Researchers identify source of opioids’ side effects – Stanford Medicine – Jan 16, 2017
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.
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.
Methylnaltrexone bromide is approved by the Food and Drug Administration for the treatment of opioid-induced constipation.
The prevalence of chronic pain in veterans is unusually high, he said. In addition to the chronic pain from such illnesses as cancer and diabetes, many veterans also face lifelong pain from battle wounds, such as traumatic brain injuries, shrapnel injuries and injuries to limbs.
“If you’re coming back from the battlefield in your 20s, what does your future look like if you are taking these drugs over the next 50 or so years of life?” he added.
Knocking out morphine receptors
At a molecular level, opioids work by attaching to specific protein-binding sites on neurons throughout the body. These sites are called mu opioid receptors.
The binding of morphine and similar painkillers, including oxycodone, fentanyl and hydrocodone, obstruct the neurons’ pain signals so that they don’t reach brain regions for pain perception.
However, mu opioid receptors are present on many types of neurons in the nerves, spinal cord and brain.
Which of these populations of receptors is specifically responsible for side effects has been unclear, preventing the development of therapeutic strategies to separate side effects from pain relief.
Based upon previous research that indicated peripheral pain neurons, known as nociceptors, may be responsible for certain unwanted side effects from opioids, the researchers hypothesized that if they could block mu opioid receptors on peripheral pain neurons specifically, they could eliminate the bad effects while keeping the good effects of the drugs.
They also concluded that the pain-relieving properties generated by opioids must occur primarily in the brain because the drugs worked without acting on the nociceptors in the altered mice.
Next, researchers showed that by using the opioid receptor antagonist drug methylnaltrexone bromide, which block mu opioid receptors in the periphery, they were able to prevent the tolerance and increased sensitivity to pain caused by opioid use while keeping the pain relief.
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.
“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.”