We Need to Do Better – The Search for Opiod Alternatives

From the news desk of UC San Diego Health:

Krishnan Chakravarthy MD, PhD, a pain management specialist at UC San Diego Health and Veterans Affairs San Diego Healthcare System, believes inflammation may be at the root cause of some types of pain. He and co-authors recently published a review article in the journal Pain about toll-like receptor 4 (TLR4), a molecule that plays an important role in inflammation, and possibly pain. He also launched a clinical stage biotechnology startup company, Douleur Therapeutics, to help develop DT-001, a drug that might prevent post-operative pain by inhibiting TLR4.

Dr Krishnan Chakravarthy explains:

What are toll-like receptors?

These molecules sit on the outside surface of cells, sampling the environment for signs of bacterial infections. There are several different types of toll-like receptors, and each recognizes different molecular signs of infection by a bacterium, virus, fungus or parasite. TLR4 specifically recognizes and binds lipopolysaccharide, a molecule that many types of bacteria have in their cell walls. TLR4 molecules are found on antigen presenting cells, which are like army generals of our host immune system directing our response. Once TLR4 binds lipopolysaccharide, these cells direct the body’s immune response to attack and clear away the bacteria that set off the TLR4 alarm.

How are TLR4 and pain connected?

The four classic signs of inflammation are, in Latin, dolor, calor, rubor and tumor. In English, that’s pain, heat, redness and swelling. We know that some component of pain is due to chronic inflammation, in which cells constantly think they are under attack. And TLR4 is part of what keeps that inflammation switch “on.”

What’s more, if you take consistently higher doses of opioids over time, eventually you become hypersensitive to pain. In other words, something that shouldn’t cause pain causes excessive pain in the chronic setting. There’s increasing evidence that TLR4 plays a role there, too, counteracting this opioid-induced hyperalgesia pathway.

How are you targeting TLR4 as a means to alleviate pain?

There are a number of small molecules and antibodies that target TLR4 receptors. But, interestingly, only a small subset of these have actually been tested in clinical trials. We wanted to start with something that has a higher chance of success, so we’re repurposing a drug that has already made it to Phase III clinical trials, where it was being tested as a treatment for sepsis. The drug was safe, but it was discontinued because it wasn’t all that effective for that particular use.

DT-001, as we now call the drug, can bind TLR4, preventing lipopolysaccharide from binding and triggering inflammation and pain. We think DT-001 will be useful for preventing persistent post-operative pain — in a truly disease-modifying way, not just in a way that masks the symptoms. DT-001 could also further reduce the need for opioids after surgery, since by blocking TLR4 activity a patient may be less likely to become hypersensitive to pain.

What still needs to be done to bring this to market?

DT-001 already cleared a phase I clinical trial for safety when delivered intravenously. We’re now fundraising for a phase II trial to test how well it can prevent post-operative pain. We hope to begin recruiting patients for that in the next three to four months. Meanwhile, we’re also bringing additional drugs into our pipeline and we’re testing other modes of delivery for DT-001.

Why is this important?

There are approximately 1.6 million surgeries per year in the U.S., and post-op pain can occur in up to approximately 60 percent of patients. This is a major health issue. Yet at the moment there are no great ways to prevent post-op pain. We can prescribe opioids before and during surgery, but there isn’t a lot of evidence that they’ll help with a patient’s post-op pain.

To make matters worse, certain high doses of opioids sedate patients and because they affect the entire body, they can become highly addictive for some patients. In non-palliative settings, studies show that the benefits of chronic opioids don’t outweigh the risks. So you go to a different class of pain relievers. But even with non-opioid classes of medications, you continue to deal with higher doses needed for desired therapeutic effects, with side effects being a major issue in patient use of these medications.

The reality is that if you ask pain physicians today to look at all the other options we have for pain relief — local anesthetics, NSAIDs, neuropathic pain relievers such as Gabapentin, Lyrica or Tri-cyclic antidepressants — the reality is nothing works well for preventing pain.

We need to do better.


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