Vol 17, No 4 (2023)
Review paper
Published online: 2023-07-07

open access

Page views 739
Article views/downloads 439
Get Citation

Connect on Social Media

Connect on Social Media

Pathophysiology and management of opioid-induced constipation: a narrative review

Jakub Kobiałka1, Bartłomiej Ludwig2, Anna Dziekiewicz3, Joanna Bystron3
Palliat Med Pract 2023;17(4):233-244.

Abstract

Background: Treatment of chronic pain is among the primary tasks of palliative care. Among the most commonly prescribed analgesics are opioid agents. Opioids, in addition to being highly effective in controlling severe pain, have a high risk of adverse effects (AEs). The most common gastrointestinal AE is opioid-induced constipation (OIC).

Methods: A search through online databases was conducted including Google Scholar and PubMed and key information on the pathophysiology, epidemiology, diagnosis and current therapeutic options for OIC has been collected.

Results: The pathophysiology of OIC is primarily related to the direct action of opioids on opioid receptors located in the wall of the gastrointestinal tract. This leads to deregulation of the mechanisms responsible for the motor and secretory functions of the gastrointestinal tract. That results in impaired digestion and delayed intestinal transit, leading to the development of constipation. Opioid-induced constipation leads to a significant reduction in patients’ quality of life and an increase in the cost of treatment and can lead to serious complications such as gastrointestinal perforation. Patients receiving palliative care due to their multiple burdens require a holistic diagnostic approach and thorough differential diagnosis of OIC. Among therapeutic approaches, we distinguish between non-specific methods related to lifestyle changes and laxatives, and cause-directed pharmacological methods related to the use of peripherally acting opioid receptor antagonists (PAMORA). The most commonly used PAMORA for the treatment of OIC include naloxegol, methylnaltrexone and naldemedine. Numerous clinical studies demonstrate the efficacy and high safety profile of PAMORA in the treatment of OIC.

Conclusions: Proper diagnosis of OIC among patients taking opioid drugs allows for the implementation of effective therapeutic measures. Appropriate treatment reduces the risk of OIC-related complications and leads to an increase in patients’ quality of life.

Article available in PDF format

View PDF Download PDF file

References

  1. Krashin D, Murinova N, Jumelle P, et al. Opioid risk assessment in palliative medicine. Expert Opin Drug Saf. 2015; 14(7): 1023–1033.
  2. Gaertner J, Boehlke C, Simone CB, et al. Early palliative care and the opioid crisis: ten pragmatic steps towards a more rational use of opioids. Ann Palliat Med. 2019; 8(4): 490–497.
  3. Mercadante S, Arcuri E, Santoni A. Opioid-Induced tolerance and hyperalgesia. CNS Drugs. 2019; 33(10): 943–955.
  4. Nafziger AN, Barkin RL. Opioid therapy in acute and chronic pain. J Clin Pharmacol. 2018; 58(9): 1111–1122.
  5. Farmer AD, Holt CB, Downes TJ, et al. Pathophysiology, diagnosis, and management of opioid-induced constipation. Lancet Gastroenterol Hepatol. 2018; 3(3): 203–212.
  6. Sarrió RG, Calsina-Berna A, García AG, et al. Working Group ActEIO Project. Delphi consensus on strategies in the management of opioid-induced constipation in cancer patients. BMC Palliat Care. 2021; 20(1): 1.
  7. Farmer AD, Drewes AM, Chiarioni G, et al. Pathophysiology and management of opioid-induced constipation: European expert consensus statement. United European Gastroenterol J. 2019; 7(1): 7–20.
  8. Wiffen PJ, Wee B, Derry S, et al. Opioids for cancer pain — an overview of Cochrane reviews. Cochrane Database Syst Rev. 2017; 7(7): CD012592.
  9. Lee AA, Hasler WL. Opioids and GI motility — friend or foe? Curr Treat Options Gastroenterol. 2016; 14(4): 478–494.
  10. Liao SS, Slatkin NE, Stambler N. The influence of age on central effects of methylnaltrexone in patients with opioid-induced constipation. Drugs Aging. 2021; 38(6): 503–511.
  11. Hanson B, Siddique SM, Scarlett Y, et al. American Gastroenterological Association Institute Clinical Guidelines Committee. American gastroenterological association institute technical review on the medical management of opioid-induced constipation. Gastroenterology. 2019; 156(1): 229–253.e5.
  12. Crockett SD, Greer KB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute Clinical Guidelines Committee. American Gastroenterological Association Institute guideline on the medical management of opioid-induced constipation. Gastroenterology. 2019; 156(1): 218–226.
  13. Liu JJ, Quinton SE, Brenner DM. Naldemedine for the treatment of opioid-induced constipation in adults with chronic noncancer pain. Pain Manag. 2020; 10(5): 301–306.
  14. De Giorgio R, Zucco FM, Chiarioni G, et al. Management of opioid-induced constipation and bowel dysfunction: expert opinion of an italian multidisciplinary panel. Adv Ther. 2021; 38(7): 3589–3621.
  15. Tomich JL, Sipe MH. Fostering best practices for reducing opioid-induced constipation using technology. Comput Inform Nurs. 2019; 37(11): 551–557.
  16. Leppert W. The role of opioid receptor antagonists in the treatment of opioid-induced constipation: a review. Adv Ther. 2010; 27(10): 714–730.
  17. Blair HA. Naldemedine: a review in opioid-induced constipation. Drugs. 2019; 79(11): 1241–1247.
  18. Camilleri M, Drossman DA, Becker G, et al. Emerging treatments in neurogastroenterology: a multidisciplinary working group consensus statement on opioid-induced constipation. Neurogastroenterol Motil. 2014; 26(10): 1386–1395.
  19. Holzer P. Opioids and opioid receptors in the enteric nervous system: from a problem in opioid analgesia to a possible new prokinetic therapy in humans. Neurosci Lett. 2004; 361(1-3): 192–195.
  20. Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept. 2009; 155(1–3): 11–17.
  21. Holzer P. Non-analgesic effects of opioids: management of opioid-induced constipation by peripheral opioid receptor antagonists: prevention or withdrawal? Curr Pharm Des. 2012; 18(37): 6010–6020.
  22. Keller MS, Jusufagic A, Spiegel BMR. Patient and provider differences in the treatment of opioid-induced constipation: a qualitative study. BMC Gastroenterol. 2019; 19(1): 182.
  23. Mesía R, Virizuela Echaburu JA, Gómez J, et al. Opioid-Induced constipation in oncological patients: new strategies of management. Curr Treat Options Oncol. 2019; 20(12): 91.
  24. Mozaffari S, Nikfar S, Abdollahi M. Methylnaltrexone bromide for the treatment of opioid-induced constipation. Expert Opin Pharmacother. 2018; 19(10): 1127–1135.
  25. Camilleri M, Lembo A, Katzka DA. Opioids in gastroenterology: treating adverse effects and creating therapeutic benefits. Clin Gastroenterol Hepatol. 2017; 15(9): 1338–1349.
  26. Candy B, Jones L, Vickerstaff V, et al. Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care. Cochrane Database Syst Rev. 2018; 6(6): CD006332.
  27. Leppert W. Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction. Drug Des Devel Ther. 2015; 9: 2215–2231.
  28. Christensen HN, Olsson U, From J, et al. Opioid-induced constipation, use of laxatives, and health-related quality of life. Scand J Pain. 2016; 11: 104–110.
  29. Sharma SK, Nirenberg M, Klee WA. Morphine receptors as regulators of adenylate cyclase activity. Proc Natl Acad Sci USA. 1975; 72(2): 590–594.
  30. Williams JT, Ingram SL, Henderson G, et al. Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev. 2013; 65(1): 223–254.
  31. Nusrat S, Syed T, Saleem R, et al. Pharmacological treatment of opioid-induced constipation is effective but choice of endpoints affects the therapeutic gain. Dig Dis Sci. 2019; 64(1): 39–49.
  32. Leppert W, Zajaczkowska R, Wordliczek J. The role of oxycodone/naloxone in the management of patients with pain and opioid-induced constipation. Expert Opin Pharmacother. 2019; 20(5): 511–522.
  33. Els C, Jackson TD, Kunyk D, et al. Adverse events associated with medium- and long-term use of opioids for chronic non-cancer pain: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2017; 10(10): CD012509.
  34. Huang L, Zhou JG, Zhang Yu, et al. Opioid-Induced constipation relief from fixed-ratio combination prolonged-release oxycodone/naloxone compared with oxycodone and morphine for chronic nonmalignant pain: a systematic review and meta-analysis of randomized controlled trials. J Pain Symptom Manage. 2017; 54(5): 737–748.e3.
  35. Nee J, Zakari M, Sugarman MA, et al. Efficacy of treatments for opioid-induced constipation: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018; 16(10): 1569–1584.e2.
  36. LoCasale RJ, Datto CJ, Margolis MK, et al. The impact of opioid-induced constipation among chronic pain patients with sufficient laxative use. Int J Clin Pract. 2015; 69(12): 1448–1456.
  37. Dzierżanowski T. The role of peripherally acting mu-opioid receptor antagonists (PAMORA) in the treatment of constipation in palliative care. Palliative Medicine. 2019; 11(2): 51–57.
  38. Dzierżanowski T, Larkin P. Proposed criteria for constipation in palliative care patients. A multicenter cohort study. J Clin Med. 2020; 10(1).
  39. Webster L, Chey WD, Tack J, et al. Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation. Aliment Pharmacol Ther. 2014; 40(7): 771–779.
  40. Mozaffari S, Nikfar S, Abdollahi M. Investigational opioid antagonists for treating opioid-induced bowel dysfunction. Expert Opin Investig Drugs. 2018; 27(3): 235–242.
  41. Lawson R, Ryan J, King F, et al. Cost effectiveness of naloxegol for opioid-induced constipation in the UK. Pharmacoeconomics. 2017; 35(2): 225–235.
  42. Omer A, Quigley EMM. An update on prucalopride in the treatment of chronic constipation. Therap Adv Gastroenterol. 2017; 10(11): 877–887.
  43. Bassotti G, Usai Satta P, Bellini M. Prucalopride for the treatment of constipation: a view from 2015 and beyond. Expert Rev Gastroenterol Hepatol. 2019; 13(3): 257–262.
  44. Webster LR, Brewer RP, Lichtlen P, et al. Efficacy of lubiprostone for the treatment of opioid-induced constipation, analyzed by opioid class. Pain Med. 2018; 19(6): 1195–1205.
  45. Spierings ELH, Drossman DA, Cryer B, et al. Efficacy and safety of lubiprostone in patients with opioid-induced constipation: phase 3 study results and pooled analysis of the effect of concomitant methadone use on clinical outcomes. Pain Med. 2018; 19(6): 1184–1194.
  46. Spierings ELH, Brewer RP, Rauck RL, et al. Lubiprostone for opioid-induced constipation does not interfere with opioid analgesia in patients with chronic noncancer pain. Pain Pract. 2017; 17(3): 312–319.
  47. Shelton KN, Clements JN. Naloxegol for managing opioid-induced constipation. JAAPA. 2017; 30(9): 51–53.
  48. Chey WD, Webster L, Sostek M, et al. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014; 370(25): 2387–2396.
  49. Mehta N, O'Connell K, Giambrone GP, et al. Efficacy of methylnaltrexone for the treatment of opiod-induced constipation: a meta-analysis and systematic review. Postgrad Med. 2016; 128(3): 282–289.
  50. Leppert W. Role of oxycodone and oxycodone/naloxone in cancer pain management. Pharmacol Rep. 2010; 62(4): 578–591.
  51. Meissner W, Schmidt U, Hartmann M, et al. Oral naloxone reverses opioid-associated constipation. Pain. 2000; 84(1): 105–109.
  52. Le BH, Aggarwal G, Douglas C, et al. Oxycodone/naloxone prolonged-release tablets in patients with moderate-to-severe, chronic cancer pain: Challenges in the context of hepatic impairment. Asia Pac J Clin Oncol. 2022; 18(1): 13–18.
  53. Hale M, Wild J, Reddy J, et al. 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.
  54. Katakami N, Harada T, Murata T, et al. Randomized phase III and extension studies of naldemedine in patients with opioid-induced constipation and cancer. J Clin Oncol. 2017; 35(34): 3859–3866.



Palliative Medicine in Practice