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CBD Substitute Shows Promising Pain-Relieving Effects in Mice

By Alexander Beadle

Published: May 12, 2021   
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Patients with chronic pain are routinely prescribed opioid medications to manage their symptoms. But for many, these opioids can come with their own set of problems, ranging from lowered productivity at work to severe problems with opioid addiction and abuse. There is also limited scientific evidence supporting the idea that opioids can effectively attenuate long-term pain.

Because of these issues, opioid medications are no longer recommended as a treatment for chronic pain in some parts of the world. But with opioids out of the question, there is an urgent need to find alternative routes of treatment for patients with chronic pain. In recent years, there has been much interest in whether CBD’s pain-relieving effects could be used to fill this treatment gap.

Now, new research from scientists at Temple University suggests that KLS-13019, an analog of CBD, may be even more promising for long-term pain management than CBD itself.

The problem with CBD

Consumers of CBD products frequently report using the drug to address problems with acute or chronic pain. But whether CBD is actually helpful or not is still hotly debated. Large clinical doses of CBD have been shown to relieve pain in a number of human studies, with commercially available hemp oils having been successfully used in animal studies to relieve neuropathic pain. Published last month in the journal Experimental and Clinical Psychopharmacology, a new blinded study also determined CBD’s effects on acute pain to be down to more than just the placebo effect.

However, in a recent review of studies looking at the use of cannabis extracts in cancer-related pain, the extracts performed no better than a simple placebo.

“I think there is great interest in cannabinoid medicines from the general public at the moment,” Mike Bennett, a professor of palliative medicine at the University of Leeds and co-author of the review, told Analytical Cannabis at the time. “But in cancer pain, using this particular product, we can't see a positive benefit.”

While the effectiveness of CBD to treat different types of pain is up for debate, there remains a central fundamental problem with CBD being used as a painkiller – it is limited by its low natural bioavailability. This means that it can take large doses of CBD for enough of the cannabinoid to be absorbed into the bloodstream, and then reach the site of action where it is needed.

Some have tried to solve this bioavailability problem by using novel nanotechnology-based drug delivery systems. Now, this new work from the Temple University researchers suggests that the bioavailability problem might be overcome though using the novel CBD analog, KLS-13019.

A comparison of CBD and KLS-13019.

KLS-13019 is one of the most promising neuroprotective CBD analogs currently being investigated by scientists. It has a modified side chain in its chemical structure, which studies suggest makes it both more potent and more bioavailable than CBD itself. Encouraged by these initial studies, the team at Temple University sat out to examine whether the CBD analog might also be more well-suited to tackling pain.

CBD analog reverses sensitivity to painful stimuli

Specifically, the researchers were interested in how CBD and KLS-13019 might affect pain in an animal model of chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a common side effect with certain types of cancer treatment which can damage the peripheral nerves. These nerves would normally carry sensory information to the arms, legs, and brain, and so the nerve damage often results in pain, tingling or burning sensations, or weakness in these limbs.

In this new study, laboratory mice were orally or intraperitoneally administered CBD, KLS‐13019, or morphine, in a series of experiments designed so that the researchers were able to assess the animals’ sensitivity to painful stimuli.

The researchers found that pain sensitivity was greatly reduced in the animals with CIPN that were treated with KLS-13019 or CBD. Additionally, KLS-13019 was able to reverse sensitivity to painful stimuli in the animals in which CIPN was already established, where CBD could not.

“In a mouse model of chemotherapy-induced peripheral neuropathy (CIPN), we’ve been able to show for the first time that KLS-13019 works as well as, if not better than, CBD in preventing the development of neuropathy and reversing pain sensitivity after pain has been established,” Sara Jane Ward, PhD, an assistant professor of pharmacology at the Katz School of Medicine and senior investigator on the new study, said in a statement.

Given the existence of previous studies linking CBD use to reductions in opioid craving, the Temple University researchers also decided to assess whether either cannabinoid had any effect on the opioid-seeking behaviors exhibited by the morphine-treated animals.

“Many patients who use opioids for pain management enter a cycle of reinforcement, where each use of opioids triggers reward pathways and perceived pain relief, leading to addiction,” Dr Ward explained.

The researchers did not find evidence supporting any role for CBD in reducing opioid cravings. However, they did observe significantly reduced opioid-seeking behavior in the animals given KLS-13019.

“This tells us that KLS-13019 has benefits beyond its ability to alleviate pain,” Dr Ward added.

The researchers hypothesize that KLS-13019 and CBD might share a mechanistic pathway for pain relief, but that KLS-13019 could have an additional mechanism through which it is able to effect opioid cravings. Moving forwards, the research team plans to investigate these mechanistic nuances, and to also assess the effects of KLS-13019 on other types of pain.


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