Failed Arthritis Drug May Help Treat Opioid Addiction

Megan Brooks

March 16, 2018

A cannabinoid type 2 (CB2) receptor agonist that failed to ease osteoarthritis pain in a clinical trial could get new life as a treatment for opioid addiction.

In tests on mice, researchers at Indiana University Bloomington (IU Bloomington) found that the drug, known as LY2828360, may prevent opioid tolerance and physical dependence when used with opioid-based pain medications. They observed that the compound can block neuropathic pain and decrease signs of 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," lead investigator Andrea Hohmann, PhD, Department of Psychological and Brain Sciences, said in a statement.

"We already know this drug is safe for use in people, so moving into human trials will not involve as many regulatory hurdles," said Hohmann.

The study was published in the February issue of Molecular Pharmacology.

Opioid-Sparing Effects

LY2828360 lacked both toxicity and efficacy in a clinical trial of patients with osteoarthritis pain conducted by Eli Lilly and Co. However, the drug's use in treating other kinds of pain and lessening opioid dependence had not been tested until now.

"The fact that this compound wasn't effective in the clinical trial for osteoarthritis doesn't mean that it wouldn't be effective in mechanistically distinct pain states," Hohmann told Medscape Medical News.

"Our lab is interested in how CB2 receptors signal within cells and how this signaling is different for different CB2 agonists," added coinvestigator Ken Mackie, MD. "We wanted to determine if [Lilly's] failed compound signaled in a particular way that would help us better understand how to develop CB2 agonists to effectively treat pain."

Lilly shared their compound with the IU Bloomington scientists. When the researchers gave mice a low dose of the compound in combination with morphine, the animals did not develop a tolerance to morphine. That lack of tolerance remained after the compound was discontinued. In addition, when given on its own at higher doses, LY2828360 produced sustained pain relief.

In a separate experiment, the investigators gave mice either morphine alone or morphine in combination with LY2828360 and then treated the animals with naloxone, which blocks the effect of opioids and induces opioid withdrawal symptoms. Remarkably, said Hohmann, LY2828360 decreased the severity of naloxone-precipitated withdrawal symptoms.

Taken together, these results suggest that the drug could be used with opioids to prevent tolerance or as a means to wean opioid-tolerant individuals off these drugs, the researchers report.

"We think from our data that the combination of the LY compound, this CB2 agonist, with an opioid would have an opioid-sparing effect," said Hohmann.

With LY2828360, "opioid tolerance didn't develop, and opioid tolerance is something that can drive increased use and dose escalation. So the potential of using a very low dose of an opioid, a dose that would not be rewarding but still produce full suppression of pathological pain, would be very significant," she added.

In light of the rapid increase in opioid overdoses and deaths, there is a huge need for nonaddictive alternatives to opioid-based pain medication. "We hope very much Lilly or another drug company will continue to work with this drug in people," Mackie told Medscape Medical News.

This study was supported in part by the National Institute on Drug Abuse and the National Cancer Institute. The authors have disclosed no relevant financial relationships.

Mol Pharmacol. 2018;93:48-62. Abstract

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