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The role of opioid receptor antagonists in the treatment of opioid-induced constipation: a review

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Abstract

Opioid-induced constipation (OIC) is associated with negative impact of opioid analgesics on opioid receptors located in the gut wall. Until recently, OIC was treated symptomatically only, with different laxatives which did not target the pathophysiology of OIC. Recently, several opioid receptor antagonists have been introduced in the treatment of OIC. Methylnaltrexone (MNTX) is a peripheral mu-opioid receptor antagonist for subcutaneous administration, which does not evoke symptoms of opioid abstinence. MNTX is indicated for patients with OIC who are not amenable to therapy with oral laxatives. In clinical trials, the effectiveness of MNTX assessed as its ability to induce spontaneous bowel movement, is 50%–60% of treated patients; MNTX demonstrates significant superiority over placebo. Another product is combination of oral formulation of prolonged release oxycodone and prolonged release naloxone (PR oxycodone/PR naloxone), indicated for patients who require opioid administration for chronic pain and have already developed OIC, and for those who need opioid therapy and take the drug to prevent OIC. Naloxone administered orally displays local, antagonist effects on opioid receptors in the gut wall, negligible systemic bioavailability, and significantly reduces the oxycodone constipating effect. PR oxycodone/PR naloxone has similar analgesic efficacy, but causes less constipation and less laxative consumption in comparison with patients treated with oxycodone alone. Both products are expensive, therefore their administration should be carefully considered. On the other hand, uncontrolled OIC and the necessity to perform rectal invasive procedures (enema, manual evacuation) lead not only to increased health care costs, but most importantly, cause severe patient suffering.

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References

  1. Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg. 2001;182:11S–18S.

    Article  PubMed  CAS  Google Scholar 

  2. Larkin PJ, Sykes NP, Centeno C, et al. The management of constipation in palliative care: clinical practice recommendations. Palliat Med. 2008;22:796–807.

    Article  PubMed  CAS  Google Scholar 

  3. Sykes N. The pathogenesis of constipation. J Support Oncol. 2006;4:213–218.

    PubMed  Google Scholar 

  4. Sykes N. The relationship between opioid use and laxative use in terminally ill cancer patients. Palliat Med. 1998;12:375–382.

    Article  PubMed  CAS  Google Scholar 

  5. Leppert W, Kozikowska J, Luczak J, Glowacka A, Malinger S. Objawy ze strony ukladu pokarmowego u chorych z zaawansowana choroba nowotworowa. (Gastrointestinal symptoms in patients with advanced cancer). Nowa Med. 2000;97:18–39.

    Google Scholar 

  6. Leppert W, Dzierzanowski T, Cialkowska-Rysz A, Jarosz J, Pyszkowska J, Stachowiak A. Postepowanie u chorych z zaparciem stolca w medycynie paliatywnej — zalecenia Grupy Roboczej Ekspertow Polskiego Towarzystwa Medycyny Paliatywnej. (The management of constipation in palliative medicine — recommendations of the Expert Working Group of the Polish Association for Palliative Medicine). Medycyna Paliatywna. 2009;1:1–10.

    Google Scholar 

  7. Sykes NP. Constipation and diarrhoea. In: Doyle D, Hanks G, Cherny N, Calman K, eds. Oxford Textbook of Palliative Medicine. Oxford: Oxford University Press; 2004: 483–496.

    Google Scholar 

  8. Benson AB, Stein R. Diarrhoea and constipation: supportive oncology management. In: Ettinger DS, ed. Supportive Care in Cancer Therapy. New York: Humana Press; 2009:213–225.

    Google Scholar 

  9. Mancini I, Bruera E. Constipation. In: Ripamonti C, Bruera E, eds. Gastrointestinal Symptoms in Advanced Cancer Patients. Oxford: Oxford University Press; 2004:193–206.

    Google Scholar 

  10. Slappendel R, Simpson K, Dubois D, Keininger DL. Validation of the PAC-SYM questionnaire for opioid-induced constipation in patients with chronic low back pain. Eur J Pain. 2006;10:209–217.

    Article  PubMed  Google Scholar 

  11. Meissner W, Leyendecker P, Meuller-Lissner S, et al. A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain. 2009;13:56–64.

    Article  PubMed  CAS  Google Scholar 

  12. Leyendecker P, Hopp M, Bosse B, et al. Bowel Function Index (BFI), a new validated questionnaire for assessing opioid induced constipation. Proceedings of the 12th IASP World Congress on Pain; August 17–22, 2008; Glasgow, Scotland, UK.

  13. Leppert W, Majkowicz M. Ocena analgezji i objawow niepozadanych tramadolu i dihydrokodeiny o kontrolowanym uwalnianiu u chorych z bolem nowotworowym — na podstawie zmodyfikowanej skali ESAS. (Assessment of analgesia and adverse effects of controlled release tramadol and dihydrocodeine in patients with cancer pain — based on a modified ESAS). Wspolcz Onkol. 2008;12:246–254.

    CAS  Google Scholar 

  14. Ueberral MA, Mueller-Schwefe G. Opioid-induced constipation — a frequent and distressing side effect in daily practice affecting oral and transdermal opioid applications. Eur J Pain. 2006;10:S172.

    Article  Google Scholar 

  15. Reimer K, Hopp M, Zenz M, et al. Meeting the challenges of opioid-induced constipation in chronic pain management — a novel approach. Pharmacology. 2009;83:10–17.

    Article  PubMed  CAS  Google Scholar 

  16. Davis MP. The opioid bowel syndrome: a review of pathophysiology and treatment. J Opioid Manage. 2005;1:153–161.

    Google Scholar 

  17. Holzer P. Treatment of opioid-induced gut dysfunction. Expert Opin Investig Drugs. 2007;16:181–194.

    Article  PubMed  CAS  Google Scholar 

  18. Holzer P. Opioids and opioid receptors in the myenteric nervous system: from a problem in opioid analgesia to a possible new prokinetic therapy in humans. Neurosci Lett. 2004;361:192–195.

    Article  PubMed  CAS  Google Scholar 

  19. Shook JE, Pelton JT, Hruby VJ, Burks TF. Peptide opioid antagonist separates peripheral and central opioid antitransit effects. J Pharmacol Exp Ther. 1987;243:492–500.

    PubMed  CAS  Google Scholar 

  20. Porecca F, Cowan A, Raffa RB, Tallarida RJ. Ketazocines and morphine: effects on gastrointestinal transit after central and peripheral administration. Life Sci. 1983;32:1785–1790.

    Article  Google Scholar 

  21. Parolado D, Sala M, Gori E. Effect of intracerebroventricular administration of morphine upon intestinal motility in rat and its antagonism with naloxone. Eur J Pharmacol. 1977;46:329–338.

    Article  Google Scholar 

  22. Stewart JJ, Weisbrodt NW, Burks TF. Central and peripheral action of morphine on intestinal transit. J Pharmacol Exp Ther. 1978;205:547–555.

    PubMed  CAS  Google Scholar 

  23. Thörn SE, Wattwil M, Lindberg G, Säwe J. Systemic and central effects of morphine on gastrointestinal motility. Acta Anaesthesiol Scand. 1996;40:177–186.

    Article  PubMed  Google Scholar 

  24. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008;358:2332–2343.

    Article  PubMed  CAS  Google Scholar 

  25. Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. J Support Oncol. 2009;7:39–46.

    PubMed  CAS  Google Scholar 

  26. Wood JD, Galligan JJ. Function of opioids in the enteric nervous system. Neurogastroenterol Motil. 2004;16(suppl. 2):181–194.

    Google Scholar 

  27. Klaschik E, Nauck F, Ostgathe C. Constipation — modern laxative therapy. Support Care Cancer. 2003;11:679–685.

    Article  PubMed  CAS  Google Scholar 

  28. Bruera E, Brenneis C, Michand M, MacDonald N. Continuous subcutaneous infusion of metoclopramide for treatment of narcotic bowel syndrome. Cancer Treat Rep. 1987;71:1121–1122.

    PubMed  CAS  Google Scholar 

  29. Basta S, Anderson DL. Mechanisms and management of constipation in the cancer patient. J Pharmaceut Care Pain Symptom Control. 1998;6:21–40.

    Article  Google Scholar 

  30. Potter J, Wagg A. Management of bowel problems in older people: an update. Clin Med. 2005;5:289–295.

    PubMed  Google Scholar 

  31. Mumford SP. Can high fibre diets improve the bowel function in patients on radiotherapy ward? In: Twycross RG, Lack SA, eds. Control of Alimentary Symptoms in Far Advanced Cancer. Edinburgh: Churchill Livingstone; 1986:183.

    Google Scholar 

  32. Sykes NP. Current approaches to the management of constipation. Cancer Surv. 1994;21:137–146.

    PubMed  CAS  Google Scholar 

  33. Mancini I, Bruera E. Constipation in advanced cancer patients. Support Care Cancer. 1998;6:356–364.

    Article  PubMed  CAS  Google Scholar 

  34. Sykes NP. A clinical comparison of laxatives in a hospice. Palliat Med. 1991;5:307–314.

    Article  Google Scholar 

  35. Miles CL, Fellowes D, Goodman ML, Wilkinson S. Laxatives for the management of constipation in palliative care patients. Cochrane Database Syst Rev. 2006;4:CD003448.

    PubMed  Google Scholar 

  36. Holzer P, Ahmedzai SH, Niederle N, et al. Opioid-induced bowel dysfunction in cancer-related pain: causes, consequences, and a novel approach for its management. J Opioid Manage. 2009;5:145–195.

    Google Scholar 

  37. Mercadante S, Bruera E. Opioid switching: a systematic and critical review. Cancer Treat Rev. 2006;32:304–315.

    Article  PubMed  CAS  Google Scholar 

  38. Leppert W. Postepy w leczeniu farmakologicznym bolu nowotworowego analgetykami opioidowymi. (Progress in pharmacological pain treatment with opioid analgesics). Wspolcz Onkol. 2009;13:66–73.

    Google Scholar 

  39. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy and quality of life. J Pain Symptom Manage. 1997;13:254–261.

    Article  PubMed  CAS  Google Scholar 

  40. Haazen L, Noorduin H, Megens A, Meert T. The constipation-inducing potential of morphine and transdermal fentanyl. Eur J Pain. 1999; 3(suppl. A):9–15.

    Article  CAS  Google Scholar 

  41. Hunt R, Fazekas B, Thorne D, Brooksbank M. A comparison of subcutaneous morphine and fentanyl in hospice cancer patients. J Pain Symptom Manage. 1999;18:111–119.

    Article  PubMed  CAS  Google Scholar 

  42. Tassinari D, Sartori S, Tamburini E, et al. Adverse effects of transdermal opiates treating moderate-severe cancer pain in comparison to long-acting morphine: a meta-analysis and systematic review of the literature. J Palliat Med. 2008;11:492–502.

    Article  PubMed  Google Scholar 

  43. Bach V, Kamp-Jensen M, Jensen N-H, Eriksen J. Buprenorphine and sustained release oral morphine — effect and side-effects in chronic use. Pain Clin. 1991;4:87–93.

    Google Scholar 

  44. Mancini IL, Hanson J, Neumann CM, Bruera E. Opioid type and other clinical predictors of laxative dose in advanced cancer patients: a retrospective study. J Palliat Med. 2000;3:49–56.

    Article  PubMed  CAS  Google Scholar 

  45. Daeninck PJ, Bruera E. Reduction in constipation and laxative requirements following opioid rotation to methadone: a report of four cases. J Pain Symptom Manage. 1999;18:303–309.

    Article  PubMed  CAS  Google Scholar 

  46. Mercadante S, Casuccio A, Fulfaro F, et al. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol. 2001;19:2898–2904.

    PubMed  CAS  Google Scholar 

  47. Grond S, Radbruch L, Meuser T, Loick G, Sabatowski R, Lehmann KA. High-dose tramadol in comparison to low-dose morphine for cancer pain relief. J Pain Symptom Manage. 1999;18:174–179.

    Article  PubMed  CAS  Google Scholar 

  48. Duggan AK. The cost of constipation in morphine patients and the economic possibilities with tramadol. Br J Med Econom. 1995;9:21–29.

    Google Scholar 

  49. Leppert W. Analgesic efficacy and side effects of oral tramadol and morphine administered orally in the treatment of cancer pain. Nowotwory. 2001;51:257–266.

    Google Scholar 

  50. Wirz S, Witmmann M, Schenk M, et al. Gastrointestinal symptoms under opioid therapy: a prospective comparison of oral sustained-release hydromorphone, transdermal fentanyl, and transdermal buprenorphine. Eur J Pain. 2009;13:737–743.

    Article  PubMed  CAS  Google Scholar 

  51. Yuan CS. Clinical status of methylnaltrexone, a new agent to prevent and manage opioid-induced side effects. J Support Oncol. 2004;2:111–122.

    PubMed  CAS  Google Scholar 

  52. Sykes NP. An investigation of the ability of oral naloxone to correct opioid-related constipation in patients with advanced cancer. Palliat Med. 1996;10:135–144.

    Article  PubMed  CAS  Google Scholar 

  53. Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J Pain Symptom Manage. 2002;23:48–53.

    Article  PubMed  Google Scholar 

  54. Meissner W, Schimdt U, Hartmann M, et al. Oral naloxone reverses opioid-induced constipation. Pain. 2000;84:105–109.

    Article  PubMed  CAS  Google Scholar 

  55. Glass PS, Jhaveri RM, Smith LR. Comparison of potency and duration of action of nalmefene and naloxone. Anesth Analg. 1994;78:536–541.

    Article  PubMed  CAS  Google Scholar 

  56. Cheskin LJ, Chami TN, Johnson RE, et al. Assessment of nalmefene glucuronide as a selective gut opioid antagonist. Drug Alcohol Depend. 1995;39:151–154.

    Article  PubMed  CAS  Google Scholar 

  57. Nadstawek J, Leyendecker P, Hopp M, et al. Patient assessment of a novel therapeutic approach for the treatment of severe, chronic pain. Int J Clin Pract. 2008;62:1159–1167.

    Article  PubMed  CAS  Google Scholar 

  58. Anon. Oxycodone/naloxone prolonged release tablets, questions and answers. In: Paineurope supplement. London: Haymarket Medical Imprint, 174 Hammersmith Road, W6 7JP, UK; 2009 (Feb): 3–10. Available at: www.paineurope.com. Item code UK/TAR-08053.

  59. Kalso E. Oxycodone. J Pain Symptom Manage. 2005;29(5S):S47–S56.

    Article  PubMed  CAS  Google Scholar 

  60. Biancofiore G. Oxycodone controlled release in cancer pain management. Therap Clinic Risk Manage. 2006;2:228–234.

    Google Scholar 

  61. Fishman J, Roffwarg H, Helman L. Disposition of naloxone-7,8-3H in normal and narcotic-dependent men. J Pharmacol Exp Ther. 1973;187:575–580.

    PubMed  CAS  Google Scholar 

  62. Müller-Lissner S, Leyendecker P, Hopp M, Ruckes C, Fleischer W, Reimer K. Oral prolonged release (PR) oxycodone/naloxone combination reduces opioid-induced bowel dysfunction (OIBD) in patients with severe chronic pain. Eur J Pain. 2007;11:Abstract 189.

  63. Vondrackova D, Leyendecker P, Meissner W, et al. Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release tablets in patients with moderate to severe chronic pain. J Pain. 2008;9:1144–1154.

    Article  PubMed  CAS  Google Scholar 

  64. Simpson K, Leyendecker P, Hopp M, 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;24:3503–3512.

    Article  PubMed  CAS  Google Scholar 

  65. Sandner-Kiesling A, Leyendecker P, Hopp M, 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. 2010;64:763–774.

    Article  PubMed  CAS  Google Scholar 

  66. Löwenstein O, Leyendecker P, Hopp M, et al. Combined prolonged release oxycodone and naloxone improves bowel function in patients receiving opioids for moderate-to-severe nonmalignant chronic pain: a randomized controlled trial. Expert Opin Pharmacother. 2009;10:531–453.

    Article  PubMed  CAS  Google Scholar 

  67. Schang JC, Devroede G. Beneficial effects of naloxone in a patient with intestinal pseudoobstruction. Am J Gastroenterol. 1985;80:407–411.

    PubMed  CAS  Google Scholar 

  68. Shaiova L, Rim F, Friedman D, Jahdi M. A review of methylnaltrexone, a peripheral opioid receptor antagonist, and its role in opioid-induced constipation. Palliat Support Care. 2007;5:161–166.

    Article  PubMed  Google Scholar 

  69. Yuan CS, Foss JF, Osinski J, Toledano A, Roizen MF, Moss J. The safety and efficacy of oral clinical methylnaltrexone in preventing morphine-induced delay in oral-cecal transit time. Clin Pharmacol Ther. 1997;61:467–475.

    Article  PubMed  CAS  Google Scholar 

  70. Yuan CS, Foss JF, O’Connor M J, Toledano A, Roizen MF, Moss J. Effects of enteric-coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time. Clin Pharmacol Ther. 2000;67:388–404.

    Article  Google Scholar 

  71. Abarca FM, Saclarides TJ, Brand MI. A review of the treatment of opioid-induced constipation with methylnaltrexone bromide. Clinical Medicine Insights: Therapeutics. 2010;2:53–60.

    CAS  Google Scholar 

  72. Portenoy RK, Thomas J, Moehl Boathwright ML, et al. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study. J Pain Symptom Manage. 2008;35:458–468.

    Article  PubMed  CAS  Google Scholar 

  73. Chamberlain BH, Cross K, Winston JL, et al. Methylnaltrexone treatment of opioid-induced constipation in patients with advanced illness. J Pain Symptom Manage. 2009;38:683–690.

    Article  PubMed  CAS  Google Scholar 

  74. Becker G, Galandi D, Blum HE. Peripherally acting opioid antagonists in the treatment of opiaterelated constipation: a systematic review. J Pain Symptom Manage. 2007;34:547–565.

    Article  PubMed  CAS  Google Scholar 

  75. Yuan CS. Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects. Ann Pharmacother. 2007;41:984–993.

    Article  PubMed  CAS  Google Scholar 

  76. Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial. JAMA. 2000;283:367–372.

    Article  PubMed  CAS  Google Scholar 

  77. Paulson DM, Kennedy DT, Donovick RA, et al. Alvimopan: an oral, peripherally acting, mu-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction — a 21-day treatment-randomized trial. J Pain. 2005;6:184–192.

    Article  PubMed  CAS  Google Scholar 

  78. US Food and Drug Administration. FDA approves Entereg to help restore bowel function following surgery. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116899.htm. Accessed May 21, 2010.

  79. McNicol E, Boyce DB, Schumann R, Carr D. Efficacy and safety of mu-opioid antagonists in the treatment of opioid-induced bowel dysfunction: systematic review and meta-analysis of randomized controlled trials. Pain Med. 2008;9:634–659.

    Article  PubMed  Google Scholar 

  80. McNicol ED, Boyce D, Schumann R, Carr DB. Mu-opioid antagonists for opioid-induced bowel dysfunction. Cochrane Database Syst Rev. 2008;2:CD006332.

    PubMed  Google Scholar 

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  1. Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Osiedle Rusa 25 A, 61-245, Poznan, Poland

    Wojciech Leppert

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Leppert, W. The role of opioid receptor antagonists in the treatment of opioid-induced constipation: a review. Adv Therapy 27, 714–730 (2010). https://doi.org/10.1007/s12325-010-0063-0

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