Treatment of Opioid-Induced Constipation: The Hard Facts
Opioids and Constipation: It Happens
You probably already know that opioid use is accompanied by many side effects like sedation, nausea, and tolerance. One of the most common and troubling side effects is constipation; 40% to 80% of patients taking opioids may suffer from this side effect. An opioid is sometimes called a narcotic.
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
- 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:
- hydrocodone (Hysingla ER, Zohydro ER)
- oxycodone (Oxycontin, Roxicodone)
- morphine (MS Contin, Kadain)
- fentanyl (Duragesic, Actiq, others)
- tramadol (ConZip, Ultram)
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 fact, in a survey from Bell and colleages (2017) of over 300 patients taking daily opioids for chronic pain, about 30 percent 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 perweek) bowel movements
- Pain during bowel movement
- Straining, incomplete evacuation of stool
- Bloating or distention in the stomach
In a research setting, the ROME III functional constipation diagnoistic criteria are used.
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. The elderly may be subject to dehydration, and certain medications, like tricyclic antidepressants or other anticholinergic drugs, can worsen constipation.
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.
Actions that can be added to drug therapy to tackle constipation include:
- Increased fluid intake, especially water; drink at least four 8-ounce glasses of water daily
- Increased dietary fiber intake
- 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 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; few risks with short-term use; first-line choice for prevention of opioid-induced constipation when treatment started. One disadvantage is that tolerance to the effect may develop 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.
First-Line Options for Opioid-Induced Constipation, Continued:
- Bisacodyl (Dulcolax) - a stimulant laxative also available without a prescription; can be used orally or as a rectal suppository, but can cause some cramping and explosive diarrhea.
- 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. 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.
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 the mechanism by which 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 because of the potential risk of myocardial infarction with long-term use.
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 cancer, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. The injection is also used in patients with advanced illness or pain caused by active cancer who require opioid dosage escalation for palliative care (treatment to improve quality of life during a serious illness).
In July, 2016 the FDA approved methylnaltrexone (Relistor) oral tablets for the treatment of 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 opioid dosage escalation.
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
- Sweating, chills, runny nose
- Muscle spasms
In September, 2014 the FDA cleared AstraZeneca’s Movantik (naloxegol) for the treatment of 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. Movantik is a pegylated form of naloxone.
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 percent of participants experienced an increase in bowel movements per week, compared to 29 percent of participants receiving placebo.
Common side effects of Movantik include stomach pain, diarrhea, headache and flatulence (gas). It's important to avoid eating grapefruit or drinking grapefruit juice during treatment with Movantik.
In March of 2017, the FDA approved Symproic (naldemedine), another peripherally-acting mu-opioid receptor antagonist for the treatment of 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. 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 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%).
Symproic is currently a Schedule II controlled substance because its structure is similar to naltrexone, but the manufacturer has asked for a DEA review to possibly remove scheduling.
Amitiza (lubiprostone) was FDA-approved in April 2013 for the treatment of opioid-induced constipation (OIC) in adult patients 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. Amitiza is also approved for chronic idiopathic constipation and constipation-predominant irritable bowel syndrome (IBS) in women. 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 clinical trials included research with opioids such as morphine, oxycodone and fentanyl; however, Amitiza has not been shown to 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) 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 side effect being so common, it may be helpful to connect with others with similar situations, concerns, and questions.
Consider joining the:
- Drugs.com Opioid-Induced Constipation Support Group
- Drugs.com General Constipation Support Group
- Drugs.com Constipation News and Medical Research
to share ideas, ask questions, and stay on top of the latest medical research.
Finished: Treatment of Opioid-Induced Constipation: The Hard Facts
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Entereg Product Labeling. Merck & Co., Inc. 2015. Accessed July 27, 2017 at http://www.merck.com/product/usa/pi_circulars/e/entereg/entereg_pi.pdf
Zdanowicz M. Treatment of Opioid-induced Constipation: A Therapeutic Update. Adv Practice Nurs 2016, 2:3-5. Accessed August 5, 2017 at https://www.omicsonline.org/open-access/treatment-of-opioidinduced-constipation-a-therapeutic-update-APN-1000118.pdf
Portenoy RK, Mehta Z, Ahmed E, et al. Cancer pain management with opioids: Prevention and management of side effects. Up to Date. Accessed August 4, 2017 at https://www.uptodate.com/contents/cancer-pain-management-with-opioids-prevention-and-management-of-side-effects
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Bell TJ, Panchal SJ, Miaskowski C, et al. The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European Patient Survey (PROBE 1). Pain Med 2009;10:35-42. Accessed August 5, 2017 at https://www.ncbi.nlm.nih.gov/pubmed/18721170
FDA Approves Symproic. Drugs.com. March 23, 2017. Accessed August 5, 2017 at https://www.drugs.com/newdrugs/fda-approves-symproic-naldemedine-opioid-induced-constipation-4503.html