Skip to main content
SpringerLink
Log in

Methylnaltrexone: A Peripherally Acting Opioid Antagonist

  • Chapter
Opiate Receptors and Antagonists

Part of the book series: Contemporary Neuroscience ((CNEURO))

Abstract

Opioids are widely used analgesics in patients with moderate or severe pain. Their effectiveness for pain relief is often limited, however, by the most frequently occurring side effect, opioid-induced constipation. Unlike the analgesic effects of opioids, which are centrally mediated, constipation is mediated mainly by peripheral opioid receptors in the gut. Conventional laxatives are often ineffective in treating opioid-inducded constipation. Methylnaltrexone is a novel quaternary derivative of naltrexone that does not cross the blood—brain barrier in humans and acts as a selective peripheral opioid receptor antagonist, recently approved by the FDA and other regulatory agencies for the treatment of opioid-induced constipation in patients with advanced illness receiving palliative care. This chapter reviews preclinical studies and data from trials of methylnaltrexone bowel dysfunction induced by opioids. Other potential clinical roles for methylnaltrexone are also briefly presented.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. McCaffrey M, Beebe A. Managing your patients' adverse reactions to narcotics. Nursing 1989;19:166–168.

    CAS  PubMed  Google Scholar 

  2. Glare P, Lickiss JN. Unrecognized constipation in patients with advanced cancer: a recipe for therapeutic disaster. J Pain Symptom Manage 1992;7:369–371.

    Article  CAS  PubMed  Google Scholar 

  3. Gowan JD, Hurtig JB, Fraser RA, Torbicki E, Kitts J. Naloxone infusion after prophylactic epidural morphine: effects on incidence of postoperative side-effects and quality of analgesia. Can J Anaesth 1988;35:143–148.

    Article  CAS  PubMed  Google Scholar 

  4. Culpepper-Morgan JA, Inturrisi CE, Portenoy RK, Foley K, Houde RW, Marsh F, Kreek MJ. Treatment of opioid-induced constipation with oral naloxone: a pilot study. Clin Pharmacol Ther 1992;52:90–95.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Sykes NP. Using of oral naloxone in the management of opioid bowel dysfunction. In: Handbook of Opioid Bowel Syndrome. Yuan CS (ed). New York: Haworth Medical Press, 2005, pp. 175–195.

    Google Scholar 

  7. Brown DR, Goldberg LI. The use of quaternary narcotic antagonists in opiate research. Neuropharmacology 1985;24:181–191.

    Article  CAS  PubMed  Google Scholar 

  8. Russell J, Bass P, Goldberg LI, Schuster CR, Merz H. Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists. Eur J Pharmacol 1982;78:255–261.

    Article  CAS  PubMed  Google Scholar 

  9. Woods JH, Medzihradsky F, Smith CB, Young AM, Swain HH. Annual report: evaluation of new compounds for opioid activity (1980). NIDA Res Monogr 1981;34:327–366.

    CAS  PubMed  Google Scholar 

  10. Gmerek DE, Cowan A, Woods JH. Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats. J Pharmacol Exp Ther 1986;236:8–13.

    CAS  PubMed  Google Scholar 

  11. Walker MJ, Le AD, Poulos CX, Cappell H. Role of central versus peripheral opioid receptors in analgesia induced by repeated administration of opioid antagonists. Psychopharmacology (Berl) 1991;104:164–166.

    Article  CAS  Google Scholar 

  12. Yuan CS. Gastric effects of mu-, delta- and kappa-opioid receptor agonists on brainstem unitary responses in the neonatal rat. Eur J Pharmacol 1996;314:27–32.

    Article  CAS  PubMed  Google Scholar 

  13. Yuan CS, Foss JF. Gastric effects of methylnaltrexone on mu, kappa, and delta opioid agonists induced brainstem unitary responses. Neuropharmacology 1999;38:425–432.

    Article  CAS  PubMed  Google Scholar 

  14. Bianchi G, Fiocchi R, Tavani A, Manara L. Quaternary narcotic antagonists' relative ability to prevent antinociception and gastrointestinal transit inhibition in morphine-treated rats as an index of peripheral selectivity. Life Sci 1982;30:1875–1883.

    Article  CAS  PubMed  Google Scholar 

  15. Koob GF, Pettit HO, Ettenberg A, Bloom FE. Effects of opiate antagonists and their quaternary derivatives on heroin self-administration in the rat. J Pharmacol Exp Ther 1984;229: 481–486.

    CAS  PubMed  Google Scholar 

  16. Kotake AN, Kuwahara SK, Burton E, McCoy CE, Goldberg LI. Variations in demethylation of N-methylnaltrexone in mice, rats, dogs, and humans. Xenobiotica 1989;19:1247–1254.

    Article  CAS  PubMed  Google Scholar 

  17. Borison HL, Wang SC. Physiology and pharmacology of vomiting. Pharmacol Rev 1953;5: 193–230.

    CAS  PubMed  Google Scholar 

  18. Foss JF, Bass AS, Goldberg LI. Dose-related antagonism of the emetic effect of morphine by methylnaltrexone in dogs. J Clin Pharmacol 1993;33:747–751.

    CAS  PubMed  Google Scholar 

  19. Foss JF, Yuan CS, Roizen MF, Goldberg LI. Prevention of apomorphine- or cisplatin-induced emesis in the dog by a combination of methylnaltrexone and morphine. Cancer Chemother Pharmacol 1998;42:287–291.

    Article  CAS  PubMed  Google Scholar 

  20. Aung HH, Mehendale SR, Xie JT, Moss J, Yuan CS. Methylnaltrexone prevents morphine-induced kaolin intake in the rat. Life Sci 2004;74:2685–2691.

    Article  CAS  PubMed  Google Scholar 

  21. Manara L, Bianchetti A. The central and peripheral influences of opioids on gastrointestinal propulsion. Annu Rev Pharmacol Toxicol 1985;25:249–273.

    Article  CAS  PubMed  Google Scholar 

  22. Ferritti P, Tavani A, Manara L. Inhibition of gastrointestinal transit and antinociceptive effects of morphine and FK-33–824 in rats are differently prevented by naloxone and the N-methyl quaternary analog. Res Commun Subst Abuse 1981;2:1–11.

    Google Scholar 

  23. Yuan CS, Foss JF, Moss J. Effects of methylnaltrexone on morphine-induced inhibition of contraction in isolated guinea-pig ileum and human intestine. Eur J Pharmacol 1995;276: 107–111.

    Article  CAS  PubMed  Google Scholar 

  24. Foss JF, O'Connor MF, Yuan CS, Murphy M, Moss J, Roizen MF. Safety and tolerance of methylnaltrexone in healthy humans: a randomized, placebo-controlled, intravenous, ascending- dose, pharmacokinetic study. J Clin Pharmacol 1997;37:25–30.

    Article  CAS  PubMed  Google Scholar 

  25. Yuan CS, Doshan H, Charney MR, O'Connor M, Karrison T, Maleckar SA, Israel RJ, Moss J. Tolerability, gut effects, and pharmacokinetics of methylnaltrexone following repeated intravenous administration in humans. J Clin Pharmacol 2005;45:538–546.

    Article  CAS  PubMed  Google Scholar 

  26. Kim C, Cheng R, Corrigall WA, Coen KM. High-perfomance liquid-chromatography with coulometric electochemical detection. Chromatographia 1989;28:359–336.

    Article  CAS  Google Scholar 

  27. Osinski J, Wang A, Wu JA, Foss JF, Yuan CS. Determination of methylnaltrexone in clinical samples by solid-phase extraction and high-performance liquid chromatography for a phar-macokinetics study. J Chromatogr B Analyt Technol Biomed Life Sci 2002;780:251–259.

    Article  CAS  PubMed  Google Scholar 

  28. Yuan CS, Foss JF, O'Connor M, Toledano A, Roizen MF, Moss J. Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin Pharmacol Ther 1996;59:469–475.

    Article  CAS  PubMed  Google Scholar 

  29. Yuan CS, Wei G, Foss JF, O'Connor M, Karrison T, Osinski J. Effects of subcutaneous methylnaltrexone on morphine-induced peripherally mediated side effects: a double-blind randomized placebo-controlled trial. J Pharmacol Exp Ther 2002;300:118–123.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Yuan CS, Foss JF, O'Connor M, Karrison T, Osinski J, Roizen MF, Moss J. Effects of enteric-coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time. Clin Pharmacol Ther 2000;67:398–404.

    Article  CAS  PubMed  Google Scholar 

  32. Amin HM, Sopchak AM, Foss JF, Esposito BF, Roizen MF, Camporesi EM. Efficacy of methylnaltrexone versus naloxone for reversal of morphine-induced depression of hypoxic ventilatory response. Anesth Analg 1994;78:701–705.

    Article  CAS  PubMed  Google Scholar 

  33. Gomery P, Chen T, Stefanovich P, Chandler L, Montgomery E, Rosow C. Antagonism of opioid bladder and pupil effects by methylnaltrexone, naloxone, or placebo. Proc Intl Soc Anesth Pharm 2003;307:1158–1162.

    Google Scholar 

  34. Bond JH Jr, Levitt MD, Prentiss R. Investigation of small bowel transit time in man utilizing pulmonary hydrogen (H2) measurements. J Lab Clin Med 1975;85:546–555.

    CAS  PubMed  Google Scholar 

  35. Read NW, Al-Janabi MN, Bates TE, Holgate AM, Cann PA, Kinsman RI, McFarlane A, Brown C. Interpretation of the breath hydrogen profile obtained after ingesting a solid meal containing unabsorbable carbohydrate. Gut 1985;26:834–842.

    Article  CAS  PubMed  Google Scholar 

  36. Yuan CS, Karrison T, Wu JA, Lowell TK, Lynch JP, Foss JF. Dose-related effects of oral acetaminophen on cold-induced pain: a double-blind, randomized, placebo-controlled trial. Clin Pharmacol Ther 1998;63:379–383.

    Article  CAS  PubMed  Google Scholar 

  37. Yuan CS, Foss JF, O'Connor M, Roizen MF, Moss J. Effects of low-dose morphine on gastric emptying in healthy volunteers. J Clin Pharmacol 1998;38:1017–1020.

    Article  CAS  PubMed  Google Scholar 

  38. Murphy DB, Sutton JA, Prescott LF, Murphy MB. Opioid-induced delay in gastric emptying: a peripheral mechanism in humans. Anesthesiology 1997;87:765–770.

    Article  CAS  PubMed  Google Scholar 

  39. Yuan CS, Foss JF, O'Connor M, Moss J, Roizen MF. Gut motility and transit changes in patients receiving long-term methadone maintenance. J Clin Pharmacol 1998;38:931–935.

    CAS  PubMed  Google Scholar 

  40. Yuan CS, Foss JF, O'Connor M, Osinski J, Roizen MF, Moss J. Effects of intravenous methyl-naltrexone on opioid-induced gut motility and transit time changes in subjects receiving chronic methadone therapy: a pilot study. Pain 1999;83:631–635.

    Article  CAS  PubMed  Google Scholar 

  41. Yuan CS, Foss JF, O'Connor M, Osinski J, Karrison T, Moss J, Roizen MF. Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial. JAMA 2000;283:367–372.

    Article  CAS  PubMed  Google Scholar 

  42. Yuan CS, Moss J, Wei G, Maleckar SA, Boyd TA, Israel RJ. Methylnaltrexone for chronic opioid-induced constipation. Am Soc Clin Oncol Proc 2002;21:376a.

    Google Scholar 

  43. Yuan CS, Foss JF. Oral methylnaltrexone for opioid-induced constipation. JAMA 2000;284: 1383–1384.

    Article  CAS  PubMed  Google Scholar 

  44. Thomas J, Portenoy RK, Moehl M, Von Gunten C, Thielemann P, Stambler N, Tran D, Galasso F, Israel R. A phase II randomized dose-finding trail of methylnaltrexone for the relief of opioid-induced constipation in hospice patients. Am Soc Clin Oncol Proc 2003; 22:2933.

    Google Scholar 

  45. Meier DE, Morrison RS, Cassel CK. Improving palliative care. Ann Intern Med 1997;127: 225–230.

    CAS  PubMed  Google Scholar 

  46. Abraham JL. A Physician's Guide to Pain and Symptom Management in Cancer Patients. Baltimore: Johns Hopkins University Press, 2000.

    Google Scholar 

  47. Mercadante S. Diarrhea, malabsorption, and constipation. In: Palliative Care and Supportive Oncology. Berger AM, Portenoy RK, Weissman DE (eds). Philadelphia: Lippincott, Williams & Wilkins, 2002, pp. 233–249.

    Google Scholar 

  48. Bauer AJ, Boeckxstaens GE. Mechanisms of postoperative ileus. Neurogastroenterol Motil 2004;16 Suppl 2:54–60.

    Article  PubMed  Google Scholar 

  49. Huge A, Kreis ME, Zittel TT, Becker HD, Starlinger MJ, Jehle EC. Postoperative colonic motility and tone in patients after colorectal surgery. Dis Colon Rectum 2000;43:932–939.

    Article  CAS  PubMed  Google Scholar 

  50. Basse L, Hjort Jakobsen D, Billesbolle P, Werner M, Kehlet H. A clinical pathway to accelerate recovery after colonic resection. Ann Surg 2000;232:51–57.

    Article  CAS  PubMed  Google Scholar 

  51. Viscusi E, Rathmell J, Alessandro F, Gan TJ, Israel RJ. A double-blind, randomized, placebo-controlled trial of methylnaltrexone for post-operative bowel dysfunction in segmental colec-tomy patients. Proc Am Soc Anesth 2005;25:1630.

    Google Scholar 

  52. Thomas J, Lipman A, Slatkin N, Wilson G, Moehl M, Wellman C, Zhukovsky D, Stephenson R, Stambler N, Israel RJ. A phase III double-blind placebo-controlled trial of methylnaltrexone (MNTX) for opioid-induced constipation (OIC) in advanced medical illness (AMI). Proc Am Soc Clin Oncol 2005;25:8003.

    Google Scholar 

  53. Slatkin N, Karver S, Thomas J, Chamberlain B, Austin-Cooney G, Watt C, Winston JL, Cross K, McGrew D, Stambler N, Israel RJ. A phase III double-blind, placebo-controlled trial of methylnaltrexone for opioid-induced constipation in advanced illness (MNTX 302). Digest Dis Week 2006;686e.

    Google Scholar 

  54. Petersen TK, Husted SE, Rybro L, Schurizek BA, Wernberg M. Urinary retention during i.m. and extradural morphine analgesia. Br J Anaesth 1982;54:1175–1178.

    Article  CAS  PubMed  Google Scholar 

  55. Levy JH, Brister NW, Shearin A, Ziegler J, Hug CC, Jr., Adelson DM, Walker BF. Wheal and flare responses to opioids in humans. Anesthesiology 1989;70:756–760.

    Article  CAS  PubMed  Google Scholar 

  56. Yuan CS, Foss JF, O'Connor M, Osinski J, Roizen MF, Moss J. Efficacy of orally administered methylnaltrexone in decreasing subjective effects after intravenous morphine. Drug Alcohol Depend 1998;52:161–165.

    Article  CAS  PubMed  Google Scholar 

  57. Chakravarty NK, Matallana A, Jensen R, Borison HL. Central effects of antitussive drugs on cough and respiration. J Pharmacol Exp Ther 1956;117:127–135.

    CAS  PubMed  Google Scholar 

  58. Adcock JJ, Schneider C, Smith TW. Effects of codeine, morphine and a novel opioid pen-tapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea-pig. Br J Pharmacol 1988;93:93–100.

    CAS  PubMed  Google Scholar 

  59. Foss JF, Orelind E, Goldberg LI. Effects of methylnaltrexone on morphine-induced cough suppression in guinea pigs. Life Sci 1996;59:PL235–PL238.

    Article  CAS  PubMed  Google Scholar 

  60. Wei G, Moss J, Yuan CS. Opioid-induced immunosuppression: is it centrally mediated or peripherally mediated? Biochem Pharmacol 2003;65:1761–1766.

    CAS  PubMed  Google Scholar 

  61. Eisenstein TK, Hilburger ME. Opioid modulation of immune responses: effects on phagocyte and lymphoid cell populations. J Neuroimmunol 1998;83:36–44.

    Article  CAS  PubMed  Google Scholar 

  62. Ho WZ, Guo CJ, Yuan CS, Douglas SD, Moss J. Methylnaltrexone antagonizes opioid-mediated enhancement of HIV infection of human blood mononuclear phagocytes. J Pharmacol Exp Ther 2003;307:1158–1162.

    Article  CAS  PubMed  Google Scholar 

  63. Kehlet H. Endogenous morphine—another component and biological modifier of the response to surgical injury? Acta Anaesthesiol Scand 2000;44:1167–1168.

    Article  CAS  PubMed  Google Scholar 

  64. Kreek MJ, Schaefer RA, Hahn EF, Fishman J. Naloxone, a specific opioid antagonist, reverses chronic idiopathic constipation. Lancet 1983;1:261–262.

    Article  CAS  PubMed  Google Scholar 

  65. Hawkes ND, Rhodes J, Evans BK, Rhodes P, Hawthorne AB, Thomas GA. Naloxone treatment for irritable bowel syndrome — a randomized controlled trial with an oral formulation. Aliment Pharmacol Ther 2002;16:1649–1654.

    Article  CAS  PubMed  Google Scholar 

  66. Singleton PA, Lingen MW, Fekete MJ, Garcia JG, Moss J. Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation. Microvasc Res 2006; 72:3–11.

    Article  CAS  PubMed  Google Scholar 

  67. Neary P, Delaney CP. Alvimopan. Expert Opin Investig Drugs 2005;14:479–488.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesia & Critical Care, Pritzker School of Medicine, The University of Chicago, 5841 S. Maryland Avenue, 4028, MC, IL, 60637, Chicago

    Chun-Su Yuan & Robert J. Israel

  2. Committee on Clinical Pharmacology, Department of Anesthesia and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, IL, 60637

    Chun-Su Yuan

  3. Progenics Pharmaceuticals, Inc., NY, Tarrytown, 10591

    Robert J. Israel

Authors
  1. Chun-Su Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert J. Israel
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Life Sciences/Toxicology, Alkermes, Inc., Cambridge, MA, 02139, USA

    Reginald L. Dean III

  2. Department of Pharmacology, College of Osteopathic Medicine, University of New England, Biddleford, ME, 04005, USA

    Edward J. Bilsky

  3. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA

    S. Stevens Negus

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Yuan, CS., Israel, R.J. (2009). Methylnaltrexone: A Peripherally Acting Opioid Antagonist. In: Dean, R.L., Bilsky, E.J., Negus, S.S. (eds) Opiate Receptors and Antagonists. Contemporary Neuroscience. Humana Press. https://doi.org/10.1007/978-1-59745-197-0_10

Download citation

Publish with us

Policies and ethics

Search

Navigation