What Is Relistor (Methylnaltrexone)? Why Do Opioids Cause Constipation?

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Main Category: Pain / Anesthetics
Also Included In: Palliative Care / Hospice Care;  Cancer / Oncology;  COPD
Article Date: 28 Jul 2009 - 0:00 PDT

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Relistor (Methylnaltrexone) is a medication for patients who suffer from constipation caused by opioid drugs. Opioid drugs are used for pain relief. An opioid is a chemical that binds to opioid receptors that exist mainly in the central nervous system and the gut (gastrointestinal tract). When people take opioids they have a lower perception of pain, a lower reaction to pain, as well as a higher pain tolerance - in other words, opioids provide effective pain relief. However, opioids also cause constipation.

The distress of constipation will usually add to the suffering that has already been caused by pain. Patients may start to reduce their intake of their opioid because the constipation causes so much discomfort - some may stop altogether. Many patients find themselves in a Catch 22 situation.

Before looking at Relistor in more detail, here is some background information on opioids and opiates:

What is the difference between an opioid and an opiate?

Opiates are derived from the natural ingredients of opium, while Opioids include the entire family of opiates, as well as synthetic and semi-synthetic substances. An opioid is any substance which activates opioid receptors - molecules that exist on the membranes of nerve cells found mainly in the central nervous system and the gut.

There are four main types of opioids:

• Endogenous opioids - our bodies produce them. Examples include endorphins, enkephalins, dynorphins, and endomorphins.


• Opium alkaloids (natural opiates) - such as morphine, codeine and thebaine.


• Semi-synthetic opioids - such as diamorphine (heroin), hydromorphone, oxycodone and buprenorphine.


• Fully synthetic opioids - such as fentanyl, pethidine, methadone, tramadol and propoxyphene.

Doctors tend to use just the word opioid.

Examples of strong opioid drugs

• Morphine - the main active ingredient is Papaver somniferum(opium poppy). It is commonly used for pain in cancer, myocardial infarction, sickle cell crisis, trauma, kidney stones, severe back pain, palliative care (relieving pain without curing underlying cause). It is also used as an adjunct (addition) to general anesthesia, in epidurial anesthesia, and intrathecal analgesia (painkiller injected into the fluid surrounding the brain and spinal cord). Morphine is also used to treat chronic diarrhea associated with AIDS.


• Diamorphine - also known as heroin. It is a semi-synthetic opioid drug synthesized from morphine. Diamorphine is prescribed in the United Kingdom for the treatment of acute pain in myocardial infarction, post-surgical pain, and chronic pain caused by cancer. It is given via subcutaneous, intramuscular, intrathecal or intravenous route. After a shortage in the UK in 2005 many hospitals switched to morphine. After the shortage was over, a significant number of hospitals did not switch back.


• Fentanyl - Fentanyl is generally used to treat post-operative, chronic pain, and breakthrough pain (acute pain on top of persistent background pain). Many see Fentanyl as the first choice for use for pain in cancer patients.


• Alfentanil - it is an analogue of Fentanyl. It has only 1/10th of the potency of Fentanyl and only lasts for about 1/3 of the time. However, it starts working four times faster than Fentanyl. It is sometimes used for patients who cannot tolerate morphine, diamorphine or oxycodone due to persistent side effects.


• Buprenorphine - it is a semi-synthetic opioid. It is used for the treatment of moderate to severe chronic pain. Its transdermal formulations are commonly used for chronic cancer pain, musculoskeletal pain (muscles, tendons and ligaments along with the bones), and neuropathic pain (chronic pain resulting from injury to the nervous system).


• Oxycodone - synthesized from opium-derived thebaine, a minor constituent of opium with stimulatory rather than the depressive effects which are found in morphine. It can be an alternative to morphine for cancer pain. It is also used to treat pain in diabetic neuropathy, postherpetic neuralgia, osteoarthritis, ambulatory laparoscopic tubal ligation surgery, unilateral total knee arthroplasty, and abdominal gynaecological surgery.


• Hydromorphone - also known as dihydromorphinone and dimorphone. It is a derivative of morphine. It is used to relieve moderate to severe pain, and is well known for treating painful, dry cough. In many cases it is preferred over morphine because of its superior solubility, rapid onset (starts working faster), milder side-effects, and lower dependence risk. It is much stronger than morphine as a painkiller.


• Methadone - it is used as an analgesic (painkiller), and antitussive (cough suppressant). It is also used as a maintenance anti-addictive medication for patients on opioids. It is commonly used in the treatment of chronic pain because it is cheap and lasts a long time. However, blood concentrations of methadone fluctuate significantly between dosing - unlike oxycodone, it is not technologically engineered for sustained release.

Examples of weak opioid drugs

• Codeine (methylmorphine) - it is used for the treatment of pain, coughs, and diarrhea. Codeine is a very popular medication for people with back pain. It is the most widely used opiate, and perhaps the most commonly used overall. It is said to have between 8% to 12% of the strength of morphine. However, people's individual metabolisms may alter its potency, as can some medications.


• Tramadol - this a synthetic opioid with a chemical structure that is quite different from those of opiates. It is commonly used to treat moderate to moderately severe pain and most types of neuralgia (pain along the course of a nerve), including trigeminal neuralgia (inflammation of the trigeminal nerve, causing intense lightning pain in the lips, eye, nose, scalp, forehead, gums, cheek and chin). Some believe it could be effective for some types of depression and anxiety treatments. It is also used off-label for diabetic neuropathy, postherpetic neuralgia (long term pain linked to shingles), fibromyalgia, restless leg syndrome, opiate withdrawal management, migraine, OCD (obsessive-compulsive disorder), and premature ejaculation. In veterinary medicine it is used for post-operative, injury-related, and chronic cancer pain.

Some types of weak opioids are OTC (over-the-counter, no prescription required) medications.

A short history of Relistor

In 1978, Dr. Leon Goldberg, a pharmacist at the University of Chicago, was presented with a challenge by one of his colleagues. A patient whose prostate cancer had metastasized to his bones would not take morphine for pain, because it would cause unbearable constipation. The colleague's challenge was a simple one - Was there anything that could be done to help the patient? i.e. create a medication to treat the constipation without undermining the painkilling effects of the opioid.

This would mean an opioid that would target only the sub-types of receptors associated with pain relief but without the side effects - one of which was severe constipation. Up to then, with the exception of in-vitro models, there had not been much success in finding one.

Dr. Goldberg noticed that medications that acted on the opioid receptors of the digestive system, such as loperamide, and did not cross into the brain were already available. Could they find an analogous opioid receptor antagonist (a similar opioid that blocked the action of the receptor)? In simple terms - could they find a drug that relieved constipation without entering the brain which would neutralize morphine's painkilling effects? Thousands of opioid-like molecules had been made by the pharmaceutical industry in its attempts at trying to find better painkilling medications. Many of the molecules that had been shelved had no pain-relieving properties.

(*an antagonist blocks against or stops an action. As opposed to an agonist which stimulates an action)

Goldberg and team screened many compounds. This led to the examination of molecules that were assumed to be antagonists but did not cross the brain barrier (did not get into the brain).

Borhringer Ingleheim, a German pharmaceutical company, had synthesized N-methyl-naltrexone (MNTX) and it seemed to be a promising compound. In 1979 MNTX passed initial screening in which mice were given opioids as well as charcoal meals to track their passage through the gastrointestinal tract, and tested for their analgesia (inability to sense pain without losing consciousness). A study carried out by Russell and team in 1982 on dogs reported that constipation caused by opioids could be prevented without affecting pain relief in this model ("Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists." European Journal of Pharmacology 78: 255-261).

Further tests demonstrated how the MNTX could stop constipation, as well as the cough reflex. MNTX was later found to have potential for the treatment of nausea caused by opioids. Unfortunately, Dr. Goldberg died before he could see where his research would eventually lead to.

The Department of Anesthesiology and Critical Care at the University of Chicago continued researching into methylnaltrexone throughout the 1990s.

In 2005, two pharmaceutical companies - Wyeth and Progenics - signed an exclusive, global agreement to jointly develop and commercialize methylnaltrexone for the treatment of opioid-induced side effects, including:

• Constipation
• Post-operative ileus - a proportion of the intestines becomes paralyzed typically after abdominal surgery; food and drink cannot be pushed forward in that part of the intestine.

Relistor is approved

Relistor was approved for the treatment of opioid -induced constipation in the following countries:

• In April, 2008 - approved by Health Canada.
• In April, 2008 - approved by the US Food and Drug Administration (FDA).
• In July, 2008 - approved by the European Commission (EMEA), representing 27 countries.

How does methylnaltrexone work?

• Opioids stop pain but also numb the digestive tract and reduce digestive secretions
  
  An opioid, such as morphine, kills pain by numbing the receptors in the brain. However, it also numbs the receptors in the digestive system. If the nerves in the digestive system are numbed, the muscles there will not propel undigested food and stools (it will not push the food and feces along properly). The slower the food moves through your digestive tract, the more water the colon will absorb from food. Consequently, the stools (feces) become dry and hard, leading to constipation.
  
  Opioids also cause contractions in the jenunum - the middle of the small intestine - to increase. These contractions are non-propulsive ones; they do not push the food forward.
  
  Opioids also numb the stomach to some extent, slowing down the digestive system even longer.
  
  Opioids reduce digestive secretions as well. This decreases a person's urge to defecate (the urge to poo is much weaker). If somebody delays going to the toilet the stools will continue losing water and become harder and drier, resulting in constipation.


• Relistor (Methylnaltrexone) blocks the numbing in the intestines
  
  Methylnaltrexone binds to those receptors in the gut, blocking morphine's effects on them - so that they are not numbed any more. This means that the muscles in the gut can react normally again.


• Relistor (Methylnaltrexone) does not block the opioids' painkilling effects
  
  Methylnaltrexone does not cross the brain barrier - it does not enter the brain. Morphine's painkilling effects inside the brain continue to work. Morphine's effects on the receptors inside the brain are what give it, and all other opioids, their painkilling qualities. If methylnaltrexone did enter the brain it would be useless because it would neutralize all morphine's effects, including its painkilling ones - the patient would be in pain again.

How effective is Relistor?

Two Randomized, double-blind, placebo-controlled clinical studies
In a double-blind clinical study, neither the doctor nor patient knows who is receiving the real drug, and who is getting the placebo. In a placebo-controlled clinical trial, some patients receive a placebo, others receive the real drug (Relistor), and the results are compared. In a randomized clinical trial, the patients are selected randomly (by chance) to receive either Relistor or a placebo.

• 62% of patients receiving Relistor in one clinical study, and 48% of patients in the other study had a bowel movement (went to the toilet successfully) within 4 hours of the first injection.


• 30% of patients receiving Relistor reported a bowel movement within 30 minutes of a dose of Relistor in both studies.

Written by Christian Nordqvist


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