Opioids were one of the earliest classes of medications used for pain across a variety of conditions, but morbidity and mortality have been increasingly associated with their chronic use. Despite these negative consequences, chronic opioid use is increasing worldwide, with the USA and Canada having the highest rates. Chronic opioid use for noncancer pain can have particularly negative effects in the gastrointestinal and central nervous systems, including opioid-induced constipation, narcotic bowel syndrome, worsening psychopathology and addiction. This Review summarizes the evidence of opioid misuse in gastroenterology, including the lack of evidence of a benefit from these drugs, as well as the risk of harm and negative consequences of opioid use relative to the brain–gut axis. Guidelines for opioid management and alternative pharmacological and nonpharmacological strategies for pain management in patients with gastrointestinal disorders are also discussed. As chronic pain is complex and involves emotional and social factors, a multimodal approach targeting both pain intensity and quality of life is best.
Prescription opioid use is a global epidemic, with substantial increases in opioid-related morbidity and mortality around the world
There is a lack of evidence supporting the use of opioids for the management of chronic abdominal pain
Opioid use can have deleterious consequences on the gastrointestinal tract, including opioid-induced constipation and narcotic bowel syndrome
Many promising non-opioid pharmacological and nonpharmacological alternatives for treating abdominal pain exist; however, additional research is needed to identify best practices for treating abdominal pain in individuals with gastrointestinal disorders
If opioids are prescribed, it is essential to have strategies to monitor and manage opioid misuse, continually monitor risk–benefit clinical profiles, and prevent and treat addiction
Subscribe to Journal
Get full journal access for 1 year
only $17.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Berterame, S. et al. Use of and barriers to access to opioid analgesics: a worldwide, regional, and national study. Lancet 387, 1644–1656 (2016).
University of Wisconsin–Madison Pain & Policy Studies Group. Opioid consumption data. Pain & Policy Studies Group http://www.painpolicy.wisc.edu/opioid-consumption-data (2017).
Denisco, R. A., Chandler, R. K. & Compton, W. M. Addressing the intersecting problems of opioid misuse and chronic pain treatment. Exp. Clin. Psychopharmacol. 16, 417–428 (2008).
Zin, C. S., Chen, L. C. & Knaggs, R. D. Changes in trends and pattern of strong opioid prescribing in primary care. Eur. J. Pain 18, 1343–1351 (2014).
Ruscitto, A., Smith, B. H. & Guthrie, B. Changes in opioid and other analgesic use 1995-2010: repeated cross-sectional analysis of dispensed prescribing for a large geographical population in Scotland. Eur. J. Pain 19, 59–66 (2015).
Weisberg, D. F., Becker, W. C., Fiellin, D. A. & Stannard, C. Prescription opioid misuse in the United States and the United Kingdom: cautionary lessons. Int. J. Drug Policy 25, 1124–1130 (2014).
The Economist. The problem of pain. The Economist http://www.economist.com/news/international/21699363-americans-are-increasingly-addicted-opioids-meanwhile-people-poor-countries-die (2016).
Berry, P. H. & Dahl, J. L. The new JCAHO pain standards: implications for pain management nurses. Pain Manag. Nurs. 1, 3–12 (2000).
World Health Organization. WHO's cancer pain ladder for adults. World Health Organization http://www.who.int/cancer/palliative/painladder/en/ (2016).
Manubay, J., Muchow, C. & Sullivan, M. Prescription drug abuse: epidemiology, regulatory issues, chronic pain management with narcotic analgesics. Prim. Care 38, 71–90 (2011).
Chang, H. Y., Daubresse, M., Kruszewski, S. P. & Alexander, G. C. Prevalence and treatment of pain in EDs in the United States, 2000 to 2010. Am. J. Emerg. Med. 32, 421–431 (2014).
Daubresse, M. et al. Ambulatory diagnosis and treatment of nonmalignant pain in the United States, 2000–2010. Med. Care 51, 870–878 (2013).
Rudd, R. A., Aleshire, N., Zibbell, J. E. & Gladden, R. M. Increases in drug and opioid overdose deaths — United States, 2000–2014. MMWR Morb. Mortal. Wkly Rep. 64, 1378–1382 (2016).
Department of Health and Human Services, USA. The opioid epidemic: by the numbers. HHS.gov http://www.hhs.gov/sites/default/files/Factsheet-opioids-061516.pdf (2016).
National Institute on Drug Abuse. Overdose death rates. National Institute on Drug Abuse https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates (2015).
Inocencio, T. J., Carroll, N. V., Read, E. J. & Holdford, D. A. The economic burden of opioid-related poisoning in the United States. Pain Med. 14, 1534–1547 (2013).
Ronan, M. V. & Herzig, S. J. Hospitalizations related to opioid abuse/dependence and associated serious infections increased sharply, 2002–2012. Health Aff. 35, 832–837 (2016).
Vowles, K. E. et al. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain 156, 569–576 (2015).
Tuteja, A. K., Biskupiak, J., Stoddard, G. J. & Lipman, A. G. Opioid-induced bowel disorders and narcotic bowel syndrome in patients with chronic non-cancer pain. Neurogastroenterol. Motil. 22, 424–e96 (2010).
Substance Abuse and Mental Health Services Administration (SAMHSA). National estimates of drug-related emergency department visits, 2004–2011. Substance Abuse and Mental Health Services Administration (SAMHSA) http://www.samhsa.gov/data/emergency-department-data-dawn/reports (2014).
Blanch, B., Pearson, S. A. & Haber, P. S. An overview of the patterns of prescription opioid use, costs and related harms in Australia. Br. J. Clin. Pharmacol. 78, 1159–1166 (2014).
Degenhardt, L. et al. The global epidemiology and burden of opioid dependence: results from the global burden of disease 2010 study. Addiction 109, 1320–1333 (2014).
Marienfeld, C. Heroin addiction, methadone, and HIV in China. Lancet Psychiatry 3, 799–800 (2016).
Boscarino, J. A. et al. Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system. Addiction 105, 1776–1782 (2010).
Fleming, M. F., Balousek, S. L., Klessig, C. L., Mundt, M. P. & Brown, D. D. Substance use disorders in a primary care sample receiving daily opioid therapy. J. Pain 8, 573–582 (2007).
Katz, N. P. et al. Behavioral monitoring and urine toxicology testing in patients receiving long-term opioid therapy. Anesth. Analg. 97, 1097–1102 (2003).
Passik, S. D., Kirsh, K. L., Donaghy, K. B. & Portenoy, R. K. Pain and aberrant drug-related behaviors in medically ill patients with and without histories of substance abuse. Clin. J. Pain 22, 173–181 (2006).
Feingold, D., Goor-Aryeh, I., Bril, S., Delayahu, Y. & Lev-Ran, S. Problematic use of prescription opioids and medicinal cannabis among patients suffering from chronic pain. Pain Med. 18, 294–306 (2016).
Hughes, P. A., Costello, S. P., Bryant, R. V. & Andrews, J. M. Opioidergic effects on enteric and sensory nerves in the lower GI tract; basic mechanisms and clinical implications. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G501–G513 (2016).
Levy, B., Paulozzi, L., Mack, K. A. & Jones, C. M. Trends in opioid analgesic-prescribing rates by specialty, U. S., 2007–2012. Am. J. Prev. Med. 49, 409–413 (2015).
IMS Institute for Healthcare Informatics. Medicines used and spending in the U. S.: A review of 2015 and outlook to 2020 (IMS Institute for Healthcare Informatics, 2016).
Bharucha, A. E., Chakraborty, S. & Sletten, C. D. Common functional gastroenterological disorders associated with abdominal pain. Mayo Clin. Proc. 91, 1118–1132 (2016).
Buckley, J. P., Kappelman, M. D., Allen, J. K., Van Meter, S. A. & Cook, S. F. The burden of comedication among patients with inflammatory bowel disease. Inflamm. Bowel Dis. 19, 2725–2736 (2013).
Buckley, J. P., Cook, S. F., Allen, J. K. & Kappelman, M. D. Prevalence of chronic narcotic use among children with inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 13, 310–315.e2 (2015).
Cross, R. K., Wilson, K. T. & Binion, D. G. Narcotic use in patients with Crohn's disease. Am. J. Gastroenterol. 100, 2225–2229 (2005).
Lichtenstein, G. R. 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. 107, 1409–1422 (2012).
Long, M. D., Barnes, E. L., Herfarth, H. H. & Drossman, D. A. Narcotic use for inflammatory bowel disease and risk factors during hospitalization. Inflamm. Bowel Dis. 18, 869–876 (2012).
Nusrat, S., Yadav, D. & Bielefeldt, K. Pain and opioid use in chronic pancreatitis. Pancreas 41, 264–270 (2012).
Dorn, S. et al. Patients with IBS commonly use narcotics [abstract]. Gastroenterology 138 (Suppl. 1), W1378 (2010).
Barth, K. S. et al. Screening for current opioid misuse and associated risk factors among patients with chronic nonalcoholic pancreatitis pain. Pain Med. 15, 1359–1364 (2014).
Olesen, S. S., Poulsen, J. L., Broberg, M. C., Madzak, A. & Drewes, A. M. Opioid treatment and hypoalbuminemia are associated with increased hospitalisation rates in chronic pancreatitis outpatients. Pancreatology 16, 807–813 (2016).
Morley, K. I., Ferris, J. A., Winstock, A. R. & Lynskey, M. T. Polysubstance use and misuse or abuse of prescription opioid analgesics: a multi-level analysis of international data. Pain 158, 1138–1144 (2017).
Sharma, A. & Jamal, M. M. Opioid induced bowel disease: a twenty-first century physicians' dilemma. Considering pathophysiology and treatment strategies. Curr. Gastroenterol. Rep. 15, 334 (2013).
American Pain Society & American Academy of Pain Medicine. Guideline for the use of chronic opioid therapy in chronic noncancer pain: evidence review (American Pain Society, 2009).
Wilder-Smith, C. H., Hill, L., Osler, W. & O'Keefe, S. Effect of tramadol and morphine on pain and gastrointestinal motor function in patients with chronic pancreatitis. Dig. Dis. Sci. 44, 1107–1116 (1999).
Tennant, F. Why oral opioids may not be effective in a subset of chronic pain patients. Postgrad. Med. 128, 18–22 (2016).
Crocker, J. A., Yu, H., Conaway, M., Tuskey, A. G. & Behm, B. W. Narcotic use and misuse in Crohn's disease. Inflamm. Bowel Dis. 20, 2234–2238 (2014).
Surdea-Blaga, T., Baban, A. & Dumitrascu, D. Psychosocial determinants of irritable bowel syndrome. World J. Gastroenterol. 18, 616–626 (2012).
Targownik, L. E., Nugent, Z., Singh, H., Bugden, S. & Bernstein, C. N. The prevalence and predictors of opioid use in inflammatory bowel disease: a population-based analysis. Am. J. Gastroenterol. 109, 1613–1620 (2014).
Edlund, M. J. et al. The role of opioid prescription in incident opioid abuse and dependence among individuals with chronic noncancer pain: the role of opioid prescription. Clin. J. Pain 30, 557–564 (2014).
Cook, S. F. et al. Gastrointestinal side effects in chronic opioid users: results from a population-based survey. Aliment. Pharmacol. Ther. 27, 1224–1232 (2008).
Kraichely, R. E., Arora, A. S. & Murray, J. A. Opiate-induced oesophageal dysmotility. Aliment. Pharmacol. Ther. 31, 601–606 (2010).
Gaertner, J. et al. Definitions and outcome measures of clinical trials regarding opioid-induced constipation: a systematic review. J. Clin. Gastroenterol. 49, 9–16 (2015).
Mearin, F. et al. Bowel disorders. Gastroenterology 150, 1393–1407.e5 (2016).
Khemani, D. et al. Opioid analgesic use among patients presenting with acute abdominal pain and factors associated with surgical diagnoses. Neurogastroenterol. Motil. 29, e13000 (2016).
Rauck, R. L., Hong, K. J. & North, J. Opioid-induced constipation survey in patients with chronic noncancer pain. Pain Pract. 17, 329–335 (2017).
Ratuapli, S. K. et al. Opioid-induced esophageal dysfunction (OIED) in patients on chronic opioids. Am. J. Gastroenterol. 110, 979–984 (2015).
Fujioka, K. et al. Patients with short bowel on narcotics during 2 randomized trials have abdominal complaints independent of teduglutide. JPEN J. Parenter. Enteral. Nutr. http://dx.doi.org/10.1177/0148607116663481 (2016).
Leppert, W. The impact of opioid analgesics on the gastrointestinal tract function and the current management possibilities. Contemp. Oncol. 16, 125–131 (2012).
Sobczak, M., Sałaga, M., Storr, M. A. & Fichna, J. Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives. J. Gastroenterol. 49, 24–45 (2014).
Galligan, J. J. & Akbarali, H. I. Molecular physiology of enteric opioid receptors. Am. J. Gastroenterol. Suppl. 2, 17–21 (2014).
Holzer, P. New approaches to the treatment of opioid-induced constipation. Eur. Rev. Med. Pharmacol. Sci. 12 (Suppl. 1), 119–127 (2008).
Browning, K. N. & Travagli, R. A. Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr. Physiol. 4, 1339–1368 (2014).
Barrett, K. E. New insights into the pathogenesis of intestinal dysfunction: secretory diarrhea and cystic fibrosis. World J. Gastroenterol. 6, 470–474 (2000).
Zhou, P., Li, T., Su, R. & Gong, Z. Effects of thienorphine on contraction of the guinea pig sphincter of Oddi, choledochus and gall bladder. Eur. J. Pharmacol. 737, 22–28 (2014).
Joehl, R. J., Koch, K. L. & Nahrwold, D. L. Opioid drugs cause bile duct obstruction during hepatobiliary scans. Am. J. Surg. 147, 134–138 (1984).
Mittal, R. K., Frank, E. B., Lange, R. C. & McCallum, R. W. Effects of morphine and naloxone on esophageal motility and gastric emptying in man. Dig. Dis. Sci. 31, 936–942 (1986).
Penagini, R., Bartesaghi, B., Zannini, P., Negri, G. & Bianchi, P. A. Lower oesophageal sphincter hypersensitivity to opioid receptor stimulation in patients with idiopathic achalasia. Gut 34, 16–20 (1993).
Schoenfeld, P. S. Advances in IBS 2016: a review of current and emerging data. Gastroenterol. Hepatol. 12 (Suppl. 3), 1–11 (2016).
Cash, B. D., Lacy, B. E., Schoenfeld, P. S., Dove, L. S. & Covington, P. S. Safety of eluxadoline in patients with irritable bowel syndrome with diarrhea. Am. J. Gastroenterol. 112, 365–374 (2017).
Chandok, N. & Watt, K. D. Pain management in the cirrhotic patient: the clinical challenge. Mayo Clin. Proc. 85, 451–458 (2010).
Bosilkovska, M., Walder, B., Besson, M., Daali, Y. & Desmeules, J. Analgesics in patients with hepatic impairment: pharmacology and clinical implications. Drugs 72, 1645–1669 (2012).
Verbeeck, R. K. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur. J. Clin. Pharmacol. 64, 1147–1161 (2008).
Hasselstrom, J. et al. The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. Br. J. Clin. Pharmacol. 29, 289–297 (1990).
Soleimanpour, H., Safari, S., Shahsavari Nia, K., Sanaie, S. & Alavian, S. M. Opioid drugs in patients with liver disease: a systematic review. Hepat. Mon. 16, e32636 (2016).
Noble, M. et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst. Rev. 1, CD006605 (2010).
Ling, G. S., Paul, D., Simantov, R. & Pasternak, G. W. Differential development of acute tolerance to analgesia, respiratory depression, gastrointestinal transit and hormone release in a morphine infusion model. Life Sci. 45, 1627–1636 (1989).
Schneider, J. P. & Kirsh, K. L. Defining clinical issues around tolerance, hyperalgesia, and addiction: a quantitative and qualitative outcome study of long-term opioid dosing in a chronic pain practice. J. Opioid Manag. 6, 385–395 (2010).
Camilleri, M. et al. Emerging treatments in neurogastroenterology: a multidisciplinary working group consensus statement on opioid-induced constipation. Neurogastroenterol. Motil. 26, 1386–1395 (2014).
Harada, Y. et al. Mashiningan improves opioid-induced constipation in rats by activating cystic fibrosis transmembrane conductance regulator chloride channel. J. Pharmacol. Exp. Ther. 362, 78–84 (2017).
Grunkemeier, D. M., Cassara, J. E., Dalton, C. B. & Drossman, D. A. The narcotic bowel syndrome: clinical features, pathophysiology, and management. Clin. Gastroenterol. Hepatol. 5, 1126–1139 (2007).
Keefer, L. et al. Centrally mediated disorders of gastrointestinal pain. Gastroenterology 150, 1408–1419 (2016).
Szigethy, E., Schwartz, M. & Drossman, D. Narcotic bowel syndrome and opioid-induced constipation. Curr. Gastroenterol. Rep. 16, 410 (2014).
Drossman, D. & Szigethy, E. The narcotic bowel syndrome: a recent update. Am. J. Gastroenterol. Suppl. 2, 22–30 (2014).
Drossman, D. A. Functional gastrointestinal disorders: history, pathophysiology, clinical features & Rome IV. Gastroenterology 150, 1262–1279.e2 (2016).
Low, Y., Clarke, C. F. & Huh, B. K. Opioid-induced hyperalgesia: a review of epidemiology, mechanisms and management. Singapore Med. J. 53, 357–360 (2012).
Watkins, L. R. & Maier, S. F. Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol. Rev. 82, 981–1011 (2002).
Crain, S. M. & Shen, K. F. Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability. Pain 84, 121–131 (2000).
Ossipov, M. H., Lai, J., King, T., Vanderah, T. W. & Porreca, F. Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers 80, 319–324 (2005).
Kurlander, J. E. & Drossman, D. A. Diagnosis and treatment of narcotic bowel syndrome. Nat. Rev. Gastroenterol. Hepatol. 11, 410–418 (2014).
Watkins, L. R., Milligan, E. D. & Maier, S. F. Glial activation: a driving force for pathological pain. Trends Neurosci. 24, 450–455 (2001).
Rattan, A. K. & Tejwani, G. A. Effect of chronic treatment with morphine, midazolam and both together on dynorphin(1–13) levels in the rat. Brain Res. 754, 239–244 (1997).
Agostini, S. et al. Evidence of central and peripheral sensitization in a rat model of narcotic bowel-like syndrome. Gastroenterology 139, 553–563.e5 (2010).
Hutchinson, M. R. et al. Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav. Immun. 24, 83–95 (2010).
Hutchinson, M. R. et al. Opioid activation of toll-like receptor 4 contributes to drug reinforcement. J. Neurosci. 32, 11187–11200 (2012).
Mattioli, T. A. et al. Toll-like receptor 4 mutant and null mice retain morphine-induced tolerance, hyperalgesia, and physical dependence. PLoS ONE 9, e97361 (2014).
Farmer, A. D., Ferdinand, E. & Aziz, Q. Opioids and the gastrointestinal tract — a case of narcotic bowel syndrome and literature review. J. Neurogastroenterol. Motil. 19, 94–98 (2013).
Kotalik, J. Controlling pain and reducing misuse of opioids: ethical considerations. Can. Fam. Physician 58, 381–385 (2012).
Dowell, D., Haegerich, T. M. & Chou, R. CDC guideline for prescribing opioids for chronic pain — United States, 2016. JAMA 315, 1624–1645 (2016).
Murthy, V. H. Ending the opioid epidemic — a call to action. N. Engl. J. Med. 375, 2413–2415 (2016).
Ballantyne, J. C. & Fleisher, L. A. Ethical issues in opioid prescribing for chronic pain. Pain 148, 365–367 (2010).
Zgierska, A., Miller, M. & Rabago, D. Patient satisfaction, prescription drug abuse, and potential unintended consequences. JAMA 307, 1377–1378 (2012).
Kelly, S., Johnson, G. T. & Harbison, R. D. “Pressured to prescribe”: the impact of economic and regulatory factors on South-Eastern ED physicians when managing the drug seeking patient. J. Emerg. Trauma Shock 9, 58–63 (2016).
Kolodny, A. et al. The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction. Annu. Rev. Publ. Health 36, 559–574 (2015).
Drossman, D. A. et al. Diagnosis, characterization, and 3-month outcome after detoxification of 39 patients with narcotic bowel syndrome. Am. J. Gastroenterol. 107, 1426–1440 (2012).
U.S. Food and Drug Administration. FDA requires strong warnings for opioid analgesics, prescription opioid cough products, and benzodiazepine labeling related to serious risks and death from combined use. U.S. Food and Drug Administration https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm518697.htm (2016).
Tornblom, H. & Drossman, D. A. Centrally targeted pharmacotherapy for chronic abdominal pain. Neurogastroenterol. Motil. 27, 455–467 (2015).
Dekel, R., Drossman, D. A. & Sperber, A. D. The use of psychotropic drugs in irritable bowel syndrome. Expert Opin. Investigat. Drugs 22, 329–339 (2013).
Stoicea, N. et al. Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin. Front. Pharmacol. 6, 104 (2015).
Arumugam, S., Lau, C. S. & Chamberlain, R. S. Use of preoperative gabapentin significantly reduces postoperative opioid consumption: a meta-analysis. J. Pain Res. 9, 631–640 (2016).
Erlendson, M. J. et al. Palonosetron and hydroxyzine pre-treatment reduces the objective signs of experimentally-induced acute opioid withdrawal in humans: a double-blinded, randomized, placebo-controlled crossover study. Am. J. Drug Alcohol Abuse 43, 78–86 (2017).
Gowing, L., Ali, R., White, J. M. & Mbewe, D. Buprenorphine for managing opioid withdrawal. Cochrane Database Syst. Rev. 2, CD002025 (2017).
Xie, C. et al. Efficacy and safety of antidepressants for the treatment of Irritable Bowel Syndrome: a meta-analysis. PLoS ONE 10, e0127815 (2015).
Thorkelson, G., Bielefeldt, K. & Szigethy, E. Empirically supported use of psychiatric medications in adolescents and adults with IBD. Inflamm. Bowel Dis. 22, 1509–1522 (2016).
Cheng, Y. et al. Association between TLR2 and TLR4 gene polymorphisms and the susceptibility to Inflammatory Bowel Disease: a meta-analysis. PLoS ONE 10, e0126803 (2015).
Daghaghzadeh, H. et al. Efficacy of duloxetine add on in treatment of inflammatory bowel disease patients: a double-blind controlled study. J. Res. Med. Sci. 20, 595–601 (2015).
Talley, N. J. et al. Effect of amitriptyline and escitalopram on functional dyspepsia: a multicenter, randomized controlled study. Gastroenterology 149, 340–349.e342 (2015).
Talley, N. J. et al. Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial. Dig. Dis. Sci. 53, 108–115 (2008).
Masand, P. S. et al. A double-blind, randomized, placebo-controlled trial of paroxetine controlled-release in irritable bowel syndrome. Psychosomatics 50, 78–86 (2009).
Grover, M. & Camilleri, M. Effects on gastrointestinal functions and symptoms of serotonergic psychoactive agents used in functional gastrointestinal diseases. J. Gastroenterol. 48, 177–181 (2013).
Grover, M. et al. Atypical antipsychotic quetiapine in the management of severe refractory functional gastrointestinal disorders. Dig. Dis. Sci. 54, 1284–1291 (2009).
Gurusamy, K. S., Lusuku, C. & Davidson, B. R. Pregabalin for decreasing pancreatic pain in chronic pancreatitis. Cochrane Database Syst. Rev. 2, CD011522 (2016).
Olesen, S. S. et al. Randomised clinical trial: pregabalin attenuates experimental visceral pain through sub-cortical mechanisms in patients with painful chronic pancreatitis. Aliment. Pharmacol. Ther. 34, 878–887 (2011).
Gale, J. D. & Houghton, L. A. Alpha 2 delta (α2δ) Ligands, gabapentin and pregabalin: what is the evidence for potential use of these ligands in irritable bowel syndrome. Front. Pharmacol. 2, 28 (2011).
Takemura, Y. et al. Effects of gabapentin on brain hyperactivity related to pain and sleep disturbance under a neuropathic pain-like state using fMRI and brain wave analysis. Synapse 65, 668–676 (2011).
Saito, Y. A. et al. A placebo-controlled trial of pregabalin for irritable bowel syndrome. Am. J. Gastroenterol. Suppl. 111, S236 (2016).
Paul, S. P. & Basude, D. Non-pharmacological management of abdominal painrelated functional gastrointestinal disorders in children. World J. Pediatr. 12, 389–398 (2016).
Srinath, A. I., Walter, C., Newara, M. C. & Szigethy, E. M. Pain management in patients with inflammatory bowel disease: insights for the clinician. Therap. Adv. Gastroenterol. 5, 339–357 (2012).
Ford, A. C. et al. Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis. Am. J. Gastroenterol. 109, 1350–1365 (2014).
Ruepert, L. et al. Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome. Cochrane Database Syst. Rev. 8, CD003460 (2011).
Brennan, B. P. et al. Duloxetine in the treatment of irritable bowel syndrome: an open-label pilot study. Hum. Psychopharmacol. 24, 423–428 (2009).
Kaplan, A., Franzen, M. D., Nickell, P. V., Ransom, D. & Lebovitz, P. J. An open-label trial of duloxetine in patients with irritable bowel syndrome and comorbid generalized anxiety disorder. Int. J. Psychiatry Clin. Pract. 18, 11–15 (2014).
Lewis-Fernandez, R. et al. An open-label pilot study of duloxetine in patients with irritable bowel syndrome and comorbid major depressive disorder. J. Clin. Psychopharmacol. 36, 710–715 (2016).
Lacy, B. E., Chey, W. D. & Lembo, A. J. New and emerging treatment options for Irritable Bowel Syndrome. Gastroenterol. Hepatol. 11 (Suppl. 2), 1–19 (2015).
Noyman-Veksler, G. et al. Role of pain-based catastrophizing in pain, disability, distress, and suicidal ideation. Psychiatry 80, 155–170 (2017).
Cheng, C., Hui, W. & Lam, S. Perceptual style and behavioral pattern of individuals with functional gastrointestinal disorders. Health Psych. 19, 146–154 (2000).
Sandner-Kiesling, A. et al. Long-term efficacy and safety of combined prolonged-release oxycodone and naloxone in the management of non-cancer chronic pain. Int. J. Clin. Pract. 64, 763–774 (2010).
Ford, A. C., Brenner, D. M. & Schoenfeld, P. S. Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and meta-analysis. Am. J. Gastroenterol. 108, 1566–1574 (2013).
Mehta, N., O'Connell, K., Giambrone, G. P., Baqai, A. & Diwan, S. Efficacy of methylnaltrexone for the treatment of opiod-induced constipation: a meta-analysis and systematic review. Postgrad. Med. 128, 282–289 (2016).
Kraft, M. D. Methylnaltrexone, a new peripherally acting mu-opioid receptor antagonist being evaluated for the treatment of postoperative ileus. Expert Opin. Invest. Drugs 17, 1365–1377 (2008).
Poulsen, J., Brock, C., Olesen, A. E., Nilsson, M. & Drewes, A. M. Evolving paradigms in the treatment of opioid-induced bowel dysfunction. Therap. Adv. Gastroenterol. 8, 360–372 (2015).
Sloots, C. E., 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. 55, 2912–2921 (2010).
Sajid, M. S., Hebbar, M., Baig, M. K., Li, A. & Philipose, Z. Use of prucalopride for chronic constipation: a systematic review and meta-analysis of published randomized, controlled trials. J. Neurogastroenterol. Motil. 22, 412–422 (2016).
Nelson, A. D. & Camilleri, M. Opioid-induced constipation: advances and clinical guidance. Ther. Adv. Chron. Dis. 7, 121–134 (2016).
Argoff, C. E. et al. Consensus recommendations on initiating prescription therapies for opioid-induced constipation. Pain Med. 16, 2324–2337 (2015).
Ducrotte, P. & Causse, C. The Bowel Function Index: a new validated scale for assessing opioid-induced constipation. Curr. Med. Res. Opin. 28, 457–466 (2012).
Slappendel, R., Simpson, K., Dubois, D. & Keininger, D. L. Validation of the PAC-SYM questionnaire for opioid-induced constipation in patients with chronic low back pain. Eur. J. Pain 10, 209–217 (2006).
Keefer, L. & Mandal, S. The potential role of behavioral therapies in the management of centrally mediated abdominal pain. Neurogastroenterol. Motil. 27, 313–323 (2015).
Eccleston, C., Morley, S. J. & Williams, A. C. Psychological approaches to chronic pain management: evidence and challenges. Br. J. Anaesth. 111, 59–63 (2013).
Ehde, D. M., Dillworth, T. M. & Turner, J. A. Cognitive-behavioral therapy for individuals with chronic pain: efficacy, innovations, and directions for research. Am. Psychol. 69, 153–166 (2014).
Kerns, R. D., Sellinger, J. & Goodin, B. R. Psychological treatment of chronic pain. Annu. Rev. Clin. Psychol. 7, 411–434 (2011).
Tang, Q. L., Lin, G. Y. & Zhang, M. Q. Cognitive-behavioral therapy for the management of irritable bowel syndrome. World J. Gastroenterol. 19, 8605–8610 (2013).
Laird, K. T., Tanner-Smith, E. E., Russell, A. C., Hollon, S. D. & Walker, L. S. Short-term and long-term efficacy of psychological therapies for Irritable Bowel Syndrome: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 14, 937–947.e4 (2016).
Altayar, O., Sharma, V., Prokop, L. J., Sood, A. & Murad, M. H. Psychological therapies in patients with irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Gastroenterol. Res. Pract. 2015, 549308 (2015).
Palsson, O. S. & Whitehead, W. E. Psychological treatments in functional gastrointestinal disorders: a primer for the gastroenterologist. Clin. Gastroenterol. Hepatol. 11, 208–216 (2013).
Regueiro, M., Greer, J. B. & Szigethy, E. Etiology and treatment of pain and psychosocial issues in patients with inflammatory bowel diseases. Gastroenterology 152, 430–439.e4 (2017).
Knowles, S. R., Monshat, K. & Castle, D. J. The efficacy and methodological challenges of psychotherapy for adults with inflammatory bowel disease: a review. Inflamm. Bowel Dis. 19, 2704–2715 (2013).
Mikocka-Walus, A., Andrews, J. M. & Bampton, P. Cognitive behavioral therapy for IBD. Inflamm. Bowel Dis. 22, E5–E6 (2016).
Lee, H. H., Choi, Y. Y. & Choi, M. G. The efficacy of hypnotherapy in the treatment of Irritable Bowel Syndrome: a systematic review and meta-analysis. J. Neurogastroenterol. Motil. 20, 152–162 (2014).
Webb, A. N., Kukuruzovic, R. H., Catto-Smith, A. G. & Sawyer, S. M. Hypnotherapy for treatment of irritable bowel syndrome. Cochrane Database Syst. Rev. 4, CD005110 (2007).
Aucoin, M., Lalonde-Parsi, M. J. & Cooley, K. Mindfulness-based therapies in the treatment of functional gastrointestinal disorders: a meta-analysis. Evid. Based Complement. Alternat. Med. 2014, 140724 (2014).
Goyal, M. et al. Meditation programs for psychological stress and well-being: a systematic review and meta-analysis. JAMA Intern. Med. 174, 357–368 (2014).
Bawa, F. L. et al. Does mindfulness improve outcomes in patients with chronic pain? Systematic review and meta-analysis. Br. J. Gen. Pract. 65, e387–e400 (2015).
Palsson, O. S. Hypnosis treatment of gastrointestinal disorders: a comprehensive review of the empirical evidence. Am. J. Clin. Hypn. 58, 134–158 (2015).
Keefer, L. et al. Gut-directed hypnotherapy significantly augments clinical remission in quiescent ulcerative colitis. Aliment. Pharmacol. Ther. 38, 761–771 (2013).
Jedel, S. et al. A randomized controlled trial of mindfulness-based stress reduction to prevent flare-up in patients with inactive ulcerative colitis. Digestion 89, 142–155 (2014).
Berrill, J. W., Sadlier, M., Hood, K. & Green, J. T. Mindfulness-based therapy for inflammatory bowel disease patients with functional abdominal symptoms or high perceived stress levels. J. Crohns Colitis 8, 945–955 (2014).
Gerbarg, P. L. et al. The effect of breathing, movement, and meditation on psychological and physical symptoms and inflammatory biomarkers in Inflammatory Bowel Disease: a randomized controlled trial. Inflamm. Bowel Dis. 21, 2886–2896 (2015).
Jones, M., Koloski, N., Boyce, P. & Talley, N. J. Pathways connecting cognitive behavioral therapy and change in bowel symptoms of IBS. J. Psychosom. Res. 70, 278–285 (2011).
Chang, L. The role of stress on physiological responses and clinical symptoms in irritable bowel syndrome. Gastroenterology 140, 761–765 (2011).
Bonaz, B. L. & Bernstein, C. N. Brain-gut interactions in inflammatory bowel disease. Gastroenterology 144, 36–49 (2013).
Carabotti, M., Scirocco, A., Maselli, M. & Severi, C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann. Gastroenterol. 28, 203–209 (2015).
Uc, A. et al. Chronic pancreatitis in the 21st century — research challenges and opportunities: summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas 45, 1365–1375 (2016).
Palsson, O. S. & van Tilburg, M. Hypnosis and guided imagery treatment for gastrointestinal disorders: experience with scripted protocols developed at the University of North Carolina. Am. J. Clin. Hypn. 58, 5–21 (2015).
Ljotsson, B. et al. Internet-delivered exposure-based treatment versus stress management for irritable bowel syndrome: a randomized trial. Am. J. Gastroenterol. 106, 1481–1491 (2011).
Ljotsson, B. et al. Long-term follow-up of internet-delivered exposure and mindfulness based treatment for irritable bowel syndrome. Behav. Res. Ther. 49, 58–61 (2011).
Eccleston, C. et al. Psychological therapies (Internet-delivered) for the management of chronic pain in adults. Cochrane Database Syst. Rev. 2, CD010152 (2014).
Krupnick, J. L. et al. The role of the therapeutic alliance in psychotherapy and pharmacotherapy outcome: findings in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. J. Consult. Clin. Psychol. 64, 532–539 (1996).
Esquibel, A. Y. & Borkan, J. Doctors and patients in pain: conflict and collaboration in opioid prescription in primary care. Pain 155, 2575–2582 (2014).
Bäckryd, E. “Professional Helper” or “Helping Professional?” The patient-physician relationship in the chronic pain setting, with special reference to the current opioid debate. J. Contin. Educ. Health Prof. 36, 133–137 (2016).
Drossman, D. A. 2012 David Sun lecture: helping your patient by helping yourself — how to improve the patient-physician relationship by optimizing communication skills. Am. J. Gastroenterol. 108, 521–528 (2013).
Frantsve, L. M. & Kerns, R. D. Patient-provider interactions in the management of chronic pain: current findings within the context of shared medical decision making. Pain Med. 8, 25–35 (2007).
Reed-Knight, B., Claar, R. L., Schurman, J. V. & van Tilburg, M. A. Implementing psychological therapies for functional GI disorders in children and adults. Expert Rev. Gastroenterol. Hepatol. 10, 981–984 (2016).
Martins, S. S. et al. Mood and anxiety disorders and their association with non-medical prescription opioid use and prescription opioid-use disorder: longitudinal evidence from the National Epidemiologic Study on Alcohol and Related Conditions. Psychol. Med. 42, 1261–1272 (2012).
Wasan, A. D. et al. Psychiatric comorbidity is associated prospectively with diminished opioid analgesia and increased opioid misuse in patients with chronic low back pain. Anesthesiology 123, 861–872 (2015).
Mason, M. J. et al. Depression moderates the relationship between pain and the nonmedical use of opioid medication among adult outpatients. J. Addict. Med. 10, 408–413 (2016).
Arteta, J., Cobos, B., Hu, Y., Jordan, K. & Howard, K. Evaluation of how depression and anxiety mediate the relationship between pain catastrophizing and prescription opioid misuse in a chronic pain population. Pain Med. 17, 295–303 (2016).
Rosenblum, A., Marsch, L. A., Joseph, H. & Portenoy, R. K. Opioids and the treatment of chronic pain: controversies, current status, and future directions. Exp. Clin. Psychopharmacol. 16, 405–416 (2008).
Cowan, D. T., Allan, L. G., Libretto, S. E. & Griffiths, P. Opioid drugs: a comparative survey of therapeutic and “street” use. Pain Med. 2, 193–203 (2001).
Lee, E. B., An, W., Levin, M. E. & Twohig, M. P. An initial meta-analysis of Acceptance and Commitment Therapy for treating substance use disorders. Drug Alcohol Depend. 155, 1–7 (2015).
Jones, C. M. Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers — United States, 2002–2004 and 2008–2010. Drug Alcohol Depend. 132, 95–100 (2013).
Des Jarlais, D. C. et al. HIV incidence among injection drug users in New York City, 1990 to 2002: use of serologic test algorithm to assess expansion of HIV prevention services. Am. J. Publ. Health 95, 1439–1444 (2005).
Hagan, H. et al. Attribution of hepatitis C virus seroconversion risk in young injection drug users in 5 US cities. J. Infect. Dis. 201, 378–385 (2010).
Paicius, R. M., Bernstein, C. A. & Lempert-Cohen, C. Peripheral nerve field stimulation in chronic abdominal pain. Pain Physician 9, 261–266 (2006).
Kapural, L. & Jolly, S. Interventional pain management approaches for control of chronic pancreatic pain. Curr. Treat. Opt. Gastroenterol. 14, 360–370 (2016).
Simis, M. et al. Investigation of central nervous system dysfunction in chronic pelvic pain using magnetic resonance spectroscopy and noninvasive brain stimulation. Pain Pract. 15, 423–432 (2015).
Moreno-Duarte, I. et al. Targeted therapies using electrical and magnetic neural stimulation for the treatment of chronic pain in spinal cord injury. Neuroimage 85, 1003–1013 (2014).
Gray, A. M. et al. Deep brain stimulation as a treatment for neuropathic pain: a longitudinal study addressing neuropsychological outcomes. J. Pain 15, 283–292 (2014).
Butler, S. F., Budman, S. H., Fanciullo, G. J. & Jamison, R. N. Cross validation of the Current Opioid Misuse Measure (COMM) to monitor chronic pain patients on opioid therapy. Clin. J. Pain 26, 770–776 (2010).
Butler, S. F., Fernandez, K., Benoit, C., Budman, S. H. & Jamison, R. N. Validation of the Revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R). J. Pain 9, 360–372 (2008).
Bao, Y. et al. Prescription drug monitoring programs are associated with sustained reductions in opioid prescribing by physicians. Health Aff. 35, 1045–1051 (2016).
Kovitwanichkanont, T. & Day, C. A. Prescription opioid misuse and public health approach in Australia. Subst. Use Misuse http://dx.doi.org/10.1080/10826084.2017.1305415 (2017).
European Monitoring Centre for Drugs and Drug Addiction. Our activities — ongoing projects and programmes. European Monitoring Centre for Drugs and Drug Addiction http://www.emcdda.europa.eu/activities (2017).
Novak, S. P. et al. Nonmedical use of prescription drugs in the European Union. BMC Psychiatry 16, 274 (2016).
University of Wisconsin–Madison Pain & Policy Studies Group. Custom consumption graphs for opioid medicines. Pain & Policy Studies Group https://ppsg-chart.medicine.wisc.edu/ (2017).
M.K. is supported by NIH Award Number T32NR009759.
E.S. is a consultant for AbbVie and has received royalties from American Psychiatric Association Publishing, grant support from the NIH, the Crohn's & Colitis Foundation and the Bruce and Cynthia Sherman Foundation, and honoraria for educational talks for Imedex and the American Academy of Child and Adolescent Psychiatry. D.D. is President of the Rome Foundation and has been on advisory boards for Allergan, AstraZeneca, Ironwood and Shionogi in the past year.
About this article
Cite this article
Szigethy, E., Knisely, M. & Drossman, D. Opioid misuse in gastroenterology and non-opioid management of abdominal pain. Nat Rev Gastroenterol Hepatol 15, 168–180 (2018) doi:10.1038/nrgastro.2017.141
Ambulatory assessment of colonic motility using the electromagnetic capsule tracking system: Effect of opioids
Neurogastroenterology & Motility (2019)
Current Gastroenterology Reports (2019)
Pain in Inflammatory Bowel Disease Is Not Improved During Hospitalization: The Impact of Opioids on Pain and Healthcare Utilization
Digestive Diseases and Sciences (2019)
Der Schmerz (2019)