Article thumbnail

Methylnaltrexone in the treatment of opioid-induced constipation

By Beverley Greenwood-Van Meerveld and Kelly M Standifer


Constipation is a significant problem related to opioid medications used to manage pain. This review attempts to outline the latest findings related to the therapeutic usefulness of a μ opioid receptor antagonist, methylnaltrexone in the treatment of opioid-induced constipation. The review highlights methylnaltrexone bromide (Relistor™; Progenics/Wyeth) a quaternary derivative of naltrexone, which was recently approved in the United States, Europe and Canada. The Food and Drug Administration in the United States approved a subcutaneous injection for the treatment of opioid bowel dysfunction in patients with advanced illness who are receiving palliative care and when laxative therapy has been insufficient. Methylnaltrexone is a peripherally restricted, μ opioid receptor antagonist that accelerates oral–cecal transit in patients with opioid-induced constipation without reversing the analgesic effects of morphine or inducing symptoms of opioid withdrawal. An analysis of the mechanism of action and the potential benefits of using methylnaltrexone is based on data from published basic research and recent clinical studies

Topics: Review
Publisher: Dove Medical Press
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. [Physiological and pharmacological investigations of small intestinal peristalsis].
  2. (2005). A double-blind, randomized, placebo-controlled trial of methylnaltrexone (MNTX) for post-operative bowel dysfunction in segmental colectomy patients [abstract]. Am Soc Anesth.
  3. (2008). a new peripherally acting mu-opioid receptor antagonist being evaluated for the treatment of postoperative ileus. Expert Opin Investig Drugs.
  4. A review of the potential role of methylnaltrexone in opioid bowel dysfunction. Am J Surg. 2001;182(5A Suppl):19S–26S.
  5. Action of opiates on gastrointestinal function.
  6. (1999). Activation of an adrenergic and vagally mediated NANC pathway in surgery-induced fundic relaxation in the rat. Neurogastroenterol Motil.
  7. Alpha2-adrenergic regulation of NO production alters postoperative intestinal smooth muscle dysfunction in rodent.
  8. Altered expression and function of P-glycoprotein in dextran sodium sulfate-induced colitis in mice.
  9. Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists.
  10. Biphasic response to gut manipulation and temporal correlation of cellular infi ltrates and muscle dysfunction in rats.
  11. (2002). Colonic postoperative infl ammatory ileus in the rat. Ann Surg.
  12. (2005). Common symptoms in advanced cancer. Surg Clin North Am.
  13. (1997). Corticotropin-releasing factor and systemic capsaicin-sensitive afferents are involved in abdominal surgery-induced Fos expression in the paraventricular nucleus of the hypothalamus. Brain Res.
  14. (2001). Dello Buono FA. Opioid antagonists in the treatment of opioid-induced constipation and pruritus. Ann Pharmacother.
  15. Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice.
  16. Effect of adrenergic and nitrergic blockade on experimental ileus in rats.
  17. (2000). Effects of enteric-coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time. Clin Pharmacol Ther.
  18. Effects of intravenous methylnaltrexone on opioid-induced gut motility and transit time changes in subjects receiving chronic methadone therapy: a pilot study.
  19. (1995). Effects of methylnaltrexone on morphineinduced inhibition of contraction in isolated guinea-pig ileum and human intestine.
  20. Effects of subcutaneous methylnaltrexone on morphine-induced peripherally mediated side effects: a double-blind randomized placebo-controlled trial.
  21. (1998). Effi cacy of orally administered methylnaltrexone in decreasing subjective effects after intravenous morphine. Drug Alcohol Depend.
  22. Electrophysiological evidence for different release mechanism of ATP and NO as inhibitory NANC transmitters in guinea-pig colon.
  23. (2007). Emerging drugs for postoperative ileus. Expert Opin Emerg Drugs.
  24. (1990). Enkephalins modulate inhibitory neuromuscular transmission in circular muscle of human colon via delta-opioid receptors.
  25. (2000). Evidence for VIP(1)/PACAP receptors in the afferent pathway mediating surgery-induced fundic relaxation in the rat.
  26. (2008). Full Prescribing Information. [linked PDF, cited
  27. (2004). Function of opioids in the enteric nervous system. Neurogastroenterol Motil.
  28. (2005). In vitro evaluation of the effect of the opioid antagonist N-methylnaltrexone on motility of the equine jejunum and pelvic fl exure. Equine Vet J.
  29. Incidence, prevalence and management of opioid bowel dysfunction.
  30. Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats.
  31. Inflammation and gut motility; neural control of intestinal immune cell activation.
  32. (1994). Inhibition of cholinergic transmission by opiates in ileal myenteric plexus is mediated by kappa receptor. Involvement of regulatory inhibitory G protein and calcium N-channels. J Pharmacol Exp Ther.
  33. Inhibition of gastrointestinal transit by morphine in rats results primarily from direct drug action on the gut opioid sites.
  34. (1996). Insights into opioid action in the intestinal tract. Pharmacol Ther.
  35. (2003). Intra-abdominal activation of a local infl ammatory response within the human muscularis externa during laparotomy. Ann Surg.
  36. Involvement of alpha-1 and alpha-2 adrenoceptors in the postlaparotomy intestinal motor disturbances in the rat.
  37. (2006). Management of common opioid-induced adverse effects. Am Fam Physician.
  38. Mechanisms of action of loperamide.
  39. (2004). Mechanisms of postoperative ileus. Neurogastroenterol Motil.
  40. Methylnaltrexone for opioid-induced constipation in advanced illness.
  41. Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial.
  42. (1996). Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebocontrolled trial. Clin Pharmacol Ther.
  43. Modulatory effect of endogenous and exogenous opioids on the excitatory refl ex pathway of the rat ileum.
  44. (2008). Mu-opioid antagonists for opioid-induced bowel dysfunction. Cochrane Database Syst Rev.
  45. (1996). Neuronal pathways involved in abdominal surgery-induced gastric ileus in rats.
  46. (2007). Nitric oxide differentially regulates renal ATP-binding cassette transporters during endotoxemia. Pfl ugers Arch.
  47. Opioid-induced bowel dysfunction.
  48. Opioid-induced delay in gastric emptying: a peripheral mechanism in humans.
  49. (2006). Overview of POI and its impact on surgical outcomes. Contemporary Surg.
  50. Participation of capsaicin-sensitive afferent neurons in gastric motor inhibition caused by laparotomy and intraperitoneal acid.
  51. (2002). Pathogenesis of paralytic ileus: intestinal manipulation opens a transient pathway between the intestinal lumen and the leukocytic infi ltrate of the jejunal muscularis. Ann Surg.
  52. (2004). Preclinical studies of opioids and opioid antagonists on gastrointestinal function. Neurogastroenterol Motil.
  53. Prevention of opioid side effects.
  54. Prolonged postoperative ileus-defi nition, risk factors and predictors after surgery.
  55. Quaternary naltrexone: evidence for the central mediation of discriminative stimulus effects of narcotic agonists and antagonists.
  56. (1983). Receptor binding, antagonist, and withdrawal precipitating properties of opiate antagonists. Life Sci.
  57. Receptors and transmission in the brain-gut axis: potential for novel therapies. III. Mu-opioid receptors in the enteric nervous system.
  58. (2006). Regulation of multidrug resistance by pro-inflammatory cytokines. Curr Cancer Drug Targets.
  59. Regulation of the hepatic multidrug resistance gene expression by endotoxin and infl ammatory cytokines in mice.
  60. (1991). Role of central versus peripheral opioid receptors in analgesia induced repeated administration of opioid antagonists. Psychopharmacology (Berl).
  61. (1993). Role of CRF on stress-related alterations of gastric and colonic motor function.
  62. (1998). Role of VIP1/ PACAP receptors in postoperative ileus in rats.
  63. Safety and tolerance of methylnaltrexone in healthy humans: a randomized, placebo-controlled, intravenous, ascending-dose, pharmacokinetic study.
  64. (1992). Sites of action of morphine on the ascending excitatory refl ex in the guinea-pig small intestine. Neurosci Lett.
  65. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study.
  66. Surgically induced leukocytic infi ltrates within the rat intestinal muscularis mediate postoperative ileus.
  67. (1985). The central and peripheral infl uence of opioids on gastrointestinal propulsion. Annu Rev Pharmacol Toxicol.
  68. The Food and Drug Administration approves methylnaltrexone bromide for opioid-induced constipation.
  69. The ICAM-1 antisense oligonucleotide ISIS3082 prevents the development of postoperative ileus in mice.
  70. (2007). The in vitro pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, ADL 08-0011 and methylnaltrexone. Naunyn Schmiedebergs Arch Pharmacol.
  71. (2008). The involvement of the mu-opioid receptor in gastrointestinal pathophysiology: therapeutic opportunities for antagonism at this receptor. Pharmacol Ther.
  72. (2004). The opioid system in the gastrointestinal tract. Neurogastroenterol Motil.
  73. (2004). The role of endogenous opioids in the control of gastrointestinal motility: prediction from in vitro modelling. Neurogastroenterol Motil.
  74. (1997). The safety and effi cacy of oral methylnaltrexone in preventing morphineinduced delay in oral-cecal transit time. Clin Pharmacol Ther.
  75. The use of quaternary narcotic antagonists in opiate research.
  76. Unrecognized constipation in patients with advanced cancer: a recipe for therapeutic disaster.