Background    Fast Fact #294 introduces OIC and discusses well-established treatments. This Fast Fact discusses emerging management approaches. In general, these agents are used for refractory OIC, which implies persistent and distressing symptoms despite exposure to typically effective doses of stimulant and osmotic laxatives.  When exactly to use these emerging therapies remains largely empiric.

Opioid antagonists    Since most symptoms associated with OIC are secondary to stimulation of µ-opioid receptors in the gut, opioid antagonists offer an attractive pharmacologic rationale for OIC (1).

• Naloxone: This is an older medication which used to have a much more established role in the off-label use for OIC. Typically, patients orally ingest the contents of IV ampules. Naloxone has a high first pass metabolism, so it is possible for patients who take it orally to have peripheral µ-opioid receptor antagonism without significant impact on central receptors which could lead to opioid withdrawal and loss of analgesia (2). In a small, non-controlled study, 80% of patients on long term opioid therapy had bowel evacuation in 1-4 hours after naloxone administration. Unfortunately, over two-thirds reported a 10-15% loss of analgesia and nearly one-third had withdrawal symptoms (3). Therefore, if used, start at a very low dose of 0.8 mg twice daily. Effective doses typically are at least 10% of equivalent daily morphine dose; titrate slowly; max dosing is 12 mg daily (2). 
• Methylnaltrexone bromide (Relistor ®) is a peripherally acting µ-opioid receptor antagonist (PAMORA). It is a methylated form of naltrexone and formulated as a subcutaneous injection. It is less able to cross the blood brain barrier, reducing the risk of altering analgesia or inducing central opioid withdrawal. An industry-funded randomized controlled trial showed that weight based methylnatrexone dosing led to laxation in nearly half of subjects on chronic opioid therapy within 4 hours as opposed to 15% of placebo (4). A subsequent meta-analysis of 6 separate trials with methylnaltrexone demonstrated the number needed to treat (NNT) is 3 for OIC patients that have failed to respond to standard laxative therapy (5). Its use is limited by cost which averages $175 per dose, and it is also contraindicated when bowel obstruction or compromised bowel integrity is suspected. Nausea, diarrhea, and cramping are common side effects and can be severe.
• Naloxegol (Movantik®) is an oral PAMORA approved for OIC in non-cancer patients. Two separate phase-three clinical trials showed an increase from 1 to >3 bowel movements per week in non-cancer patients on chronic opioids compared to placebo. There was also a significant improvement in a subset of patients who had failed traditional laxative therapy as well (7). Scheduled use of 12.5 mg and 25 mg/day have been studied; the 25 mg dose has a higher success rate but is associated with more abdominal pain, nausea, vomiting and diarrhea (7). It is approximately $435 for 30 pills.
• Naldemedine (Symproic) is another oral PAMORA approved for OIC. Usual dosage is 0.2 mg per day. Several phase II/III randomized clinical trials showed a significant increase in bowel movements to ≥ 3 a week in the treatment group with similar reported adverse events as the placebo group (8). Common side effects include diarrhea, abdominal pain, and nausea. Patients with GI obstruction should avoid using naldemedine. The average cost is about $483 for 30 tablets.

Other agents 

• Lubiprostone (Amitiza®): Lubiprostone is a selective chloride channel-2 activator that acts locally on the small intestine to increase fluid secretion and GI motility. It is FDA approved for OIC. Two randomized controlled trials in non-cancer chronic opioid users demonstrated an increase in frequency of spontaneous bowel movements by week 8.  Moreover, approximately 40% of subjects had a bowel movement at 24 hours, 60% within 48 hours, and 27% of subjects had > 3 bowel movements per week (9,10). The most studied dose is 24 mcg orally twice per day. Common side effects included nausea, diarrhea, and abdominal distension. Curiously, lubiprostone does not appear to be effective for methadone induced constipation (11). Average cost for 60 capsules is about $60.
• Linactolide (Linzess ®) has a different mechanism than lubiprostone but is also a small intestinal secretogogue. It is approved for irritable bowel syndrome. A phase 2 study evaluating linaclotide use in OIC patients with chronic noncancer pain showed a significant increase in bowel movements compared to placebo (12). It was safe, however, the rate of diarrhea in the treatment group was greater (32.2% vs. 16.7%). With this data, the Multinational Association for Supportive Care in Cancer (MASCC) guidelines were updated with the recommendation to consider linaclotide as an alternative agent in patients with advanced cancer who do not respond to first-line treatment (12). Use is limited to those aged >2 years due to the risk of serious dehydration and should be avoided in patients with mechanical GI obstruction. The average cost of 30 capsules is $560.
• Prucalopride (Motegrity ®) is a serotonin receptor type-4 agonist that stimulates peristalsis and intestinal secretions. It is approved to treat chronic idiopathic constipation (5). A phase 2 randomized controlled trial showed significant improvement in bowel movements during week 1 in the treatment groups (35.9% (2mg), 40.3% (4mg), and 23.4% (placebo)) for patients on chronic opioid therapy for noncancer pain. These findings led the MASCC to recommend considering prucalopride as an alternative agent in patients who do not respond to first-line treatment (13). Common adverse effects include abdominal pain, nausea, and diarrhea. Use should be avoided in patients with intestinal perforations, obstructions, GI functional disorders, or severe inflammatory conditions of the GI tract. Cost for 30 tablets of 2 mg prucalopride is about $40. 

Practical advice    Traditional oral and rectal laxatives have been the mainstay of treatment in OIC for many years. However, novel approaches to treat OIC show promise. Of the pharmacologic interventions described above, methylnaltrexone has been the best studied. It is reasonable to give methylnaltrexone after failure of oral laxatives (see Fast Facts #294) in OIC, and potentially can be used prior to using more invasive rectal based interventions. Oral formulations targeting OIC may become more standard of care. Patient and caregiver education about the importance of adherence to recommended therapy and guidance about signs and symptoms of OIC is essential to ensure effective treatment.

References

1. Holzer, Peter. Opioids and Opioid Receptors in the Enteric Nervous System: From a Problem in Opioid Analgesia to a Possible New Prokinetic Therapy in Humans. Neuroscience Letters. 2004; 361(1–3): 192–95.
2. Choi YS, Billings JA. Opioid Antagonists: A Review of Their Role in Palliative Care, Focusing on Use in Opioid-Related Constipation. Journal of Pain and Symptom Management. 2002; 24(1): 71–90.
3. Latasch L, Zimmermann M, Eberhardt B, Jurna I. Treament of morphine-induced constipation with oral naloxone. Der Anaesthesist. 1997; 46 (3): 191–94.
4. Thomas J, Karver S, Cooney GA, Chamberlain BH, Watt CK, Slatkin NE, Stambler N, Kremer AB, Israel RJ. Methylnaltrexone for Opioid-Induced Constipation in Advanced Illness. The New England Journal of Medicine. 2008; 358 (22): 2332–43.
5. Ford AC, Brenner DM, Schoenfeld PS. Efficacy of Pharmacological Therapies for the Treatment of Opioid-Induced Constipation: Systematic Review and Meta-Analysis. The American Journal of Gastroenterology. 2013; 108(10): 1566–74.
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8. Stern EK, Brenner DM. Spotlight on naldemedine in the treatment of opioid-induced constipation in adult patients with chronic noncancer pain: design, development, and place in therapy. J Pain Res. 2018;11:195-199. Published 2018 Jan 15. doi:10.2147/JPR.S141322.
9. Cryer B, Katz S, Vallejo R, Popescu A, Ueno R. A Randomized Study of Lubiprostone for Opioid-Induced Constipation in Patients with Chronic Noncancer Pain. Pain Medicine. 2014; 15(11): 1825–34.
10. Jamal M, Mazen, Mareya SM, Woldegeorgis F, Joswick TR, Ueno R. 848a Lubiprostone Significantly Improves Treatment Response in Non-Methadone Opioid-Induced Bowel Dysfunction Patients with Chronic, Non-Cancer Pain: Results from a Phase 3, Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Gastroenterology 2012; 142(5):144 –145S.
11. Brenner DM, Chey DM. An Evidence-Based Review of Novel and Emerging Therapies for Constipation in Patients Taking Opioid Analgesics. The American Journal of Gastroenterology Supplements 2014; 2(1): 38–46.
12. Brenner DM, Argoff CE, Fox SM, et al. Efficacy and safety of linaclotide for opioid-induced constipation in patients with chronic noncancer pain syndromes from a phase 2 randomized study. Pain. 2020;161(5):1027-1036. doi:10.1097/j.pain.0000000000001754.
13. Sloots CE, Rykx A, Cools M, Kerstens R, De Pauw M. Efficacy and safety of prucalopride in patients with chronic noncancer pain suffering from opioid-induced constipation. Dig Dis Sci. 2010;55(10):2912-2921. doi:10.1007/s10620-010-1229-y.

Authors’ Affiliations: University of Utah, Salt Lake City, UT (AB); University of Minnesota Health, Minneapolis, MN (DAR).
Conflict of Interest: The authors have disclosed no relevant conflicts of interest.
Version History: First electronically published April 2015. Reviewed and updated by Nusaiba Hamsho, Nakia Duncan in January 2026.