Opiate drugs such as morphine are some of the most successful and commonly used for severe pain, whether acute or chronic. However, not only are they addictive, but they have nasty side-effects, including urinary retention, constipation and nausea and vomiting. Occasionally, respiratory depression can also occur.
The constipation results from opioid induced bowel dysfunction, which has a number of other symptoms such as reduced peristalsis and stronger intestinal sphincters. Dryer stools and slower gastrointestinal transit lead to constipation. As much as half of those using opioid analgesics for chronic pain such as cancer will develop this condition.
The main cause of these effects is thought to be peripheral action at the mu receptors in the gut wall, although central action may play a part too. A logical approach to minimising side effects in the gut would therefore be to block this mu receptor activity, and mu antagonists such as naltrexone and naloxone have been tried. However, these all cross the blood-brain barrier, which means they may also block the drugs" painkilling effects or case withdrawal symptoms.
A mu antagonist that does not cross the blood-brain barrier would thus have great potential, and Progenics developed methylnaltrexone bromide, a quaternary salt of naltrexone, which is too polar to cross the brain. It is being co-developed with Wyeth.
In a trial to investigate transit time and analgesia, 12 subjects were given intravenous methylnaltrexone (0.45mg/kg) plus morphine (0.5mg.kg), the morphine alone, or placebo.1 Transit times were 106 and 105 min in those given naltrexone and placebo respectively, compared with 163 min for those given morphine alone. Pain in response to the cold pressor test was reduced in both groups given morphine, regardless of whether the subjects also received methylnaltrexone.
A subcutaneous injection formulation would be extremely beneficial for the large numbers of patients in hospices with advanced disease such as cancer. In volunteer studies, subcutaneous doses of 0.1 and 0.3mg/kg reversed the delay in transit times induced by 0.05mg/kg of morphine.2 It was also effective orally, but much larger doses of up to 19mg/kg were needed to produce the same effect; an enteric coated tablet was also developed to release the drug only in the intestines, and proved effective at a dose of 3mg/kg.3
Phase III trials have been carried out in patients with advanced illness and opioid induced constipation. One included 154 patients with cancer, who were given 0.15 or 0.30mg/kg of methylnaltrexone, and bowel movements occurred within four hours.4 Another looked at the effects of 0.15mg/kg doses given every other day for a week, and the dose doubled if necessary in the second week.5 Almost half the subjects had bowel movements within four hours with the lower dose. None experienced opiate withdrawal, and few adverse effects were reported.