Opioids increase risk of chronic pain – potentiate pain – faster, stronger, longer. Activate TLR4 receptor on microglia, blocked by low dose naltrexone (LDN)

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Professor Linda Watkins was the distinguished keynote speaker at the May 2015 American Pain Society annual meeting and gave the NIH 2015 Kreshover Lecture:

“Targeting Glia to Treat Chronic Pain: Moving from Concept to Clinical Trials.”

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The University of Colorado at Boulder describes her work: 

She has authored or co-authored over 190 book chapters, review articles and journal articles.

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Dr. Watkins’ research focuses on 3 inter-related areas. Her primary research interest is understanding how to control clinically relevant pathological pain states. Her group’s research points to a novel reason that clinical pain has been impossible to successfully control. That is, pathological pain is being created and maintained by a surprising cell type, namely glia. These cells, upon activation, dysregulate normal pain processing by the spinal cord neurons.

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Medical News Today published news of her recent study April 19, 2018

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“Opioids may increase risk of chronic pain.” They potentiate pain “faster, stronger, longer” and activate the TLR4 receptor on microglia. That receptor is blocked by low dose naltrexone (LDN).

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Opioids trigger inflammation in the brain and spinal cord. This is an elegant study by renowned Prof. Linda Watkins at the University of Colorado Boulder, with Peter Grace. His early work on LDN brought him from Australia to postdoc at her lab and now research at MD Anderson Cancer Center.

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“Having been used in one form or another for millennia, opioids beat pain into submission, quickly making the patient more comfortable. The latest study, which was carried out at the University of Colorado Boulder, turns this firmly held notion on its head.

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Senior author Prof. Linda Watkins, from the Department of Psychology and Neuroscience, says, ominously, “[…] there is another dark side of opiates that many people don’t suspect.”

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In this case, it is not addiciton issues that Prof. Watkins is referring to. Paradoxically, opioids may actually prolong pain following surgery. The results were published recently in the journal Anesthesia and Analgesia.

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Postsurgical pain and opioids examined

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For the study, Prof. Watkins and colleague Peter Grace, of MD Anderson Cancer Center in Houston, TX, carried out laparotomies on male mice. This procedure involves making an incision through the abdominal wall to access the interior of the abdomen, and it is done on tens of thousands of U.S. individuals each year.

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“Opiates are really effective for acute pain relief. There is no drug that works better. But very little research has been done to look at what it is doing in the weeks to months after it’s withdrawn.”

Peter Grace

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Following surgery, one group of rats received the equivalent of a moderate dose of morphine for the next 7 days, while another group received morphine for 8 days, and the dosage was tapered off by day 10.

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Another group was given morphine for 10 days, after which point treatment stopped abruptly. A final group was given saline injections rather than morphine as a control.

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And, in another experiment, a group of rats received a 7-day course of morphine that ended 1 week before surgery was carried out.

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Before the morphine regimes commenced, and after they had been completed, the rats’ sensitivity to touch was measured, as was the activity of genes related to inflammation in the spinal cord.

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Compared with rats given saline, those that received morphine endured postoperative pain for over 3 additional weeks. Also, the longer the morphine was provided, the longer the rats’ pain lasted.

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The study also revealed that tapering of morphine dosage makes no difference. As Grace explains, “This tells us that this is not a phenomenon related to opioid withdrawal, which we know can cause pain. Something else is going on here.”

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How can morphine raise postoperative pain?

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The next question to ask, of course, is what drives this counterintuitive effect. Prof. Watkins calls it the result of a “one-two hit” on glial cells.

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In the brain, glial cells are more numerous than neurons. They protect and support nerve cells and, as part of their role as protector, they direct the brain’s immune response, including inflammation.

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The first “hit” occurs when surgery activates glial cells’ toll-like receptor 4 (TLR4). Prof. Watkins calls these “not me, not right, not O.K.” receptors; they help to orchestrate the inflammatory response. This first hit primes them for action when the second hit occurs.

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The second hit is morphine, which also stimulates TLR4. As Prof. Watkins explains:

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“With that second hit, the primed glial cells respond faster, stronger, and longer than before, creating a much more enduring state of inflammation and sometimes local tissue damage.”

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Although the study is in an animal model and will need replicating in humans, it does line up with previous findings.

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For instance, in 2016, the same scientists published another animal study, which found that a few days of opiate treatment for peripheral nerve pain exacerbated and prolonged pain. In that study, the activation of inflammatory pathways was also implicated.

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“An unusually high number of people end up with postoperative chronic pain,” explains Prof. Watkins. In fact, millions of U.S. individualssuffer with chronic pain. “This new study lends insight into one explanation for that.”

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Interestingly, the rats that received a course of morphine that ended a week before surgery did not experience prolonged postsurgical pain, leading the study authors to conclude that there is “a critical window for morphine potentiation of pain.”

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Because opioids are currently considered the best course of action to deal with postoperative pain, if these results are replicated in humans, it leaves medical science in a difficult situation.

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This is why Prof. Watkins is focusing much of her energy on designing drugs that could be given alongside opioids to dampen down the inflammatory response. She is also exploring alternative painkillers, such as cannabinoids.”

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