Peripherally acting mu-opioid antagonists (PAMORA). PAMORAs indicated for the treatment of OIC include naloxegol, naldemedine, and methylnatrexone. These agents are opioid antagonists selective to peripheral μ-receptors and are unable to cross the blood-brain barrier.18,19 Of note, oral naloxone, a systemic opioid antagonist used to treat opioid addiction, has been shown to be effective in treating the symptoms of OIC; however, it is a nonselective opioid antagonist and therefore may reduce analgesic effects and is not routinely used in clinical practice to treat OIC.20
Naloxegol blocks peripheral μ receptors and includes a PEG component to limit the ability to cross the blood-brain barrier.21,22 Between 2011 and 2012, two identical multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase 3 studies were conducted in the United States and Europe.19 Patients were randomly assigned in a 1:1:1 ratio to receive naloxegol 25 mg vs naloxegol 12.5 mg vs placebo with a primary end point of achieving spontaneous bowel movements without the use of rescue laxatives over a 12-week treatment period. Response rates were greatest in patients who received naloxegol 25 mg compared with those receiving placebo (in one study: 44.4 % vs 29.4 %, P =.001; in the second study: 39.7% vs. 29.3%, P =.02), without significant pain score or daily opioid dose requirement.19
Naldemedine is the latest PAMORA to be approved by the FDA, receiving approval for treatment of OIC in March 2017, and is structurally similar to naltrexone.8 Four randomized control trials enrolling more than 2400 patients combined investigated the efficacy of naldemedine compared with placebo.23-25 Across all studies, 52% of patients receiving naldemedine achieved at least 3 spontaneous bowel movements per week compared with 35% in the placebo arm.8 One of these studies also investigated the safety of long-term use of naldemedine with patients enrolled for 52 weeks.24 Treatment-emergent adverse effects in the naldemedine arm were 68% compared with 72.1% in the placebo group with a difference of -3.6% (95% CI, -8.7 to 1.5).24 Further, sustained improvement in bowel movements and overall quality of life was observed in the naldemedine arm compared with placebo at all time points throughout the study (P< .0001).24
The inability of methylnaltrexone to cross the blood-brain barrier is due to an added quaternary functional group, which inhibits the constipating effects of opioids without effecting analgesia.18,26 In a double-blinded, randomized, placebo-controlled study conducted between 2004 and 2005, 133 patients with OIC were randomly assigned to receive methylnaltrexone subcutaneously or placebo every other day. Primary outcomes of this study included laxation within 4 hours of the first dose and laxation without rescue laxatives after 2 or more doses. Of the patients who received methylnaltrexone, 48% achieved laxation within 4 hours and 52% achieved laxation within 4 hours after 2 or more doses without the use of a rescue laxative compared with 15% and 8% in the placebo group, respectively (P <.001).27 An oral formulation of methylnaltrexone is also available. A randomized, double-blinded study was conducted between 2010 and 2011 with a primary end point of achieving rescue-free bowel movements.28 The response rate of patients who received oral methylnaltrexone 300 mg/d or 450 mg/d was significantly greater than that seen in patients administered placebo.28
Chloride channel activators. Lubiprostone is an oral chloride channel activator that increases intestinal fluid secretion. By selectively activating chloride channel 2, fluid is secreted into the lumen of the gut without disturbing serum electrolyte levels.29 A randomized, double-blind, placebo-controlled, parallel-group phase 3 study was conducted between 2010 and 2011 in patients receiving COT for chronic nonmalignant pain with OIC.30 Patients were randomly assigned to receive lubiprostone 24 mcg or placebo twice daily. The primary end point was overall spontaneous bowel movement response rate based on constipation events recorded daily in a patient diary. Overall spontaneous bowel movement response rates were found to be improved in patients treated with lubiprostone vs placebo (27.1% vs 18.9%, respectively; P =.030).30 Although approved by the FDA for use in OIC, the AGA currently makes no recommendation for the use of lubiprostone in OIC due to poor quality of evidence; this is therefore identified as a research gap.8
OIC is a common side effect of opioid treatment but is often undertreated by clinicians. Identification of OIC can be challenging as it presents similarly to functional constipation; however, it is important to distinguish between the two as clinical course and treatment options differ. A detailed history and physical examination are crucial for identifying the underlying cause of constipation and excluding the presence of alarm features. Prevention is the foundation of management, which includes taking the time to discuss constipation as well as starting a bowel regimen when initiating opioid treatment. The newly issued AGA guidelines recommend laxatives as first-line agents for treating OIC, with PAMORAs the recommended class of pharmacologic agents for laxative-resistant OIC. Further research is ongoing to identify newer agents that may be effective in treating OIC.
Frank R. Giannelli, MS, PA-C, and Sarah Patel, MS, PA-C, MBA, are RBHS Lecturers at Rutgers School of Health Professions, in Newark, New Jersey, and practice at the Hope Clinic in Plainfield, New Jersey.
- Gaertner J, Siemens W, Camilleri M, et al. Definitions and outcome measures of clinical trials regarding opioid-induced constipation: a systematic review. J Clin Gastroenterol. 2015;49(1):9-16.
- Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. J Pain. 2015;16(8):769-780.
- Use of opioids for the treatment of chronic pain. 2009. http://americanpainsociety.org/uploads/education/guidelines/chronic-opioid-therapy-cncp.pdf. Accessed December 6, 2018.
- Dowell D, Haegerich TM, Chou R. CDC Guideline for prescribing opioids for chronic pain — United States. MMWR Recomm Rep. 2016;65(1):1-49.
- Centers for Disease Control and Prevention. US Opioid Prescribing Rate Maps. 2018. Accessed January 11, 2019, 2019.
- Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112(3):372-380.
- Panchal SJ, Müller-Schwefe P, Wurzelmann JI. Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. Int J Clin Pract. 2007;61(7):1181-1187.
- Crockett SD, Greer KB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute guideline on the medical management of opioid-induced constipation. Gastroenterology. 2019;156(1):218-226.
- Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs. 2003;63(7):649-671.
- Nelson AD, Camilleri M. Chronic opioid induced constipation in patients with nonmalignant pain: challenges and opportunities. Therap Adv Gastroenterol. 2015;8(4):206-220.
- Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg. 2001;182(5A Suppl):11S-18S.
- Camilleri M, Drossman DA, Becker G, Webster LR, Davies AN, Mawe GM. Emerging treatments in neurogastroenterology: a multidisciplinary working group consensus statement on opioid-induced constipation. Neurogastroent Motil. 2014;26(10):1386-1395.
- Drossman DA, Chang LC, Kellow WJ, Tack J, Whitehead WE. ROME IV Diagnostic Algorithms for Common GI Symptoms. Raleigh, North Carolina: The ROME Foundation; 2016.
- Kumar L, Barker C, Emmanuel A. Opioid-induced constipation: pathophysiology, clinical consequences, and management. Gastroenterol Res Pract. 2014;2014:141737.
- Twycross RG, McNamara P, Schuijt C, Kamm MA, Jordan C. Sodium picosulfate in opioid-induced constipation: results of an open-label, prospective, dose-ranging study. Palliat Med. 2006;20(4):419-423.
- Wirz S, Nadstawek J, Elsen C, Junker U, Wartenberg HC. Laxative management in ambulatory cancer patients on opioid therapy: a prospective, open-label investigation of polyethylene glycol, sodium picosulphate and lactulose. Eur J Cancer Care (Engl). 2012;21(1):131-140.
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- Yuan CS, Foss JF, OConnor M, Toledano A, Roizen MF, Moss J. Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin Pharmacol Ther. 1996;59(4):469-475.
- Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. New Engl J Med. 2014;370(25):2387-2396.
- Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J Pain Symptom Manage. 2002;23(1):48-53.
- Webster L, Dhar S, Eldon M, Masuoka L, Lappalainen J, Sostek M. A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipation. Pain. 2013;154(9):1542-1550.
- Camilleri M. Opioid-induced constipation: challenges and therapeutic opportunities. Am J Gastroenterol. 2011;106(5):835-842; quiz 843.
- Hale M, Wild J, Reddy J, Yamada T, Arjona Ferreira JC. Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials. Lancet Gastroenterol Hepatol. 2017;2(8):555-564.
- Webster LR, Nalamachu S, Morlion B, et al. Long-term use of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: a randomized, double-blind, placebo-controlled phase 3 study. Pain. 2018;159(5):987-994.
- Webster LR, Yamada T, Arjona Ferreira JC. A phase 2b, randomized, double-blind placebo-controlled study to evaluate the efficacy and safety of naldemedine for the treatment of opioid-induced constipation in patients with chronic noncancer pain. Pain Med. 2017;18(12):2350-2360.
- Russell J, Bass P, Goldberg LI, Schuster CR, Merz H. Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists. Eur J Pharmacol. 1982;78(3):255-261.
- Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. New Engl J Med. 2008;358(22):2332-2343.
- Rauck R, Slatkin NE, Stambler N, Harper JR, Israel RJ. Randomized, double-blind trial of oral methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic noncancer pain. Pain Pract. 2017;17(6):820-828.
- Lacy BE, Levy LC. Lubiprostone – a chloride channel activator. J Clin Gastroenterol. 2007;41(4):345-351.
- Jamal MM, Adams AB, Jansen JP, Webster LR. A randomized, placebo-controlled trial of lubiprostone for opioid-induced constipation in chronic noncancer pain. Am J Gastroenterol. 2015;110(5):725-732.