Morphine side-effect inhibitor – methylnaltrexone
Morphine is a highly effective analgesic agent, widely used in treating severe pain. It interacts with the opioid receptors in the brain and spinal cord. However, it has a number of significant side-effects that result from its interaction with other receptors. These include constipation, delayed gastric emptying, nausea and vomiting, pruritis and urinary retention, and these adverse effects may lead to patients being forced to reduce or even stop their medication.
An answer could be the drug methylnaltrexone, being developed by Progenics Pharmaceuticals in the US. it has been designed to prevent morphine from activating the peripheral receptors in the body. However, it has no effect at the opioid pain receptors in the central nervous system as, unlike morphine, it is unable to cross the blood-brain barrier, so the pain-relieving properties of morphine are unaffected.1 Earlier opioid antagonists, such as naloxone, naltrexone and nalmefene, can enter the central nervous system and negate the desired analgesic effect of the opioids as well as preventing the peripheral symptoms.
Initial studies were carried out on intravenous methylnaltrexone, and it was shown to prevent morphine-induced delay in gastrointestinal transit time, as well as decreasing some of the troublesome morphine-induced subjective effects. However, the drug has a very low oral availability and intravenous administration is not ideal, so being able to give the drug by subcutaneous injection would be preferable.
In a placebo controlled Phase II study in 12 healthy volunteers,2,3 subcutaneous doses of 0.1mg/kg or 0.3mg/kg were given. It significantly reduced the morphine-induced delay in mean oral–caecal transit times to near baseline rates. Five minutes after administration, morphine-induced side-effects were significantly reduced, at p<0.05 or p<0.01 respectively for the two doses, compared with the placebo. The opioid side-effects, including flushing, difficulty in concentration, skin itch, dry mouth and nausea, were assessed individually, and then combined to give a total subjective score.
Further trials are needed, but subcutaneous methylnaltrexone could well prove to be a useful addition to cancer pain therapy by reducing the side-effects of analgesic morphine.