Stanford researchers said they have identified the receptors to which opioids bind to produce tolerance to the drugs and increased sensitivity to pain. They also found that a commercially available drug limited those side effects in mice.

A commercially available drug may help drastically reduce two side effects of opioid painkillers – a growing tolerance to them and a paradoxical increased sensitivity to pain – without affecting the drugs’ ability to reduce pain, according to a study by researchers at the Stanford University School of Medicine.

These two side effects often mean patients require higher doses of opioids to maintain pain relief, increasing the risk of addiction and respiratory failure.

“In some patients, you don’t have much margin between how much painkiller you can give and their ability to breathe normally, or the occurrence of other significant side effects,” said Gregory Scherrer, PhD, PharmD, assistant professor of anesthesiology, perioperative and pain medicine and of neurosurgery. “Our goal was to understand how opioids cause their side effects, to find ways to separate these detrimental side effects from pain relief properties and to make these painkillers safer.”

Scherrer is the senior author of the study, published online Jan. 16 in the journal Nature Medicine.

Working in mouse models, Scherrer and his colleagues found that tolerance and increased sensitivity to pain may be specifically caused by opioids’ effect on peripheral pain neurons in the body, not those in the spinal cord and brain. They also established that contrary to the prevailing view in the field, microglia — non–neuronal cells found in the spinal cord and brain — are not initiating opioids’ side effects because they lack the gene that forms the receptors necessary to cause them.

By using a drug that blocks only the effects of opioids on the periphery, they were able to eliminate the two side effects without reducing pain relief.

“We demonstrate that these two side effects can be drastically reduced with co–administration of an already used compound, methylnaltrexone bromide, currently used to combat constipation, which is another unwanted side effect of opioids, while still maintaining pain relief,” Scherrer said.

Results showed that with co–administration of methylnaltrexone bromide and morphine to mice, no significant difference in pain relief occurred, but the two side effects — tolerance and increased pain sensitivity — were almost completely lost, the study said.

There’s an urgent need to test the findings of this mouse study in human trials, Scherrer said.

“This is the same drug which is used for reducing the side of effect of constipation caused by opioid painkillers,” Scherrer said, adding that the drug works by blocking neurons in the gut to stop constipation, a totally different process. “It’s a safe drug. There is great potential for translating this to the clinic.”