Abstract
Most prescribed opioids exert their analgesic effects via activation of central μ-opioid receptors. However, μ-opioid receptors are also located in the gastrointestinal (GI) tract, and activation of these receptors by opioids can lead to GI-related adverse effects, in particular opioid-induced constipation (OIC). OIC has been associated with increased use of healthcare resources, increased healthcare costs, and decreased quality of life for patients. Nonpharmacologic (e.g., increased fiber uptake) and pharmacologic agents (e.g., laxatives) may be considered for the treatment and prevention of OIC. However, many interventions, such as laxatives alone, are generally insufficient to reverse OIC because they do not target the underlying cause of OIC, opioid activation of μ-opioid receptors in the GI tract. Therefore, there has been keen interest in antagonism of the μ-opioid receptor in the periphery to inhibit the effects of opioids in the GI tract. In this review, currently available pharmacologic therapies for the treatment and prevention of OIC are summarized briefly, with a primary focus on the administration of the peripheral μ-opioid receptor antagonist methylnaltrexone bromide in patients with OIC and advanced illness who are receiving palliative care. Also, clinical trial data of methylnaltrexone treatment in patients with OIC and other pain conditions (i.e., chronic noncancer pain and pain after orthopedic surgery) are reviewed. Data support that methylnaltrexone is efficacious for the treatment of OIC and has a favorable tolerability profile.
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References
American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(Suppl 1):S1–4.
McMillan SC. Assessing and managing opiate-induced constipation in adults with cancer. Cancer Control. 2004;11(3 Suppl):3–9.
Hsieh C. Treatment of constipation in older adults. Am Fam Physician. 2005;72(11):2277–84.
Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology. 2006;130(5):1480–91.
Schumacher MA, Basbaum AI, Way WL. Opioid analgesics and antagonists. In: Katzung BG, editor. Basic and Clinical Pharmacology. New York: McGraw-Hill Medical; 2009. p. 531–52.
Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept. 2009;155(1–3):11–7.
Yuan CS, Foss JF, O’Connor M, et al. 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):469–75.
Manara L, Bianchi G, Ferretti P, et al. Inhibition of gastrointestinal transit by morphine in rats results primarily from direct drug action on gut opioid sites. J Pharmacol Exp Ther. 1986;237(3):945–9.
Tavani A, Bianchi G, Ferretti P, et al. Morphine is most effective on gastrointestinal propulsion in rats by intraperitoneal route: evidence for local action. Life Sci. 1980;27(23):2211–7.
Leppert W. The role of opioid receptor antagonists in the treatment of opioid-induced constipation: a review. Adv Ther. 2010;27(10):714–30.
Chou R, Fanciullo GJ, Fine PG, American Pain Society; American Academy of Pain Medicine Opioid Guidelines Panel, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113–30.
Brock C, Olesen SS, Olesen AE, et al. Opioid-induced bowel dysfunction: pathophysiology and management. Drugs. 2012;72(14):1847–65.
Cook SF, Lanza L, Zhou X, et al. Gastrointestinal side effects in chronic opioid users: results from a population-based survey. Aliment Pharmacol Ther. 2008;27(12):1224–32.
Sykes NP. The relationship between opioid use and laxative use in terminally ill cancer patients. Palliat Med. 1998;12(5):375–82.
Candrilli SD, Davis KL, Iyer S. Impact of constipation on opioid use patterns, health care resource utilization, and costs in cancer patients on opioid therapy. J Pain Palliat Care Pharmacother. 2009;23(3):231–41.
Iyer S, Davis KL, Candrilli S. Opioid use patterns and health care resource utilization in patients prescribed opioid therapy with and without constipation. Manage Care. 2010;19(3):44–51.
Bell T, Annunziata K, Leslie JB. Opioid-induced constipation negatively impacts pain management, productivity, and health-related quality of life: findings from the National Health and Wellness Survey. J Opioid Manage. 2009;5(3):137–44.
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(1):35–42.
Penning-van Beest FJ, van den Haak P, Klok RM, et al. Quality of life in relation to constipation among opioid users. J Med Econ. 2010;13(1):129–35.
Camilleri M. Opioid-induced constipation: challenges and therapeutic opportunities. Am J Gastroenterol. 2011;106(5):835–42.
Panchal SJ, Muller-Schwefe P, Wurzelmann JI. Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. Int J Clin Pract. 2007;61(7):1181–7.
Ternent CA, Bastawrous AL, Morin NA, et al. Practice parameters for the evaluation and management of constipation. Dis Colon Rectum. 2007;50(12):2013–22.
Walters JB, Montagnini M. Current concepts in the management of opioid-induced constipation. J Opioid Manage. 2010;6(6):435–44.
Brandt LJ, Prather CM, Quigley EM, et al. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(Suppl 1):S5–21.
Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2—guidance. Pain Physician. 2012;15(Suppl 3):S67–116.
Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol. 2012;13(2):e58–68.
Candy B, Jones L, Goodman ML, et al. Laxatives or methylnaltrexone for the management of constipation in palliative care patients. Cochrane Database Syst Rev. 2011;(1):CD003448.
Thomas JR, Cooney GA, Slatkin NE. Palliative care and pain: new strategies for managing opioid bowel dysfunction. J Palliat Med. 2008;11(Suppl 1):S1–19.
Tack J. Current and future therapies for chronic constipation. Best Pract Res Clin Gastroenterol. 2011;25(1):151–8.
Bader S, Jaroslawski K, Blum HE, et al. Opioid-induced constipation in advanced illness: safety and efficacy of methylnaltrexone bromide. Clin Med Insights Oncol. 2011;5:201–11.
Emmanuel A. Current management strategies and therapeutic targets in chronic constipation. Ther Adv Gastroenterol. 2011;4(1):37–48.
Amitiza (lubiprostone) capsules [package insert]. Deerfield: Takeda Pharmaceuticals America, Inc.; 2013.
Entereg (alvimopan) capsules [package insert]. Lexington, MA: Cubist Pharmaceuticals, Inc., 2012.
Relistor (methylnaltrexone bromide) subcutaneous injection [package insert]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012.
van der Spoel JI, Oudemans-van Straaten HM, Kuiper MA, et al. Laxation of critically ill patients with lactulose or polyethylene glycol: a two-center randomized, double-blind, placebo-controlled trial. Crit Care Med. 2007;35(12):2726–31.
Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev. 2004;(3):CD004847.
Dale O, Moksnes K, Kaasa S. European Palliative Care Research Collaborative pain guidelines: opioid switching to improve analgesia or reduce side effects. A systematic review. Palliat Med. 2011;25(5):494–503.
Fallon M, O’Neill B. ABC of palliative care. Constipation and diarrhoea. BMJ. 1997;315(7118):1293–6.
Sykes NP. An investigation of the ability of oral naloxone to correct opioid-related constipation in patients with advanced cancer. Palliat Med. 1996;10(2):135–44.
Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J Pain Symptom Manage. 2002;23(1):48–53.
Cassel JA, Daubert JD, DeHaven RN. [3H]alvimopan binding to the μ opioid receptor: comparative binding kinetics of opioid antagonists. Eur J Pharmacol. 2005;520:29–36.
Diego L, Atayee R, Helmons P, et al. Novel opioid antagonists for opioid-induced bowel dysfunction. Expert Opin Investig Drugs. 2011;20(8):1047–56.
A study of S-297995 for the treatment of opioid-induced constipation in subjects with non-malignant chronic pain receiving opioid therapy [ClinicalTrials.gov identifier NCT01443403]. 2012 Nov 27 [online]. Bethesda: US National Institutes of Health, ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01443403. (Accessed 1 Feb 2013).
Paulson D, Kennedy DT, Donovick RA, et al. Alvimopan: an oral, peripherally acting, μ-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction—a 21-day treatment-randomized clinical trial. J Pain. 2005;6(3):184–92.
Webster L, Jansen JP, Peppin J, et al. Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain. Pain. 2008;137:428–40.
Jansen J-P, Lorch D, Langan J, et al. A randomized, placebo-controlled phase 3 trial (Study SB-767905/012) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain. J Pain. 2011;12(2):185–93.
Irving G, Pénzes J, Ramjattan B, et al. A randomized, placebo-controlled phase 3 trial (Study SB-767905/013) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain. J Pain. 2011;12(2):175–84.
Bream-Rouwenhorst HR, Cantrell MA. Alvimopan for postoperative ileus. Am J Health Syst Pharm. 2009;66(14):1267–77.
Solomon DH, Rassen JA, Glynn RJ, et al. The comparative safety of analgesics in older adults with arthritis. Arch Intern Med. 2010;170(22):1968–78.
Carman WJ, Su S, Coo SF, et al. Coronary heart disease outcomes among chronic opioid and cyclooxygenase-2 users compared with a general population cohort. Pharmacoepidemiol Drug Saf. 2011;20:754–62.
Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. J Support Oncol. 2009;7(1):39–46.
Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008;358(22):2332–43.
Chamberlain BH, Cross K, Winston JL, et al. Methylnaltrexone treatment of opioid-induced constipation in patients with advanced illness. J Pain Symptom Manage. 2009;38(5):683–90.
Slatkin NE, Lynn R, Su C, et al. Characterization of abdominal pain during methylnaltrexone treatment of opioid-induced constipation in advanced illness: a post hoc analysis of two clinical trials. J Pain Symptom Manage. 2011;42(5):754–60.
Corken Mackey A, Green L, Greene P, et al. Methylnaltrexone and gastrointestinal perforation. J Pain Symptom Manage. 2010;40(1):e1–3.
Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study. J Pain. 2011;12(5):554–62.
Michna E, Weil AJ, Duerden M, et al. Efficacy of subcutaneous methylnaltrexone in the treatment of opioid-induced constipation: a responder post hoc analysis. Pain Med. 2011;12(8):1223–30.
Blonsky E, Watier A, Schulman S, et al. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic non-malignant pain: open-label results [abstract no. 149]. Reg Anesth Pain Med. 2009;34(5):98.
Webster L, Michna E, Khan A, et al. The long-term efficacy of subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic nonmalignant pain [abstract no. 376]. J Pain. 2011;12(Suppl 4):P70.
Webster L, Michna E, Khan A, et al. The long-term safety of subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic nonmalignant pain [abstract no. 378]. J Pain. 2011;12(Suppl 4):P70.
Anissian L, Schwartz HW, Vincent K, et al. Subcutaneous methylnaltrexone for treatment of acute opioid-induced constipation: phase 2 study in rehabilitation after orthopedic surgery. J Hosp Med. 2012;7(2):67–72.
Cryer BL, Katz S, Vallejo R, et al. A phase 3, randomized, double-blind, placebo- controlled clinical trial of lubiprostone for the treatment of opioid-induced bowel dysfunction in patients with chronic, non-cancer pain [abstract no. 906]. Gastroenterology. 2010;138(5 Suppl 1):S129.
Jamal MM, Mareya SM, Woldegeorgis F, et al. 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 [poster no. 848a]. Digestive Diseases Week 2012, San Diego; May 19–22, 2012.
Spierings E, Joswick T, Lindner E, et al. Long-term safety and efficacy of lubiprostone in opioid-induced bowel dysfunction in patients with chronic, non-cancer pain: results of a phase 3, open-label clinical trial [abstract no. 322]. Am J Gastroenterol. 2012;107(Suppl 1):S138.
Mohammad S, Zhou Z, Gong Q, et al. Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride. Am J Physiol. 1997;273(5 Pt 2):H2534–8.
Pasricha PJ. Desperately seeking serotonin… A commentary on the withdrawal of tegaserod and the state of drug development for functional and motility disorders. Gastroenterology. 2007;132(7):2287–90.
Tack J, Camilleri M, Chang L, et al. Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment Pharmacol Ther. 2012;35(7):745–67.
Zelnorm (tegaserod maleate) information. 2012 May 11 [online]. Silver Spring, MD: US Department of Health and Human Services, US Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103223.htm (Accessed 1 Feb 2013).
Sloots CEJ, Rykx A, Cools M, et al. Efficacy and safety of prucalopride in patients with chronic noncancer pain suffering from opioid-induced constipation. Dig Dis Sci. 2010;55(10):2912–21.
Quigley EMM. Prucalopride: safety, efficacy and potential applications. Therap Adv Gastroenterol. 2012;5(1):23–30.
Acknowledgments
Technical editorial and medical writing support was provided by Sophie Bolick, PhD, and Marci Mikesell, PhD, Synchrony Medical Communications, LLC, West Chester, PA, USA, under the direction of the author, Richard Rauck, MD. Funding for this support was provided by Salix Pharmaceuticals, Inc., Raleigh, NC, USA.
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Rauck, R.L. Treatment of Opioid-Induced Constipation: Focus on the Peripheral μ-Opioid Receptor Antagonist Methylnaltrexone. Drugs 73, 1297–1306 (2013). https://doi.org/10.1007/s40265-013-0084-5
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DOI: https://doi.org/10.1007/s40265-013-0084-5