloride channels located in the jejunum and colon, resulting in secretion of water and sodium chloride into the colonic lumen. These actions result in an 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, compared to a placebo. Further, the drug can also shorten the mean time to a first bowel movement when compared to a placebo. 
Lubiprostone can also is also able to improve the symptoms of constipation such as abdominal pain, stool consistency, the degree of straining, and hard stools. Lubiprostone has been well-tolerated in most studies, and the most common adverse effects were diarrhea and abdominal discomfort.
In laboratory studies, lubiprostone stimulated secretion of chloride via the CLC2 channel, but methadone blocks this action, and hence, its use is contraindicated in patients with methadone-induced constipation. Lubiprostone is consumed twice a day orally at a dose of 4 micrograms. The drug has been approved for the treatment of opioid-induced constipation in patients with pain from non-malignant causes.
Naloxegol is a polyethylene glycol derivative of naloxone. The pegylated formula decreases the permeability of the naloxegol to cross the BBB but does not affect the centrally mediated analgesia effects of the opiate. Naloxegol has been shown to reverse the delay in orocecal transit time. Preliminary studies from phase 1 clinical trials reveal that naloxegol can improve spontaneous bowel movements and the response rates to the laxative were much higher compared to individuals just treated with a placebo. Further naloxegol has been shown to improve stool consistency, reduce straining, and improve the quality of life. The drug has been found to be safe and well tolerated.
The most common side effects noted in the trials in patients with OIC and non-cancer pain were nausea, diarrhea, headache, and flatulence. However, the drug should be used with caution in patients with moderate to severe renal and liver impairment.
Naloxegol has been FDA approved at doses of 12.5 and 25 mg to be administered orally once a day for OIC. However, cardiac surveillance is still required in patients prescribed naloxegol.
Alvimopan is a newer peripheral acting opioid receptor antagonist that does not cross the blood-brain barrier. These properties permit alvimopan to antagonize the peripheral effect of opiates on the gastrointestinal tract without affecting the centrally mediated analgesic activity. A phase ll trial has shown that the drug is more effective than placebo at enhancing bowel movements compared to placebo. Also, the individual has fewer hard stools and straining. Unfortunately, the early clinical studies do not show a consistent effect of alvimopan in all patients with OIC. At present alvimopan has only been approved to treat recalcitrant cases of postoperative ileus.
No matter which treatment is selected to treat OIC, the patient’s BFI scores should be obtained regularly to determine if the treatment is of benefit.
Even though it is recommended that patients start laxatives at the same time as the opioid, for most healthcare providers, this, unfortunately, is not routine practice. Most healthcare workers only recommend the laxative after the patient complaints of constipation and associated GI symptoms. Consequently, less than 60% of patients achieve the desired relief from constipation. Once prescribed, the laxatives are well tolerated. The few side effects of these drugs include nausea, diarrhea, vomiting, and mild abdominal cramps which sometimes lead to discontinuation of therapy. The other feature of laxatives is that a fair number of patients may develop tolerance to them. This is most common in patients with slow transit time and severe constipation. Further, since none of the laxatives address the mechanisms that underlie OIC, adequate symptomatic relief is not obtained in most patients. The often leads to the prescription of a supramaximal dose of laxatives which unfortunately leads to the development of adverse effects. Even with the newer peripheral opioid antagonists, the data on their benefits are not clear-cut, and no data from long-term studies are available. Hence, if a laxative fails to work within 2 to 3 weeks, an alternative treatment strategy should be considered. In some cases, this may mean also changing the management of pain.
Adverse effects of laxatives
All laxatives have adverse effects if they are abused. The adverse effects include:
Thus, when patients are started on laxatives, they should be monitored. Once the opioid has been discontinued, the laxatives should also be stopped as long as there is no residual constipation.
Whenever an opiate is prescribed, the patient should be educated on 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.
While there is no question that opioids are useful drugs for the management of moderate to severe pain, these agents also have a variety of adverse effects, of which one of them is OIC. The latter syndrome is not benign and can significantly alter the quality of life. The adverse gastrointestinal symptoms can be distressing and lead to non-compliance with pain management. The best way to manage OIC is to prevent it in the first place. Both non-pharmacological and pharmacological therapies should be instituted at the same time the opioid is prescribed. There is no evidence that one type of laxative is better than the other, but bulk-forming laxatives should be avoided. Unfortunately, since the currently available laxatives do not target the underlying cause of OIC, their effectiveness is variable and not consistent. There are several newer laxatives that target OIC and early results suggest they do work well, but long-term data on their effectiveness and safety are not yet available. The patient should be educated on changes in lifestyle when prescribed opioids and limit the intake of pain medications for trivial reasons.
OIC may present immediately when a patient takes the opioid, or it may present gradually over a few weeks. The vast majority of patients on opioids will complain of constipation at some point during the treatment. Constipation can occur immediately and can be pronounced. In association with constipation, patients may also develop other GI side effects like nausea, vomiting, bloat, abdominal pain, and straining. The longer patients take opioids, the intensity of constipation increases. The condition can have significant morbidity and lower the quality of life. Ways to prevent this complication 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. 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. Only a multidisciplinary approach may help prevent this agonizing problem. (Level V)
Unfortunately once OIC has developed, returning bowel function to the pre-opiate status is difficult. Plus, one still has to manage the pain and the overall quality of life is very poor. 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)