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:

• hydrocodone (Hysingla ER, Zohydro ER)
• oxycodone (Oxycontin, Roxicodone)
• morphine (MS Contin, Kadian)
• fentanyl (Duragesic, Actiq)
• methadone
• codeine
• tramadol (ConZip, Ultram)

How common is Opioid-Induced Constipation?

You probably already know that opioid use is accompanied by many side effects like sedation, nausea, and drug tolerance. An opioid is sometimes called a narcotic, and they are used for varying degrees of moderate-to-severe pain.

But what you may not know is that one of the most common and troubling side effects with opioids is Opioid-Induced Constipation (OIC). 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
• fibromyalgia
• headache
• other degenerative joint pain

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.

Guidelines state opioids should not be used first-line as treatment for chronic, non-cancer pain, but Opioid-Induced Constipation can happen quickly -- in a matter of days. This 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 constipation concerns with your doctor.

What are the symptoms of Opioid-Induced Constipation?

Frequent symptoms of Opioid-Induced Constipation 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, in addition to a high risk for tolerance and addiction. 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.

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

Other contributing factors include:

• dehydration; 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 do I 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 Opioid-Induced Constipation 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 principles of treating OIC 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.

Which lifestyle changes help prevent opioid-induced constipation?

It's important to address Opioid-Induced Constipation (OIC) with dietary and lifestyle changes, even if medications are still needed. Prevention is preferred over treatment, when possible; however, it is unlikely that dietary and lifestyle changes alone will prevent or treat OIC. 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 eight 8-ounce glasses of water daily
• increased dietary soluble fiber intake (but not if dehydrated, debilitated or a bowel obstruction). Fiber supplements and/or bulk-forming laxatives (eg, psyllium) require good oral hydration; but effectiveness is generally modest in patients with OIC.
• daily exercise and activity, when able and approved by your doctor
• timely toileting habits
• bathroom privacy.

How do I prevent Opioid-Induced Constipation?

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.

Bisacodyl (Dulcolax)

• 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.

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.

Osmotic cathartics

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 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.

Which prescription drugs are FDA-approved for Opioid-Induced Constipation?

Peripheral opioid receptor antagonists

Opioid antagonists work peripherally (in the gut, not in the brain) binding to the opioid receptor and prevent the constipating effect from narcotics. Unlike laxatives, peripherally acting μ-opioid receptor antagonists directly affect how opioids cause constipation; however, the pain-relieving effect of the opioid is not blocked.

FDA-approved regimens include:

• methylnaltrexone (Relistor)
• naloxegol (Movantik)
• naldemidine (Symproic)
• alvimopan (Entereg)

Relistor

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 various strengths. In 2016, the 150 mg oral tablets were also approved.

• Both the injection and tablets are approved to treat Opioid-Induced Constipation in adults with chronic non-cancer pain.
• Relistor injection (but not the oral tablets) is approved for Opioid-Induced Constipation in adults with advanced illness.

Common side effects include abdominal (stomach area) pain or distention, diarrhea, excessive sweating, chills, gas, and nausea.

Do not use Relistor if you have a blockage in your stomach or intestines, or are at risk, due to a possible perforation (tear). The use of Relistor injection longer than 4 months has not been studied in patients with advanced illness.

Learn more: Side effects with Relistor (in more detail)

Movantik

In September, 2014 the FDA cleared AstraZeneca’s Movantik (naloxegol) to treat opioid-induced constipation (OIC) in adults with long-lasting (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. Movantik may be more effective in people who have been taking opioid pain medicine for at least 4 weeks.

• Like Relistor, Movantik is a peripherally acting mu-opioid receptor antagonist that blocks opioid receptors in the intestines with little 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.
• Do not take Movantik if you have a bowel blockage (intestinal obstruction) or a history of bowel blockage.

It's important to avoid eating grapefruit or drinking grapefruit juice during treatment with Movantik, as this can increase drug levels in your blood, which may worsen side effects. Take Movantik on an empty stomach at least 1 hour prior to the first meal of the day or 2 hours after the meal.

Learn more: Movantik side effects (in more detail)

Symproic

In March of 2017, the FDA approved Shionogi's Symproic (naldemedine), another peripherally-acting mu-opioid receptor antagonist. Symproic treats OIC without reducing the pain-relieving effects of the narcotic.

• Symproic is 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 (who 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.
• If your opioid pain medication is stopped, your doctor will also stop your use of Symproic.
• Symproic comes as a 0.2 mg oral tablet and is taken once a day. Your pharmacist or doctor should review your medicines, including non-prescription drugs, for CYP450 3A drug interactions.
• Most common adverse reactions (≥2%) are: abdominal pain, diarrhea,
  nausea and gastroenteritis.

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 OIC and chronic non-cancer pain. Symproic met its primary and key secondary endpoints in both COMPOSE I and II.

Learn more: Side effects with Symproic (in more detail)

Entereg

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 therapeutic 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.
• Most common adverse reaction (≥1.5%): dyspepsia (heartburn).

A Boxed Warning, the FDA's most stringent safety warning, is on the labeling 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 its 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.

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Chloride channel activator

Amitiza

Amitiza (lubiprostone) was FDA-approved in April 2013. It's not an opioid antagonist, but an osmotic laxative that works locally as a selective chloride channel activator (CIC-2) to increase intestinal fluids that help in the passing of stool.

Chloride channel activator agent is a locally acting agent that activates chloride channels in the intestine and increases secretion of intestinal fluid that helps in passing of the stool. It is used to treat chronic constipation especially in patients who have little or no benefit from stool softeners or laxatives.

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 Amitiza 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.

What do guidelines suggest for 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, the prescription drugs 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.

Are there any support groups for Opioid-Induced Constipation (OIC)?

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

As always, your healthcare provider's medical directions should be followed. However, you may consider joining the following groups to share ideas, ask questions, and stay on top of the latest medical research:

• Drugs.com - Opioid-Induced Constipation Support Group
• Drugs.com - Chronic Constipation Support Group
• Drugs.com - Chronic Constipation News and Medical Research

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

This is not all you need to know about Opioid-Induced Constipation and treatment and does not replace your healthcare providers directions. Consult with your doctor or healthcare provider for further information.