Physicians may have noticed a recent increased focus on the constipating effect of opioids. This appears to be due, not to new research, but to the FDA approval of a new medication, naloxegol (Movantik), which treats opioid-induced constipation (OIC) and is expected to be available soon, as well as the recent approval for an expanded indication of the currently available methylnaltrexone bromide (Relistor). Previously, methylnaltrexone was only approved for cancer patients receiving palliative care but is now approved for treatment of OIC in patients with chronic non-cancer pain.
Both of these medications are peripherally acting µ-opioid receptor antagonists (PAMORA). As the name implies, they block the receptors in the gut, thereby reducing the constipation that opioids may cause without affecting the opioid receptors in the brain.
A major difference between these two medications is that naloxegol is an oral medication, while methylnaltrexone is administered by subcutaneous injection.
I support the introduction of new medications, especially those that exert their effects in ways that differ from previously available ones, as the PAMORA agents do. However, I am concerned that older medications that can be equally effective in the management of OIC and, even more important, the prophylactic measures that can prevent OIC may be overlooked, with the attention paid to these new agents.
Old reliable prevention
OIC occurs frequently and is considered the most common side effect related to the use of opioids. Various studies have reported that 25% to 50% of patients taking opioid analgesics on an extended basis develop OIC. Unfortunately, it appears that physicians prescribing these medications often fail to provide their patients with much information on OIC. This may be the result of the focus on the pain being treated with the opioid and other health problems during physician visits, but it may also reflect the fact that many patients are uncomfortable discussing their bowel habits, unless specifically asked or until constipation becomes a marked problem.
This is disturbing to me for several reasons. The main reason is that OIC can often be prevented by prophylactic measures that are both inexpensive and usually carry minimal risk of causing significant adverse events. In fact, of all the potential side effects from opioids, including nausea, vomiting, and pruritus, constipation is usually the only one that is generally recommended to be addressed prophylactically.
OIC differs from other common side effects in that once it occurs, it can be difficult to treat, and unlike other opioid-related problems, patients don’t usually develop tolerance to it over time.
If opioids are going to be prescribed for more than a few days, prophylactic treatment of OIC should be discussed with the patient. Obviously, this would include any patients for whom long-acting, extended-release opioids are prescribed, since the use of these drugs should be limited to patients who have frequent pain that is expected to last for an extended period.
Unfortunately, because patients may receive limited information on OIC from their prescribers, they may be left on their own to decide how best to treat it. The problem is that although there are many medications available over the counter (OTC) to treat constipation, some of the most commonly used ones can actually exacerbate OIC rather than relieve it.
It is worthwhile to advise all patients treated with opioids on the things that are considered important for healthy bowel function in all people: drink plenty of water, exercise regularly, and eat a healthy diet, especially fruits and vegetables. However, high-fiber foods can exacerbate the problem for the reason discussed below regarding bulk laxatives.
It should be noted that patients taking opioids for chronic pain may have difficulty in exercising, and those with cancer-related pain may find eating difficult because of the underlying disease or the side effects related to chemotherapy or radiation therapy.
And the choices are . . .
With regard to medications, the usual starting point for the prophylactic treatment of OIC is a stool softener, usually docusate sodium (Colace), available OTC. It is worth noting that patients taking opioid analgesics are often receiving medications for other problems, and at least some of them may not want to add to their list. For these patients, certain foods, such as prunes and bananas, may provide an alternative and also an additional nutritional benefit. If docusate sodium appears to be insufficient treatment, senna, a large-bowel stimulant, can be added.
It is important to advise patients against the use of bulk laxatives, such as Metamucil, which contain psyllium seed husk as the active ingredient. The problem with these is that one of the effects of opioids is that they reduce the amount of water in the intestine itself and not just in the lumen. Since the bulk laxatives work by drawing fluid into the lumen, patients will simply become more impacted with the laxative added to the feces if fluid is not available.
Osmotic agents such as lactulose and saline agents such as magnesium are alternatives if senna and docusate sodium provide insufficient relief. Although these also depend to some degree on increasing the amount of water in the bowel, they appear to be safer for OIC than the bulk laxatives. Mineral oil may also provide relief for certain patients.
Another FDA-approved prescription medication for the treatment of OIC that works in a different way from the PAMORA agents is lubiprostone (Amitiza). This is a locally acting chloride channel activator that promotes fluid secretion in the bowel.
Just as there is variability in individual patient’s response to opioid analgesia, there appears also to be variation in the development of side effects related to opioids, including OIC. If constipation is developing and the OTC medications are not providing relief, it is worth considering switching to another opioid. Obviously, the amount of pain relief the patient is receiving would be a factor in this decision and it would be important to choose an opioid that is not chemically related to the one currently being used and causing the OIC. (Several opioids are metabolized to others: oxycodone to oxymorphone; codeine to morphine; hydrocodone to hydromorphone.)
Dosing of any of the medications for OIC can be tricky with some trial and error required to find the proper balance between relieving the constipation without inducing loose stools or too frequent bowel movements that can be equally distressing.
There is no doubt that patients with OIC benefit from the use of naloxegol and methylnaltrexone, and we shouldn’t hesitate to prescribe them for certain patients. However, we should make sure that we don’t overuse them in the place of less expensive and safe alternatives that may also serve as prophylaxis.
Opioids are notorious for causing constipation but many prescription drugs also cause the problem. Do you proactively discuss the potential for prescription drug–related constipation with your patients?