The widespread efficacy of opioids in treating patients with moderate to
severe acute and chronic pain is often accompanied by untoward side
effects. In particular, opioid-induced bowel dysfunction is one of the
more common and debilitating consequences afflicting up to 50% of
patients. To counteract the peripherally-mediated adverse effects, opioid
antagonists such as naloxone, naltrexone, and nalmephene are sometimes prescribed. The latest market entry exploits a strategic
modification of naltrexone to lower its lipid solubility and increase its
polarity: quaternization of the amine of naltrexone by methylation
(methyl bromide) prevents crossing of the blood–brain barrier thereby
creating an effective peripheral antagonist. Despite a loss of potency
upon methylation, methylnaltrexone antagonizes opioid binding at
m-opioid receptors with an IC50 of 70 nM. Its affinity for k-opioid receptors
is approximately eightfold less (IC50＝ 575 nM) with no significant binding
to d-opioid, orphanin, or non-opioid receptors. Methylnaltrexone bromide
has been approved for the treatment of opioid-induced constipation in
patients with advanced illness receiving palliative care.Regarding metabolism, methylnaltrexone bromide is eliminated primarily as intact drug (85% based on administered radioactivity) by slightly more renal than hepatic clearance.
The most common adverse events were abdominal pain and flatulence followed by nausea, dizziness, and diarrhea.
