Methylnaltrexone
Encyclopedia
Methylnaltrexone 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 withdrawal
s. 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. However, since a significant fraction (up to 60 %) of opioid analgesia can be mediated by opioid receptors on peripheral sensory neurons, particularly in inflammatory conditions such as arthritis, traumatic or surgical pain, MNTX may increase pain under such circumstances.
, which acted on the opioid receptors in the gut without crossing the blood brain barrier, Goldberg proposed a targeted 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. 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. 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. 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. Goldberg died before he could see the core of this 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. More recent investigations, however, discovered opioid receptors on peripheral sensory neurons. Since inflammatory pain is blunted by endogenous opioid peptides activating such peripheral opioid receptors, MNTX may increase pain under such circumstances.
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 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.
The use of methylnaltrexone (Relistor) for more than 4 months has not been studied.
It was later approved by the US FDA on April 24, 2008.
.
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
that act to reverse some of the side effects of opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
drugs such as constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
without affecting analgesia or precipitating withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
s. Because it contains a permanently charged tetravalent nitrogen atom, it cannot cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
, 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. However, since a significant fraction (up to 60 %) of opioid analgesia can be mediated by opioid receptors on peripheral sensory neurons, particularly in inflammatory conditions such as arthritis, traumatic or surgical pain, MNTX may increase pain under such circumstances.
Development
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 constipation. Research on opioids which would target only the sub-types of receptors associated with pain relief and not with side effects had seen little success outside of in-vitro models. Considering drugs such as loperamideLoperamide
Loperamide , a synthetic piperidine derivative, is an opioid drug used against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, and Pepto Diarrhea Control...
, which acted on the opioid receptors in the gut without crossing the blood brain barrier, Goldberg proposed a targeted 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. 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. 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. 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. Goldberg died before he could see the core of this 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. More recent investigations, however, discovered opioid receptors on peripheral sensory neurons. Since inflammatory pain is blunted by endogenous opioid peptides activating such peripheral opioid receptors, MNTX may increase pain under such circumstances.
In December 2005, Wyeth
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
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
Ileus
Ileus is a disruption of the normal propulsive ability of the gastrointestinal tract.Ileus is commonly defined simply as bowel obstruction. However, authoritative sources define it as decreased motor activity of the GI tract due to non-mechanical causes...
(POI), a prolonged dysfunction of the gastrointestinal 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.
The use of methylnaltrexone (Relistor) for more than 4 months has not been studied.
Approval
On April 1, 2008, Progenics and Wyeth announced that Health Canada has approved methylnaltrexone for the treatment of opioid induced constipation.It was later approved by the US FDA on April 24, 2008.
Indications
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.Mechanism of action
Methylnaltrexone binds to the same receptors as opioid analgesics such as morphine, but it acts as an antagonist, blocking the effects of those analgesics, specifically the constipating effects on the gastrointestinal tract. Furthermore, as methylnaltrexone cannot cross the blood-brain barrier, it does not reverse the pain-killing properties of opioid agonists or cause withdrawal symptoms. Methylnaltrexone is unable to enter the brain primarily because it carries a positive charge on its nitrogen atom. This is the primary difference that makes methylnaltrexone behave differently from naltrexoneNaltrexone
Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade...
.
Forms
As of 2010, methylnaltrexone is supplied as an injection in trays containing seven one dose vials containing 0.6 mL of solution. Each vial contains 12 mg of methylnaltrexone bromide. Each tray also contains seven 12 mm (0.47244094488189 in) 1 mL 27 gauge needles with retractable tips, and alcohol wipes for home use. A single vial can treat someone who weighs as much as 115 kilograms (253.5 lb). For hospital use, vials are available separately.See also
- LoperamideLoperamideLoperamide , a synthetic piperidine derivative, is an opioid drug used against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, and Pepto Diarrhea Control...
- an Mu-opioid receptor agonist that "does" cross the BBB, and treats diarrhea (in contrast to methynaltrexone, a Mu-opioid receptor antagonist that "doesn't" cross the BBB, avoiding opiate withdrawal effects in patients, while treating constipation) - (+)-Naloxone(+)-Naloxone-Naloxone is a drug which is the "unnatural" enantiomer of the opioid antagonist drug -naloxone. Unlike "normal" naloxone, -naloxone has no significant affinity for opioid receptors, but instead has been discovered to act as a selective antagonist of Toll-like receptor 4...
- a non-opioid drug which also reduces some side effects of opioids without affecting analgesia