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Treatment of Opioid-Induced Constipation: The Hard Facts

Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on Oct 24, 2020.

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 what you may not know is that one of the most common and troubling side effects with opioids is opioid-induced constipation. In fact, 40% to 80% of patients taking opioids over the long-term may suffer from this side effect.

Talking about constipation can be embarrassing, but it can be a serious side effect and deserves your attention. Opioid-induced constipation (OIC) 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 states 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 up constipatin concerns with your doctor.

Which Drugs Cause Opioid-Induced Constipation?

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

There is some evidence that morphine (oral or parenteral) may be more constipating than transdermal opioids such as fentanyl, per 2019 AGA guidelines.

While many opioid side effects such as drowsiness, nausea and vomiting, and respiratory depression may lessen 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 how well you stick to your pain-relieving medication regimen. In a survey 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 (OIC) 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
  • bathroom 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)
    • Intermittent or daily use of an oral stimulant laxative (senna, 2 tablets at bedtime) usually given with a stool softener like docusate (100 mg orally twice a day), 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)
    • Daily use of a common surfactant stool softener available over-the-counter (OTC). As noted above, docusate is probably best combined with senna (Senokot S) for treatment or prevention of OIC in patients with hard, dry stools. Used by itself, docusate is often not effective.

See next slide for additional first-line options.

More Options for Opioid-Induced Constipation: Prevention

Osmotic cathartics such as lactulose (Cholac, Constilac, Enulose, Generlac) or polyethylene glycol (MiraLax) 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 opioid-induced constipation (OIC) - (17 grams or one heaping teaspoonful), or can be used intermittently (every 2 or 3 days).
  • Lactulose can be given in a daily dose of 30 mL as a preventive for OIC. It can lead to excessive gas, cramping and bloating, and may need to be avoided in patients who are lactose-intolerant and those who require a low galactose diet.

Bisacodyl (Dulcolax) is a stimulant laxative that is also available without a prescription.

  • It can be used intermittently (every 2 to 3 days) orally or as a rectal suppository for constipation, but can cause some cramping and explosive diarrhea.
  • Bisacodyl suppositories usually produce a bowel movement within 1/2 to 1 hour, while tablets usually take 6 to 12 hours.

It is reasonable to consider switching or combining conventional laxative-type therapies to optimize treatment if initial therapy is not optimal for OIC. According to the AGA 2019 guidelines, there is little evidence to suggest that routine use of stimulant laxatives is harmful to the colon.

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 prevent the constipating effect from narcotics.

Unlike laxatives, peripherally acting μ-opioid receptor antagonists (PAMORAs) directly affect how opioids cause constipation; however, the pain-relieving effect of the opioid is not blocked.

FDA-approved PAMORA regimens include:

Lubiprostone (Amitiza) is also used for opioid-induced constipation (OIC), but is not an opioid antagonist. Pharmacologically it is a type-2 chloride channel activator and is classified as an osmotic laxative.

  • Amitiza is FDA-approved for treatment of OIC in adults with chronic noncancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (eg, weekly) opioid dosage escalation. Can lead to nausea and stomach pain side effects.
  • It is also approved for irritable bowel syndrome (IBS) with constipation and idiopathic (cause unknown) chronic constipation.

Relistor (methylnaltrexone)

Relistor (methylnaltrexone), 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, and does not induce opioid withdrawal symptoms.

Relistor was originally approved in 2008 as a subcutaneous (under the skin) injection. In 2016, the oral tablets were also approved. Both the injection and tablets are approved to treat:

  • opioid-induced constipation (OIC) in adults with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.
  • Relistor injection (but not the oral tablets) is approved for OIC in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. The use of Relistor injection beyond four months has not been studied in the advanced illness population.

Do not use Relistor if you have a blockage in your stomach or intestines.

Side effects with Relistor (in more detail)

Movantik (naloxegol)

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

  • Like Relistor, Movantik is an oral, opioid receptor antagonist that blocks opioid receptors in the intestines with negligible penetration into the the brain.
  • 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.

Movatik side effects (in more detail)

It's important to avoid eating grapefruit or drinking grapefruit juice during treatment with Movantik, as thhis can increase drug levels in your blood. Do not take Movantik if you have have a bowel blockage (intestinal obstruction) or a history of bowel blockage.

Symproic (naldemedine)

In March of 2017, the FDA approved Shionogi's Symproic (naldemedine), another peripherally-acting mu-opioid receptor antagonist.

  • Used in adults to treat opioid-induced constipation (OIC) due to opioid use for chronic non-cancer pain or pain related to prior cancer or its treatment. Patients do not require frequent (e.g., weekly) opioid dosage escalation. Those who have received opioids for less than 4 weeks may be less responsive to Symproic.
  • Symproic treats OIC without reducing the pain-relieving effects of the narcotic.
  • Symproic comes as a 0.2 mg oral tablet and is taken once a day. Naldemedine is a Schedule II controlled substance.
  • 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.

Side effects with Symproic (in more detail)

Amitiza (lubiprostone)

Amitiza (lubiprostone) was first FDA-approved in April 2013. 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 approved for:

  • the treatment of opioid-induced constipation (OIC) in adults with chronic pain that is not caused by active cancer. This includes patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.
  • for chronic idiopathic constipation (constipation due to an unknown cause and not due to an underlying illness or medication) in adults
  • for constipation-predominant irritable bowel syndrome (IBS) in women at least 18 years of age.

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. Adjust doses in liver impairment. 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 a peripherally-acting mu opioid receptor antagonist used to help patients regain gastrointestinal (GI) function earlier following bowel resection surgery (surgery to remove a portion of your intestine).

  • 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, due to the potential risk of heart attack with long-term use.
  • It is not used to treat opioid-induced constipation on an outpatient basis.
  • Entereg is for short-term use after bowel resection surgery only. Patients should not receive more than 15 doses of Entereg or use it for longer than 7 days.
  • Entereg should not be used in patients who have received therapeutics doses of opioids for more than 7 consecutive days immediately prior to taking Entereg due to possible side effects such as stomach pain, nausea, vomiting, and diarrhea.

A Boxed Warning, the FDA's most stringent safety warning, is in place 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 the heart attacks is not known. In short-term use, such as it's approved use for 7 days (15 doses), an increased risk of heart attack has not been seen. Discuss any questions or concerns with your doctor.

2019 AGA Guidelines on Treatment of Opioid-Induced Constipation

In the 2019 American Gastroenterological Association (AGA) guidelines for opioid-induced constipation, laxative use is strongly recommended as a first-line agent.

  • For patients with opioid-induced constipation who do not respond to laxatives, naldemidine (Symproic) and naloxegol (Movantik) have a strong recommendation for use, with methylnaltrexone (Relistor) having a conditional recommendation. All of these agents are recommended over no treatment.
  • The intestinal secretagogue Amitiza (lubiprostone) was FDA-approved for OIC in 2013, but AGA makes no recommendations in the guideline due to an evidence gap.
  • No recommendations are made for use of the selective 5-HT agonist prucalopride (Motegrity) because the available evidence is insufficient to determine a true effect. Motegrity is not currently FDA approved for OIC, even though some clinicians may consider its use off-label.

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 with you. Plus, there's a wealth of options to help prevent and treat this common -- but sometimes serious -- condition.

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

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