1. Belavic, Jennifer M. PharmD

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The FDA recently approved the novel agent, methylnaltrexone bromide (Relistor) marketed by Wyeth, for the treatment of opioid-induced constipation. This agent gives patients on chronic opioid therapy an option that may help improve their symptoms of constipation, as well as their quality of life.


Opioid-induced constipation

Patients who use opioids continuously for pain management are at risk to develop or experience sedation, respiratory depression, impaired orthostatic pressure, loss of appetite, pruritus, constipation, and ileus.1,2 Constipation is the adverse reaction that occurs most frequently and affects the patient's quality of life. It occurs in almost half of all patients who have advanced cancer and in over 85% of patients on opioid treatment.3 Constipation is only part of a multifactorial problem list that is encompassed as opiate-induced bowel dysfunction (OBD). OBD is also characterized by an accumulation of gas and retention of stomach contents by decreasing gastrointestinal (GI) secretions. This leads to hard stools, incomplete evacuation, bloating, pain, and increased reflux, as well as nausea and vomiting.3


Prophylactic laxative therapy is used in patients taking chronic opioid therapy to prevent OBD. If the patient develops constipation, additional laxatives that have different mechanisms of action will be prescribed to relieve symptoms. Examples of these agents include docusate, senna, and bisacodyl. Sometimes, laxative therapy does not help. In these cases, a new agent, methylnaltrexone bromide, was developed to treat OBD since it is hypothesized that this effect is mediated by the peripheral mu receptors.3 With limited ability to cross the blood-brain barrier, it functions in tissues such as the GI tract to inhibit opioid-induced delay of GI transit time while maintaining analgesic effects on the central nervous system.



Methylnaltrexone bromide is administered as a subcutaneous injection, and is a selective mu-opioid receptor antagonist indicated for the treatment of opioid-induced constipation. In particular, methylnaltrexone bromide can help patients with advanced illness who are receiving palliative care when response to laxative therapy has not been effective.4,5 Methylnaltrexone bromide is a novel therapy that provides patients experiencing opioid-induced constipation a therapeutic option that may help improve symptoms, in addition to quality of life.


Mechanism of action

Methylnaltrexone bromide is a water-soluble quaternary ammonium derivative of naltrexone. Naltrexone, an opioid antagonist, has the ability to cross the blood-brain barrier. This can cause pain and opioid withdrawal due to the blockage of the central mu-opioid receptors.6 The methyl group added to the nitrogen ring on naltrexone increases the polarity of methylnaltrexone bromide, and decreases its ability to cross the blood-brain barrier.3,7,8 Due to this mechanism, methylnaltrexone bromide affects the peripheral mu-receptor as an antagonist in the GI tract, which in turn decreases constipation without affecting the opioid actions of the central nervous system, brain, and spinal cord.5,9



Methylnaltrexone is absorbed rapidly, achieving a peak concentration after approximately 0.5 hours, and is 11-15% protein-bound. The terminal half-life of methylnaltrexone is approximately 8 hours. It is eliminated mainly as the unchanged drug with half excreted in the urine and less in the feces.5


Contraindications and precautions

Methylnaltrexone is contraindicated in patients who are diagnosed with known or suspected mechanical GI obstruction.4,9 It has been noted that methylnaltrexone can cause severe diarrhea. If this occurs, the medication must be stopped and the patient should contact a healthcare provider immediately.5 Methylnaltrexone bromide is a pregnancy category B drug. It is not known whether the drug is excreted in human milk.5


Adverse drug reactions

Methylnaltrexone bromide has a limited adverse reaction profile. Through all the clinical trials, the noted adverse events were abdominal pain, flatulence, nausea, dizziness, and diarrhea.4,5 Therapy should be stopped if severe or persistent diarrhea occurs.


Methylnaltrexone is not metabolized by CYP450 enzymes. Drug interactions between methylnaltrexone and medications that are actively secreted by the kidney have not been evaluated yet in humans.5


Dosing and administration

It is recommended that one dose be administered every other day as needed, up to a maximum of one dose every 24 hours.5 A dose of methylnaltrexone bromide should be injected subcutaneously in the abdomen, upper arm, or thigh.4


The dosing of methylnaltrexone bromide is determined by the patient's weight. The usual dosing is either 8 or 12 mg, depending on if the patient's weight falls between 38 and 62 kg, or 62 and 114 kg, respectively. Any weights not in these ranges are dosed at 0.15 mg/kg4,5 (see Dosing recommendations for methylnaltrexone).


Special considerations/Patient education

As a healthcare provider, it is important to consider all aspects of methylnaltrexone bromide treatment, as well as provide your patients with the correct information to make therapy more complete. Keep the following in mind when prescribing methylnaltrexone bromide therapy:


* Methylnaltrexone bromide has been shown to be effective in about 50% of the patients who develop opioid-induced constipation while on palliative care.6


* It is important to note that patients who use methylnaltrexone bromide may develop laxation within 4 hours after administration (sometimes as early as 30 minutes).6 Be sure to instruct your patients to be near a bathroom when methylnaltrexone bromide is administered.


* Patients should be informed that the usual dosing schedule of methylnaltrexone bromide is every other day, on an as-needed basis. The patient should not use the drug more than once in a 24-hour period.5


* The most common adverse reactions that patients may experience include abdominal pain, nausea, and vomiting. These reactions are transient and should not be a problem as therapy continues.5 If these adverse reactions persist or progressively worsen, it is important that the patient knows to inform the healthcare provider immediately.


* Another adverse reaction of methylnaltrexone bromide is diarrhea. The patient should inform the healthcare provider if diarrhea is severe or persistent and should stop using the medication immediately.5


* Methylnaltrexone bromide therapy must be stopped when opioid pain medication is discontinued.5


* Since methylnaltrexone is a subcutaneous injection that the patient may self-administer, proper technique must be taught to every patient prescribed this medication. The injection must be given in the thigh, abdomen, or upper arm.5





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9. Progenics and Wyeth announce FDA has approved Relistor. [Context Link]