Failed arthritis drug appears to reduce opioid tolerance, dependence

Mar 16 2018

Failed arthritis drug appears to reduce opioid tolerance, dependence

A drug previously used to treat osteoarthritis pain may prevent opioid tolerance and physical dependence when used in combination with opioid-based pain medications, according to researchers at Indiana University.

Researchers in the Linda and Jack Gill Center for Biomolecular Science at IU Bloomington have discovered that a compound previously tested to treat osteoarthritis pain appears to block neuropathic pain and decrease signs of opioid dependence. The work is reported in the journal Molecular Pharmacology.

The drug had failed to provide relief from osteoarthritis pain, in previous human trials conducted by Indianapolis-based drug manufacturer Eli Lilly and Co. This new, Indiana University study was the first time the compound had been tested to treat other types of pain, and reducing opioid dependence.

“The potential to quickly begin using this compound in combination with opioid-based medication to treat pain and reduce addiction makes this discovery very significant,” said lead investigator Andrea G. Hohmann, a Linda and Jack Gill Chair of Neuroscience and professor in the IU Bloomington College of Arts and Sciences’ Department of Psychological and Brain Sciences.

“We already know this drug is safe for use in people, so moving into human trials will not require as many regulatory hurdles.”

To test the potential of the experimental drug to treat pain and reduce addiction symptoms, IU scientists administered the compound and the opioid morphine to male mice with neuropathic pain. While morphine initially reduced the pain, mice quickly developed tolerance to morphine’s effectiveness, similar to people who require higher doses of opioid over time to achieve relief.

However, when a low dose of the experimental drug was combined with morphine, the mice no longer became tolerant to morphine, and that lack of tolerance remained even after the experimental drug was discontinued. The researchers also found the experimental drug could provide lasting pain relief, used on its own at higher doses.

In another experiment, mice were given either morphine alone or morphine in combination with the experimental drug, and then treated with naloxone, which blocks the effect of opioids and induces opioid withdrawal symptoms. The scientists were surprised to find that the experimental drug also decreased the severity of these symptoms, Hohmann said.

Together, the results suggest the experimental drug could be used in combination with opioids to prevent tolerance, allowing satisfactory pain treatment with fewer side effects, or as a way to wean opioid-tolerant individuals off these drugs.

The researchers had decided to try the failed osteoarthritis drug as a painkiller because they had found that the compound had a unique effect on a target in the body previously proven to play a role in pain relief.

The first author on the study is Xiaoyan Lin, a postdoctoral research associate in the Gill Center for Biomolecular Science. Additional authors are Amey S. Dhopeshwarkar, assistant scientist; Megan Huibregtse, an undergraduate student at the time of the study; and Dr. Ken Mackie, Linda and Jack Gill Chair of Neuroscience and professor of psychological and brain sciences.

This study was supported in part by the National Institute on Drug Abuse and National Cancer Institute.

Last year, Indiana University officials launched a new response to the opiate epidemic, the Responding to the Addictions Crisis Grand Challenge initiative to invest $50 million to prevent and reduce addictions in Indiana.

Using the resources of IU’s seven campuses across the state, and in partnership with state officials, IU Health, Eskenazi Health and others, officials said the statewide effort represents one of the nation’s largest and most comprehensive state-based responses to the opioid addiction crisis, and the largest led by a university.

The Responding to the Addictions Crisis initiative is intended to bring together the expertise of the university’s faculty, along with a number of business, nonprofit and government partners. The goals are to develop and implement a comprehensive plan to reduce deaths from addiction, ease the burden of drug addiction on Hoosier communities, and improve health and economic outcomes.

Indiana is one of four states where the fatal drug overdose rate has more than quadrupled since 1999.