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Methylnaltrexone: Wikis


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Systematic (IUPAC) name
CAS number 83387-25-1
ATC code A06AH01
PubChem 5361918
Chemical data
Formula C21H26NO4 
Mol. mass 356.44 g/mol
Synonyms MNTX, naltrexone-methyl-bromide
Therapeutic considerations
Licence data

US FDA:link

Pregnancy cat.  ?
Legal status Schedule VI (CA) -only (US)
Routes Oral, intravenous, subcutaneous

Methylnaltrexone (MNTX, trade name Relistor) is one of the newer agents of peripherally-acting μ-opioid antagonists that act to reverse some of the side effects of opioid drugs such as constipation without affecting analgesia or precipitating withdrawals. Because it contains a permanently charged tetravalent nitrogen atom, it cannot cross the blood-brain barrier, and so has antagonist effects throughout the body, counteracting effects such as itching and constipation, but without affecting opioid effects in the brain such as analgesia.[1]



In 1978 a colleague presented Leon Goldberg with a clinical challenge. One of his patients, struggling with the pain of prostatic cancer that had metastasized to his bones, was now declining the morphine he required for analgesia because of the constipation he was suffering. He asked the simple question "Isn't there something we can do?" The search for the "silver bullet" of analgesia - an opioid that would target only the sub-types of receptors associated with pain relief and not with side effects was well under way - but had seen little success out side of in-vitro models. Dr. Goldberg proposed an alternate approach. Drugs that acted on the opioid receptors of the gut - notably loperamide - and did not cross into the brain were available. Could we find an analogous opioid receptor antagonist? Thousands of opioid-like molecules had been synthesized by pharmaceutical companies looking for the better analgesic - and many of those with no pain relieving properties had been shelved. Screening these compounds led to the examination of putative antagonists which when modified had properties that suggested they might not readily cross the blood-brain barrier based on their size and charge. One of these compounds, N-methyl-naltrexone (MNTX), was amongst a group of compounds synthesized by Boehringer Ingleheim.(Zeil, 1963) The compound looked promising and passed initial screening in which rodents were given opioids along with charcoal meals to track GI transit, and were tested for analgesia.(Goldberg, 1979) In a 1982 paper by Russell et. Al it was first reported that the GI effects of the opioids could be prevented without affecting centrally mediated analgesia in this model. Subsequent preclinical studies also demonstrated this separation of central and peripherally mediated opioid effects for other smooth muscles of the GI tract and the cough reflex.(Yuan, 1995; Foss, 1996) Interest also developed in the potential for MNTX to act at the chemoreceptor trigger zone and block the emetic effect of opioids. This blockade of opioid-induced emesis was demonstrated in a canine model.(Foss, 1993; Goldberg, 1988) Unfortunately Dr. Goldberg died before he could see the core of his idea come into clinical practice.

Research on methylnaltrexone continued in the Department of Anesthesiology and Critical Care at the University of Chicago through the 1990s.

In December 2005, Wyeth and Progenics entered into an exclusive, worldwide agreement for the joint development and commercialization of methylnaltrexone for the treatment of opioid-induced side effects, including constipation and post-operative ileus (POI), a prolonged dysfunction of the gastrointestinal (GI) tract following surgery. Under the terms of the agreement, the companies are collaborating on worldwide development. Wyeth received worldwide rights to commercialize methylnaltrexone, and Progenics retained an option to co-promote the product in the United States. Wyeth will pay Progenics royalties on worldwide sales and co-promotion fees within the United States.

Methylnaltrexone is being developed in subcutaneous and oral forms to treat opioid induced constipation (OIC).

Progenics and Wyeth are conducting two global phase 3 clinical trials in POI, targeting an NDA submission in this indication in early 2008. An oral formulation for OIC in patients with chronic pain currently is under development with an anticipated NDA submission in late 2009 or early 2010.


On April 1, 2008, Progenics and Wyeth announced that Health Canada has approved methylnaltrexone for the treatment of opioid induced constipation.[2] It was later approved by the US FDA on April 24, 2008.[3][4]


Methylnaltrexone is approved for the treatment of Opioid Induced Constipation or OIC. It is generally only to be used when ordinary laxatives have failed. Because of its mechanism of action, it will not have any effect on constipation that is not OIC.

How it works

Methylnaltrexone bromide is a selective antagonist of opioid binding at the mu-opioid receptor.
As a quaternary amine, the ability of methylnaltrexone bromide to cross the blood-brain barrier
is restricted. This allows methylnaltrexone bromide to function as a peripherally-acting
mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing ::the constipating effects of opioids without impacting opioid-mediated analgesic effects on the
central nervous system. [5]

In other words, methylnaltrexone binds to the same receptors in the gut, the mu-opioid receptor, that opioid analgeisic drugs bind to. This stops the opioid agonist from having its effect on those receptors in the gut, but because methylnaltrexone cannot cross into the brain, it only blocks the effects in places like the gut, thus allowing bowel motility, otherwise suppressed by opioid agonists, to proceed normally. However, analgesia mostly happens in the brain and is unaffected.

How Supplied

Relistor is supplied in trays which contain seven one dose vials containing 0.6 ml of solution which contains 12 mg of methylnaltrexone bromide, seven 12 mm (1/2") 1 mL 27 cauge needles with retractable tips, and alcohol wipes for home use. A single vial can treat someone who weighs as much as 115 kg (251lbs)[5] For hospital use, vials are available separately.



  • Zeil, K & K Freter, "Quaternary salts of normorphine and its acylated derivatives.", [1], issued 1963
  • Goldberg, L; H Merz & K Stockhaus, "Quaternary derivatives of noroxymorphone which relieve intestinal immobility", [2], issued 1979
  • Russell J, Bass P, Goldberg LI, Schuster CR, Merz H (1982;). "Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists.". Eur J Pharmacol (78:): 255–61. 
  • Yuan CS, Foss JF, Moss J (1995;). "Effects of methylnaltrexone on morphine-induced inhibition of contraction in isolated guinea-pig ileum and human intestine.". Eur J Pharmacol (276:): 107–11. 
  • Foss JF, Orelind E, Goldberg LI (1996;). "Effects of methylnaltrexone on morphine-induced cough suppression in guinea pigs.". Life Sci (59:): PL235-8. 
  • Foss JF, Bass AS, Goldberg LI (1993;). "Dose-related antagonism of the emetic effect of morphine by methylnaltrexone in dogs.". J Clin Pharmacol (33:): 747–51. 
  • Goldberg LI (1988). "Quaternary derivatives of noroxymorphone which relieve nausea and emesis". Abstract, University of Chicago,. 
  • Yuan CS and Foss JF (2000). "Oral Methylnaltrexone for Opioid-Induced Constipation". JAMA (284): 1383–1384. 


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