Methylnaltrexone (MNTX, brand name Relistor), used in form of methylnaltrexone bromide ( INN, USAN, BAN), is a medication that acts as a peripherally acting μ-opioid receptor antagonist that acts to reverse some of the side effects of

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

drugs such as

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

without significantly affecting

pain relief Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...

or precipitating withdrawals. Because MNTX is a

quaternary ammonium cation In organic chemistry, quaternary ammonium cations, also known as quats, are positively-charged polyatomic ions of the structure , where R is an alkyl group, an aryl group or organyl group. Unlike the ammonium ion () and the primary, secondary, ...

, it cannot cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

, and so has antagonist effects throughout the body, counteracting effects such as

itching An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...

and constipation, but without affecting opioid effects in the brain such as pain relief. 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.

Medical uses

Methylnaltrexone is approved for the treatment of opioid-induced constipation in chronic non cancer pain or when ordinary

laxatives Laxatives, purgatives, or aperients are substances that loosen human feces, stools and increase defecation, bowel movements. They are used to treat and prevent constipation. Laxatives vary as to how they work and the side effects they may have. ...

have failed.

Mechanism of action

Methylnaltrexone is a peripheral acting mu-opioid receptor antagonist, and does not cross the blood brain barrier. Methylnaltrexone has restricted access through the blood brain barrier because it is a quaternary amine, which carries a positive charge when in a solution. This positive charge increases polarity and decreases lipid solubility when compared to traditional opioid agonists used for pain treatment. The peripheral action of methylnaltrexone makes it effective for decreasing the constipating effects of opioids, without interfering with the analgesic effects (of opioids) on the central nervous system. This is the primary characteristic that makes methylnaltrexone behave differently than

naltrexone Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol use or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been ...

. Furthermore, as methylnaltrexone cannot cross the blood–brain barrier, it does not reverse the pain-killing properties of opioid agonists or cause withdrawal symptoms, but since a small portion of analgesia comes from the peripheral opioid receptors, it can increase pain from inflammatory conditions such as

arthritis Arthritis is a general medical term used to describe a disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, Joint effusion, swelling, and decreased range of motion of ...

Side effects

The most common side effects for methylnaltrexone include: * Abdominal pain *Dizziness *Vomiting *Nausea *Diarrhea

History

In 1978, a dying friend and colleague presented the late University of Chicago pharmacologist Leon Goldberg with a clinical challenge. Struggling with the pain of prostatic cancer that had metastasized to his bones, the man 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

loperamide Loperamide, sold under the brand name Imodium, among others,Drugs.co Page accessed 4 September 2015 is a medication of the opioid receptor agonist class used to decrease the frequency of diarrhea. It is often used for this purpose in irritable ...

, which acted on the opioid receptors in the gut without acting on the central nervous system, 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 Ingelheim. 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. In December 2005,

Wyeth Wyeth Pharmaceuticals Inc. was a pharmaceutical company until it was purchased by Pfizer in 2009. The company was founded in Philadelphia, Pennsylvania, in 1860 as John Wyeth and Brother. Its headquarters moved to Collegeville, Pennsylvania, a ...

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 is a disruption of the normal propulsive ability of the intestine. It can be caused by lack of peristalsis or by mechanical obstruction. The word 'ileus' derives . The term 'subileus' refers to a partial obstruction. Signs and symptoms S ...

(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). The use of methylnaltrexone (Relistor) for more than 4 months has not been studied.

Society and culture

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.

Forms

As of 2010, methylnaltrexone is supplied as an injection in trays containing seven one-dose vials containing 0.6 mL of solution. Each tray also contains seven 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 . For hospital use, vials are available separately.