Abstract
Purpose of Review
The opioid epidemic in the USA has led to a rise in opioid-related gastrointestinal (GI) side effects that are often difficult to diagnose and treat. The aim of this report is to discuss opioid pathophysiology, opioid-related GI side effects, clinical presentation, and diagnostic criteria and to review the current pharmacotherapy available.
Recent Findings
Opioid-related GI disorders are increasingly recognized and include, but are not limited to, opioid-induced esophageal dysfunction (OIED), gastroparesis, opioid-induced constipation (OIC), narcotic bowel syndrome (NBS), acute post-operative ileus, and anal sphincter dysfunction. Treatment of these conditions is challenging. OIC has the most available pharmacotherapy for treatment, including classical laxatives, peripherally acting μ-receptor antagonists (PAMORAs), novel therapies (lubiprostone, prucalopride- 5-HT agonist), and preventative therapies (PR oxycodone/naloxone).
Summary
The gastrointestinal effects of opioid therapy are variable and often debilitating. While medical management for some opioid-related GI side effects exists, limiting or completely avoiding opioid use for chronic non-cancer pain will mitigate these effects most effectively.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
Dart RC, Surratt HL, Cicero TJ, Parrino MW, Severtson SG, Bucher-Bartelson B, et al. Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med. 2015;372(3):241–8.
Wide-ranging online data for epidemiologic research (WONDER). CDC, National Center for Health Statistics. Atlanta, GA. 2017.
Gomes T, Tadrous M, Mamdani MM, Paterson JM, Juurlink DN. The burden of opioid-related mortality in the United States. JAMA Netw Open. 2018;1(2):e180217.
Dorn SD, Meek PD, Shah ND. Increasing frequency of opioid prescriptions for chronic abdominal pain in US outpatient clinics. Clin Gastroenterol Hepatol: the official clinical practice journal of the American Gastroenterological Association. 2011;9(12):1078–85.e1.
Szigethy E, Knisely M, Drossman D. Opioid misuse in gastroenterology and non-opioid management of abdominal pain. Nat Rev Gastroenterol Hepatol. 2018;15(3):168–80.
Acharya C, Betrapally NS, Gillevet PM, Sterling RK, Akbarali H, White MB, et al. Chronic opioid use is associated with altered gut microbiota and predicts readmissions in patients with cirrhosis. Aliment Pharmacol Ther. 2017;45(2):319–31.
Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol. 2012;107(9):1409–22.
•• Hughes PA, Costello SP, Bryant RV, Andrews JM. Opioidergic effects on enteric and sensory nerves in the lower GI tract: basic mechanisms and clinical implications. Am J Physiol Gastrointest Liver Physiol. 2016;311(3):G501–13 This study provides in-depth detail of opioids pathophysiology and effect on ENS.
Galligan JJ, Akbarali HI. Molecular physiology of enteric opioid receptors. American journal of gastroenterology supplements (Print). 2014;2(1):17–21.
Ono H, Nakamura A, Matsumoto K, Horie S, Sakaguchi G, Kanemasa T. Circular muscle contraction in the mice rectum plays a key role in morphine-induced constipation. Neurogastroenterol Motil: the official journal of the European Gastrointestinal Motility Society. 2014;26(10):1396–407.
Banerjee S, Sindberg G, Wang F, Meng J, Sharma U, Zhang L, et al. Opioid-induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation. Mucosal Immunol. 2016;9(6):1418–28.
Penagini R, Bianchi PA. Effect of morphine on gastroesophageal reflux and transient lower esophageal sphincter relaxation. Gastroenterology. 1997;113(2):409–14.
Penagini R, Bartesaghi B, Zannini P, Negri G, Bianchi PA. Lower oesophageal sphincter hypersensitivity to opioid receptor stimulation in patients with idiopathic achalasia. Gut. 1993;34(1):16–20.
Gonzalez ES, Bellver VO, Jaime FC, Cortes JA, Gil VG. Opioid-induced lower esophageal sphincter dysfunction. Journal of neurogastroenterology and motility. 2015;21(4):618–20.
Ratuapli SK, Crowell MD, DiBaise JK, Vela MF, Ramirez FC, Burdick GE, et al. Opioid-induced esophageal dysfunction (OIED) in patients on chronic opioids. Am J Gastroenterol. 2015;110(7):979–84.
Ortiz V, Garcia-Campos M, Saez-Gonzalez E, delPozo P, Garrigues V. A concise review of opioid-induced esophageal dysfunction: is this a new clinical entity? Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus. 2018;31(5).
•• Camilleri M, Lembo A, Katzka DA. Opioids in gastroenterology: treating adverse effects and creating therapeutic benefits. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2017;15(9):1338–49 This review provides updated summary of current therapy for opioid-related GI side effects.
Jehangir A, Parkman HP. Chronic opioids in gastroparesis: relationship with gastrointestinal symptoms, healthcare utilization and employment. World J Gastroenterol. 2017;23(40):7310–20.
Jeong ID, Camilleri M, Shin A, Iturrino J, Boldingh A, Busciglio I, et al. A randomised, placebo-controlled trial comparing the effects of tapentadol and oxycodone on gastrointestinal and colonic transit in healthy humans. Aliment Pharmacol Ther. 2012;35(9):1088–96.
Abramowitz L, Beziaud N, Labreze L, Giardina V, Causse C, Chuberre B, et al. Prevalence and impact of constipation and bowel dysfunction induced by strong opioids: a cross-sectional survey of 520 patients with cancer pain: DYONISOS study. J Med Econ. 2013;16(12):1423–33.
Veiga DR, Mendonca L, Sampaio R, Lopes JC, Azevedo LF. Incidence and health related quality of life of opioid-induced constipation in chronic noncancer pain patients: a prospective multicentre cohort study. Pain Res Treat. 2018;2018:5704627.
•• Muller-Lissner S, Bassotti G, Coffin B, Drewes AM, Breivik H, Eisenberg E, et al. Opioid-induced constipation and bowel dysfunction: a clinical guideline. Pain medicine (Malden, Mass). 2017;18(10):1837–63 This study providers current evidence behind OIC management.
Knowles CH, Aziz Q. Basic and clinical aspects of gastrointestinal pain. Pain. 2009;141(3):191–209.
•• Crockett S, Greer KB, Sultan S. Opioid-induced constipation (OIC) guideline. Gastroenterology. 2019;156(1):228 Most updated review on OIC therapies with evidence and AGA recommendations.
Simren M, Palsson OS, Whitehead WE. Update on Rome IV criteria for colorectal disorders: implications for clinical practice. Current gastroenterology reports. 2017;19(4):15.
Ueberall MA, Muller-Lissner S, Buschmann-Kramm C, Bosse B. The bowel function index for evaluating constipation in pain patients: definition of a reference range for a non-constipated population of pain patients. J Int Med Res. 2011;39(1):41–50.
Duenas M, Mendonca L, Sampaio R, Gouvinhas C, Oliveira D, Castro-Lopes JM, et al. Reliability and validity of the bowel function index for evaluating opioid-induced constipation: translation, cultural adaptation and validation of the Portuguese version (BFI-P). Curr Med Res Opin. 2017;33(3):563–72.
Bragg D, El-Sharkawy AM, Psaltis E, Maxwell-Armstrong CA, Lobo DN. Postoperative ileus: recent developments in pathophysiology and management. Clinical nutrition (Edinburgh, Scotland). 2015;34(3):367–76.
Choung RS, Locke GR 3rd, Zinsmeister AR, Schleck CD, Talley NJ. Opioid bowel dysfunction and narcotic bowel syndrome: a population-based study. Am J Gastroenterol. 2009;104(5):1199–204.
Drossman D, Szigethy E. The narcotic bowel syndrome: a recent update. American journal of gastroenterology supplements (Print). 2014;2(1):22–30.
Kurlander JE, Drossman DA. Diagnosis and treatment of narcotic bowel syndrome. Nat Rev Gastroenterol Hepatol. 2014;11:410.
Chowdhury AR, Lorber SH. Effects of glucagon and secretin on food- or morphine-induced motor activity of the distal colon, rectum, and anal sphincter. Am J Dig Dis. 1977;22(9):775–80.
Gronlund D, Poulsen JL, Krogh K, Brock C, Liao D, Gregersen H, et al. The impact of naloxegol on anal sphincter function - using a human experimental model of opioid-induced bowel dysfunction. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2018;117:187–92.
Goke M, Ewe K, Donner K, Meyer zum Buschenfelde KH. Influence of loperamide and loperamide oxide on the anal sphincter. A manometric study. Dis Colon Rectum. 1992;35(9):857–61.
Read M, Read NW, Barber DC, Duthie HL. Effects of loperamide on anal sphincter function in patients complaining of chronic diarrhea with fecal incontinence and urgency. Dig Dis Sci. 1982;27(9):807–14.
Targownik LE, Nugent Z, Singh H, Bugden S, Bernstein CN. The prevalence and predictors of opioid use in inflammatory bowel disease: a population-based analysis. Am J Gastroenterol. 2014;109(10):1613–20.
Sanford D, Thornley P, Teriaky A, Chande N, Gregor J. Opioid use is associated with decreased quality of life in patients with Crohn’s disease. Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association. 2014;20(3):182–7.
Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology (Baltimore, Md). 2014;60(2):715–35.
Soleimanpour H, Safari S, Shahsavari Nia K, Sanaie S, Alavian SM. Opioid drugs in patients with liver disease: a systematic review. Hepat Mon. 2016;16(4):e32636.
Simpson PM, Bendall JC, Middleton PM. Review article: prophylactic metoclopramide for patients receiving intravenous morphine in the emergency setting: a systematic review and meta-analysis of randomized controlled trials. Emergency medicine Australasia : EMA. 2011;23(4):452–7.
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 medicine (Malden, Mass). 2017;18(12):2350–60.
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. The Lancet Gastroenterology & hepatology. 2017;2(8):555–64.
Webster LR, Nalamachu S, Morlion B, Reddy J, Baba Y, Yamada T, 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):987–94.
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):1542–50.
Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014;370(25):2387–96.
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 practice : the official journal of World Institute of Pain. 2017;17(6):820–8.
Michna E, Blonsky ER, Schulman S, Tzanis E, Manley A, Zhang H, et al. Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study. The journal of pain : official journal of the American Pain Society. 2011;12(5):554–62.
Camilleri M, Bharucha AE, Ueno R, Burton D, Thomforde GM, Baxter K, et al. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers. Am J Physiol Gastrointest Liver Physiol. 2006;290(5):G942–7.
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):2912–21.
Simpson K, Leyendecker P, Hopp M, Muller-Lissner S, Lowenstein O, De Andres J, et al. Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain. Curr Med Res Opin. 2008;24(12):3503–12.
Lowenstein O, Leyendecker P, Hopp M, Schutter U, Rogers PD, Uhl R, et al. Combined prolonged-release oxycodone and naloxone improves bowel function in patients receiving opioids for moderate-to-severe non-malignant chronic pain: a randomised controlled trial. Expert Opin Pharmacother. 2009;10(4):531–43.
Ahmedzai SH, Nauck F, Bar-Sela G, Bosse B, Leyendecker P, Hopp M. A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain. Palliat Med. 2012;26(1):50–60.
Meissner W, Leyendecker P, Mueller-Lissner S, Nadstawek J, Hopp M, Ruckes C, et al. A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. European journal of pain (London, England). 2009;13(1):56–64.
Xu LL, Zhou XQ, Yi PS, Zhang M, Li J, Xu MQ. Alvimopan combined with enhanced recovery strategy for managing postoperative ileus after open abdominal surgery: a systematic review and meta-analysis. J Surg Res. 2016;203(1):211–21.
Poulsen JL, Brock C, Gronlund D, Liao D, Gregersen H, Krogh K, et al. Prolonged-release oxycodone/naloxone improves anal sphincter relaxation compared to oxycodone plus Macrogol 3350. Dig Dis Sci. 2017;62(11):3156–66.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Topical Collection on Nutrition and Obesity
Rights and permissions
About this article
Cite this article
Thapa, N., Kappus, M., Hurt, R. et al. Implications of the Opioid Epidemic for the Clinical Gastroenterology Practice. Curr Gastroenterol Rep 21, 44 (2019). https://doi.org/10.1007/s11894-019-0712-7
Published:
DOI: https://doi.org/10.1007/s11894-019-0712-7