Methylnaltrexone was invented in 1979 by the late University of Chicago pharmacologist Leon Goldberg, who wanted to help a dying friend who suffered from morphine-induced constipation. Goldberg started with naltrexone, an established drug that completely blocks the effects of morphine. He altered the drug slightly by attaching a methyl group, which changed the charge of the molecule so that it could no longer cross the protective barrier that surrounds the brain.
Consequently, it did not interfere with morphine's effect on pain, which is centered in the brain, but it did block morphine's effects on gut motility, which are mediated by receptors in the peripheral gastrointestinal tract.
It worked like a charm for his dying friend, who shared the drug with several of his friends also suffering from cancer. Its initial success in this compassionate-use setting drew the notice of Goldberg's colleagues. After Goldberg's demise, they continued to develop the compound, testing it in animals, performing the initial human safety trials and a completing a series of pre-clinical studies in volunteers.
In this JAMA study, rather than risk interrupting pain relief for patients with terminal cancer, the researchers focused on 22 volunteers who were enrolled in a methadone maintenance program for opioid addiction. All 22 suffered from opioid-induced constipation, which affects about 60 percent of long-term methadone users. The volunteers averaged 1.5 bowel movements a week.
Eleven of the 22 subjects received low doses of intravenous methylnaltrexone and 11 received a placebo. Ten of the 11 who received the drug had an immediate laxation response following the first infusion and all 11 responded to a second infusion on day two.
"By immediate response we mean you did not want to be between the
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Contact: John Easton
jeaston@mcis.bsd.uchicago.edu
773-702-6241
University of Chicago Medical Center
18-Jan-2000