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Stanford University School of Medicine

Existing drug found to limit some side effects of opioids in mice

military-men-569899_1280David Clark, MD, PhD, believes that opioid painkillers are not only a safety concern for patients — with risks of addiction and possible overdose — they also just don’t work very well.

“They don’t in general provide substantial pain relief for a long period of time,” said Clark, who leads the pain service at VA Palo Alto Health Care System. He said his patients regularly return to ask for increased doses of prescription painkillers such as oxycodone and hydrocodone because their pain returns.

He is co-author of a new study published in Nature Medicine that shows in mouse models that the use of a commercially available drug can almost eliminate two common side effects of opioids — a growing tolerance and a paradoxical increased sensitivity to pain — without reducing its painkilling properties. If the results can be replicated in humans, it could mean a world of difference for the veterans he treats, Clark said.

Based on previous research, the authors of the study postulated that at the molecular level, painkillers binding to neurons on the periphery of the body cause these two unwanted side effects, while the pain relief occurred at sites in the brain and spinal cord.

To test their theory, they injected morphine into both normal mice and a group of mice in which the receptors on these peripheral neurons had been knocked out. They found that when they injected the drugs chronically, pain relief actually lasted much longer in the knock-out mice compared with the normal mice. Their conclusion: the action of morphine on the periphery was causing the growing tolerance to the drug in the normal mice.

They then found a drug that worked to block these peripheral binding sites. As Gregory Scherrer, PhD, Pharm.D, senior author for the study, explains in our release:

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.

For Clark, who treats veterans with chronic pain, one of his priorities is to find medicine that can relieve this pain without facing the risks of addiction and overdose. In addition to the pain from such illnesses as cancer and diabetes, veterans face lifelong pain from battle wounds, such as traumatic brain injuries, shrapnel injuries and injuries to limbs. As Clark says in the release, "If you’re coming back from the battlefield in your 20's, what does your future look like if you are taking these drugs over the next 50 or so years of life?"

Previously: A real medical problem: a Stanford physician reflects on treating patients with opioid addictions, Drug dealer MD: a look at the opioid epidemic and Shifting the focus from opioids to life beyond pain: A Q&A with pain expert Beth Darnall
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