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Treatment of Opioid-Induced Constipation: The Hard Facts

Medically reviewed on Sep 26, 2018 by L. Anderson, PharmD

Opioids and Constipation: It Happens

You probably already know that opioid use is accompanied by many side effects like sedation, nausea, and tolerance. An opioid is sometimes called a narcotic, and they are used for varying degrees of pain. But you may not know that one of the most common and troubling side effects is constipation; in fact, 40% to 80% of patients taking opioids may suffer from this side effect.

Talking about constipation can be embarrassing, but it can be a serious side effect. Constipation associated with opioid treatment can occur among patients with chronic non-cancer pain, such as:

  • musculoskeletal pain like severe back pain
  • osteoarthritic knee pain
  • fibromylagia
  • headache
  • other degenerative joint pain

Although guidelines suggest opioids should not be used first-line as treatment for chronic pain, they may still be prescribed in certain acute circumstances when benefit outweights risk. In addition, opioid-induced constipation can happen quickly -- in a matter of days -- and can result in more serious complications, like fecal impaction, anal fissures, rectal bleeding or prolapse, stomach pain, hemorrhoids, or perforation. It's nothing to laugh about, and it is important you bring it up with your doctor.

Which Drugs Cause Opioid-Induced Constipation?

Any drug that is classified as an "opioid" can theoretically cause constipation. Examples of commonly prescribed opioids that can lead to this side effect include:

While many opioid side effects such as drowsiness, nausea and vomiting, and respiratory depression may diminish over time due to the development of tolerance, the constipating effects of opioids can last throughout the entire period of treatment.

Symptoms of Opioid-Induced Constipation

Opioid-induced constipation can affect adherence to a pain-relieving medication regimen. In a survey from Bell and colleagues of over 300 patients taking daily opioids for chronic pain, about 30% of patients missed, decreased or stopped opioid use to ease their bowel movements.

Frequent symptoms might include:

  • difficulty passing stools
  • hard, dry or infrequent (< 3 per week) bowel movements
  • pain during bowel movement
  • straining, incomplete evacuation of stool
  • bloating or distention in the stomach

Constipation and infrequent bowel movements can lead to more serious complications. Opioid-induced constipation should be addressed or prevented to help avoid issues such as stool impaction or bowel perforation. If you've recently started an opioid, and notice these symptoms above, contact your doctor to discuss treatment options.

What Causes Opioid-Induced Constipation?

Opioids work well for pain but are known for causing stomach and bowel side effects. Opioid-induced constipation (OIC) is one of the most common side effects of opioid use, and can start quickly and last as long as the patient takes the opioid.

Opioids attach to special receptors, called μ (mu) receptors in the central nervous system to help block pain. Opioids like codeine or hydrocodone are used for pain because they block these pain signals in the brain. But μ receptors are also found in the bowel, and when the opioid attaches here, it can slow down bowel movement and lead to opioid-induced constipation (OIC).

Pain and chronic illness can also lead to immobility and infrequent exercise, which can worsen constipation.

Other contributing factors include:

  • the elderly may be more likely to get dehydrated
  • certain medications, like tricyclic antidepressants or other anticholinergic drugs, can worsen constipation
  • hypercalcemia (high blood calcium levels)
  • bowel obstruction
  • certain chemotherapy regimens.

How to Treat Opioid-Induced Constipation?

Opioid-induced constipation (OIC) results in bowel movements that are infrequent or incomplete due to a side effect of opioid medications.

Prevention of OIC is always preferred over waiting to treat it due to the possibility of complications from unaddressed constipation. For example, changing diet, increasing fluids, adding dietary fiber, stool softeners, or other laxatives -- along with opioids -- to help prevent constipation from opioids is a common and accepted practice.

This may be especially important in the elderly, those with limited mobility, or those who take other drugs that also cause constipation (such as tricyclic antidepressants, antihistamines, calcium or iron supplements, and aluminum-containing antacids).

However, when OIC does occur, the basic principals of treating opioid-induced constipation are similar to the methods used to handle most other opioid side effects:

  • lower the opioid dose, which may not always be possible dependent upon pain levels
  • manage the side effect(s) with other medications or lifestyle changes
  • change the opioid to a different class of pain medication that is less constipating.

Lifestyle Changes to Help Prevent Opioid-Induced Constipation

It's important to address opioid-induced constipation with lifestyle changes, even if medications are still needed. Prevention is preferred over treatment, when possible. It's best to start OIC prevention strategies when the opioid is initiated.

Nondrug actions that can be added to OIC drug therapy to help prevent constipation when an opioid is started include:

  • increased fluid intake, especially water; drink at least four 8-ounce glasses of water daily
  • increased dietary soluble fiber intake (but not if dehydrated, debilitated or a bowel obstruction)
  • daily exercise and activity, when able
  • timely toileting habits and privacy.

First-Line Medications for OIC

Prevention of opioid-induced constipation (OIC) is always preferred over treatment. Exercise, added fiber in the diet with whole grains, fruits and leafy vegetables, and plenty of fluids can be helpful, but may not work for everyone.

In these cases, typical first-line agents used in OIC (many available over-the-counter) include:

  • Senna (Senokot, Senokot-S) - an oral stimulant laxative (senna) usually given with a stool softener (docusate) that increases the movement of stool through the gut and helps to keep stool softer by reducing water absorption out of the intestines. There are few risks with short-term use. It is often the first-line choice for prevention of OIC when pain treatment is started. One disadvantage is that its effectiveness may wane over time.
  • Docusate (Colace) - a common surfactant stool softener available over-the-counter (OTC); as noted above, is probably best combined with senna (Senokot S) for treatment or prevention of OIC.

See next slide for additional first-line options.

More Options for Opioid-Induced Constipation: Prevention

Osmotic cathartics such as lactulose or polyethylene glycol (MiraLax) - these agents increase water in the bowel and help to move the bowel movement more quickly through the intestine.

  • Polyethylene glycol (MiraLax) is not absorbed into the bloodstream and can be used longer-term, if needed. It can be given daily as a preventive for OIC (17 grams or one heaping teaspoonful).
  • Lactulose may lead to flatulence and may need to be avoided in patients who are lactose-intolerant and those who require a low galactose diet. It can be given in a daily dose of 30 mL as a preventive for OIC.

Bisacodyl (Dulcolax) is a stimulant laxative that is also available without a prescription. It can be used orally or as a rectal suppository for constipation, but can cause some cramping and explosive diarrhea.

Additional Options: Opioid Antagonists and a New Laxative

Opioid antagonists work peripherally (not in the brain, but in the gut) binding to the opioid receptor and preventing the constipating effect from narcotics.

Unlike laxatives, opioid antagonists directly affect how opioids cause constipation. However, the pain-relieving effect of the opioid is not blocked.

FDA-approved regimens include:

Alvimopan (Entereg) is a μ-opioid receptor antagonist, but is only for short-term use in a hospital after bowel resection surgery. Entereg requires REMS program enrollment (for safety) because of the potential risk of a heart attack (myocardial infarction) with long-term use.

Lubiprostone (Amitiza) is also used for opioid-induced constipation (OIC), but is not an opioid antagonist; it is classified as an osmotic laxative.

Relistor (methylnaltrexone)

Relistor, a derivative of naltrexone, is classified as a mu-opioid receptor antagonist, and blocks receptors in the bowel that can interact with pain medications and lead to constipation. However, Relistor does not block the pain receptors in the brain, so the pain-relieving action of the opioid medication still takes effect.

Relistor was originally approved in 2014 as a subcutaneous (under the skin) injection for OIC and is used to treat:

  • constipation caused by opioids in adults with long-lasting (chronic) pain that is not caused by active cancer.
  • constipation in patients with advanced illness or pain caused by active cancer who require increases in their opioid dose escalation for pain management (palliative care).

In July, 2016 the FDA approved methylnaltrexone (Relistor) oral tablets for the treatment of opioid-induced constipation (OIC) in adults with long-lasting (chronic) pain that is not caused by active cancer.

In patients who have been receiving opioids for less than 4 weeks, Relistor may be less effective.

You should not use Relistor if you have a blockage in your stomach or intestines. Side effects with Relistor can include:

  • stomach pain, bloating, diarrhea - if severe contact your doctor immediately
  • headaches
  • sweating, chills, runny nose
  • anxiety
  • muscle spasms

Movantik (naloxegol)

In September, 2014 the FDA cleared AstraZeneca’s Movantik (naloxegol) to treat opioid-induced constipation in adults with long-lasting pain that is not caused by cancer.

Like Relistor, Movantik is an oral, opioid receptor antagonist that blocks opioid receptors in the intestines. In clinical studies, 1,352 participants received 12.5 milligrams (mg) or 25 mg of Movantik or a placebo (sugar pill) once daily for 12 weeks. Results showed that 41% to 44% of participants experienced an increase in bowel movements per week, compared to 29% of participants receiving placebo.

Common side effects of Movantik include:

  • stomach pain
  • diarrhea
  • headache
  • flatulence (gas).

It's important to avoid eating grapefruit or drinking grapefruit juice during treatment with Movantik.

Symproic (naldemedine)

In March of 2017, the FDA approved Symproic (naldemedine), another peripherally-acting mu-opioid receptor antagonist used in adults to treat constipation that is caused by prescription pain medicines called opioids used for long-lasting (chronic) pain that is not caused by active cancer. Symproic comes in 0.2 mg oral tablets and is taken once a day.

Symproic approval was based on the COMPOSE I and II randomized trials: two 12-week, randomized efficacy studies and one 52-week safety study conducted in adult patients with opioid-induced constipation (OIC) and chronic non-cancer pain. Symproic met its primary and key secondary endpoints in both COMPOSE I and II.

The most common side effects with Symproic as compared to placebo in clinical trials were:

  • abdominal pain (8% vs 2%)
  • diarrhea (7% vs 2%)
  • nausea (4% vs 2%)
  • gastroenteritis (2% vs 1%).

Amitiza (lubiprostone)

Amitiza (lubiprostone) was FDA-approved in April 2013 for the treatment of constipation caused by opioids (opioid-induced constipation or OIC) in adults with chronic pain that is not caused by active cancer. It's not an opioid antagonist, but an osmotic laxative that works as a selective chloride channel activator (CIC-2) to increase bowel movement and fluid secretions.

Amitiza is also approved for chronic idiopathic constipation (constipation due to an unknown cause and not due to an underlying illness or medication) and constipation-predominant irritable bowel syndrome (IBS) in women.

Amitiza clinical trials included research with opioids such as morphine, oxycodone and fentanyl; however, it is not known if Amitiza would be effective for constipation due to diphenylheptane opioids such as methadone. Studies have shown a significant effect to improve spontaneous bowel movements, stool consistency, and to reduce straining.

For OIC, Amitiza is usually taken as a 24 microgram (mcg) capsule twice daily by mouth. Common side effects include nausea, diarrhea, and stomach pain. Shortness of breath or chest tightness has also been reported within 2 hours of taking the drug in some patients.

Entereg (Alvimopan)

Entereg (alvimopan) is also a peripherally-acting mu opioid receptor antagonist used to help patients regain gastrointestinal (GI) function earlier following bowel resection surgery. Entereg is only approved for use in patients in a hospital enrolled in the Entereg Access Support and Education (E.A.S.E) REMS program to dispense Entereg to patients. It is not used to treat OIC on an outpatient basis.

Entereg is for short-term use after bowel resection surgery only. Patients should not receive more than 15 doses of alvimopan or use it for longer than 7 days. Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation.

A Boxed Warning exists for Entereg. A larger number of heart attacks happened in people taking Entereg compared to people not taking it during long-term use. The cause of this is not known. In short-term use, such as it's approved use, an increased risk of heart attack has not been seen. Discuss any questions or concerns with your doctor.

Support for OIC: Join the Group

With many new treatments approved for opioid-induced constipation (OIC), and with this bothersome side effect being so common, it may be helpful to connect with others with similar situations, concerns, or questions.

Consider joining the:

to share ideas, ask questions, and stay on top of the latest medical research.

And if you are experiencing constipation due to opioids for pain, be sure to talk your doctor. Don't worry -- it's not embarrassing for them to discuss OIC, and there are a wealth of options out there to help prevent and treat this common -- but sometimes serious -- condition.

Finished: Treatment of Opioid-Induced Constipation: The Hard Facts

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