Opioids Increase Pain Through Endotoxin Receptor, Minocycline Reverses The Effect

haidut

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Most people here know Peat's opinion about opioids due to their effects on histamine, estrogen, and promoting tissue growth. A few weeks ago I posted a link in regards to the so-called "endotoxin receptor" known as TLR4, and how opioids are the main class of substances that activate that "receptor".
This study found that chronic consumption of opioids actually increases sensitivity to pain, by promoting inflammation through that same TLR4 "receptor". Quietly, and without much fanfare in the news, the same group of scientists is running a clinical trial with minocycline as it is apparently capable of completely blocking that effects of opioids AND also acting like painkiller itself. This is not surprising as minocycline (and the other tetracyclines, as well as potentially methylene blue, vitamin K, emodin, beta lapachone, etc) is a potent antagonist of TLR4. In addition, minocycline seems to target the CNS more than any other antibiotic, and the CNS is the primary site of opioid effects and inflammatory targets.


http://www.sciencemag.org/news/2016/05/why-taking-morphine-oxycodone-can-sometimes-make-pain-worse
"...There’s an unfortunate irony for people who rely on morphine, oxycodone, and other opioid painkillers: The drug that’s supposed to offer you relief can actually make you more sensitive to pain over time. That effect, known as hyperalgesia, could render these medications gradually less effective for chronic pain, leading people to rely on higher and higher doses. A new study in rats—the first to look at the interaction between opioids and nerve injury for months after the painkilling treatment was stopped—paints an especially grim picture. An opioid sets off a chain of immune signals in the spinal cord that amplifies pain rather than dulling it, even after the drug leaves the body, the researchers found. Yet drugs already under development might be able to reverse the effect. It’s no secret that powerful painkillers have a dark side. Overdose deaths from prescription opioids have roughly quadrupled over 2 decades, in near lockstep with increased prescribing. And many researchers see hyperalgesia as a part of that equation—a force that compels people to take more and more medication, while prolonging exposure to sometimes addictive drugs known to dangerously slow breathing at high doses. Separate from their pain-blocking interaction with receptors in the brain, opioids seem to reshape the nervous system to amplify pain signals, even after the original illness or injury subsides. Animals given opioids become more sensitive to pain, and people already taking opioids before a surgery tend to report more pain afterward."

"...The authors propose that the nerve damage and the morphine delivered a kind of one-two punch to cells in the spinal cord called microglia—sentinels of the nervous system that scout for infection. Microglia release inflammatory signaling molecules into the spinal cord, which activate neurons that shoot pain signals up to the brain. Previous studies have shown that opioids make microglia more sensitive to activation. In the new study, the authors found that morphine activates a specific group of signaling proteins in microglia, collectively known as an inflammasome. That’s not likely to be the only mechanism behind hyperalgesia, Apkarian notes. But in the study, inhibiting microglia—by inserting a gene for a receptor that makes them susceptible to a deactivating drug—reversed the pain-prolonging effect in morphine treated-rats, as did blocking certain proteins in the inflammasome. Researchers are already exploring drugs that interrupt this pathway to treat pain or improve the performance of opioids. A clinical trial recently launched at Yale University, for example, will test whether an antibiotic that inhibits glial cells prevents the inflammatory effects of opioids. And Linda Watkins, a CU Boulder neuroscientist and senior author on the new study, co-founded a company to develop a chronic pain treatment that blocks one of the signaling proteins in the inflammasome, called toll-like receptor 4."

The clinical trial with minocycline referred to by the study above. I wonder how long before minocycline gets pulled from the shelves due to an application for "alternative use" or being labeled as a blockbuster drug for an "oprhan condition".
The Effects of Minocycline in Opioid-maintained Patients - Full Text View - ClinicalTrials.gov

If TLR4 antagonists are viable treatment for pain this means all of the substances I mentioned above are a potential safe painkiller. I would add cyproheptadine, Benadryl, and mianserin / mirtazapine to the list as they also block TLR4.
If opioids induce and promote chronic brain inflammation and their use is skyrocketing, this could explain (at least partially) the recent boom in neurodegenerative conditions like ALS, which of course minocycline is also known to treat. It also shows how opioids are a perfect drug for Big Pharma since the more you use it, the more it promotes inflammation and increases sensitivity to pain and the more of that drug you need to control that pain.
Oh, and one last thing. Good old sodium is an opioid antagonist and as such may be a cheaper and safer OTC option for the people looking to block the effects of opioids. But I don't know sodium also blocks TLR4. It would be really awesome if it did. If somebody here knows please chime in. Hey, @tyw any clues?
Sodium (Salt, Soda, Etc) Acts Like Naltrexone
 

tyw

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heh, I dunno :bag:. First, we are broadly talking about 2 separate systems here:
  • Opioid Receptors -- specifically those associated with nervous system tissue
  • Toll-Like Receptor 4 (and Toll-Liker Receptors in general) -- all of these are in sentinel cells, which means that they are functionally and location specific (I'll get back to this point later)
NOTE: I hate it when authors use terms like "inflammasome" :punch:. Words like that provide zero context as to what inflammation is for, and does not distinguish between what is a useful and not-useful inflammatory response .....

I personally view the 2 systems I listed above as completely distinct systems o_O, which cannot be grouped into a simple "inflammasome" category

----
Regarding compounds like morphine, we'll usually be referring about the µ-opioid receptors and the κ-opioid receptors. (that's 'mu' and 'kappa' respectively upload_2016-6-19_7-56-43.png)

The literature is complex here, but I think it's fair to say that activating these 2 classes of opioid receptors acts to "shut down transmission".

The total signal magnitude (rate of nervous system firing x number of signals fired) is what is responsible for a "pain response".

It then makes sense that chronic overuse of a compound like Morphine, will lead to down-regulation of receptor activity (through reduction of gene expression needed for these opioid receptors to be activated). It is then likely that the nervous system ramps up the signalling sensitivity in the face of lower receptor activity.

Then when the opioid receptor activating is removed, receptor activity bounces back to normal levels before the nervous system can down regulate it's now-increased sensitivity, and more pain is the result.

Now, this is purely referring to signal transmission now. Pain is basically a damaged system component sending a "danger signal" to the rest of the body. There is no pain if there is no damage (assume a working nervous system here pleez ;)), and there is no pain if there is no way to transmit the signal.

The Pain-killers here are purely about inhibiting the signal. This doesn't solve the initial root cause of the signal, though it can stop any systemic side effects that would worsen the problem.

This is why I go "this is complex as hell :arghh:". I have no clue how to quantify whether a systemic pain response is harmful or not. It usually is, but then again, the treatment using a brute-force strategy like these often-prescribed opioid compounds is also not the complete answer.

This is also why I think a statement like "Opioids promote brain inflammation" needs to be qualified some more. It is more likely that opioids prime the nervous for excessive activation IN THE FACE OF STRESSORS. If there is no stressor, then this doesn't become a problem. If there is a stressor, then the chronically opioid-dosed individual is prone to over-react, with symptoms as bad as seizures. Of course, most people are chronically stressed, so this becomes a moot point.

Personal example -- 6 years ago I got a right-biased herniation in L3-L4 (between lumbar vertebrae discs 3 and 4). The context was improper form on what should have been a light deadlift of 135kg (max was 165kg at the time). Basically had 2 years of radiating pain in that region, plus I refused to take any sort of medication whatsoever :bigtears: (which was all that doctors seemed to know how to do). Note that telling patients to "suck it up" isn't a viable strategy in most cases.

I was already right-side dominant on my movement patterns due to a history of throwing sports in high school, but this injury made that bias worse -- movement patterns adjusted to avoid painful positions, and the nervous system was trained to shorten the musculature in particular points, in a way that does not support optimal function.

Doing something like taking painkillers would not actually solve the root problem in this situation, which is so systemic in nature. The correct solution would have been to both support healing of the injured tissues, in conjunction with re-training the nervous system to move in the right way. Pavel Kolar's 'Dynamic Neuromuscular Stabilization', in conjunction with red light therapy is probably the right approach here.

This is all to say that: Pain-killing is just a single tactic. The real goal is holistic treatment of the underlying pathology, whatever that may be. Discussion of tactics must be qualified by the context that the tactics are used in.

-----

On to Toll-like Receptors, like I mentioned, these are in sentinel cells -- those are built for defence of invading compounds.

(Image from wikipedia -- File:Toll-like receptor pathways revised.jpg - Wikimedia Commons)

People familiar with the bio-mechanic would recognise the following diagram as a depiction of your typical generic inflammatory cascade (mediated through MyD88 and TRIF).

upload_2016-6-19_8-36-41.png

In this sense, the use of TLR4 antagonists for Pain-killing is only useful if the root cause of the pain is an attack perceived by Sentinel Cells. ie: It probably wouldn't help as much in my cases of blunt trauma. It probably would help in cases where pain is made worse by environment toxins (anything from endotoxin to direct infectious agents, to smoke from your car's exhaust)

I personally think that TLR4 antagonists also serve to "shut down the immune system" to some degree. Is this a good thing? :shifty: I have no clue, though I am biased to say that there may be some transient alleviation of symptoms, while leading to long term loss of resilience.


As for sodium, I think that is a completely different mechanic, because it allows for all of the regulator inflammatory cascade to continue, while only adding extra controls to select parts of the system. This is basically support for endogenous immune function and nervous system regulation. Philosophically, I like that sort of approach better :oldman:

....
 

jaa

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Interesting stuff!

@tyw

OT - did you use any DNS therapy? If so, do you have any resource recommendations? I have a bit of thoracic rotation I'm trying to fix and this DNS stuff is appealing. I've had some success with Original Strength which shares a similar principle of copying infant to child movements for body restoration.
 

tyw

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Interesting stuff!

@tyw

OT - did you use any DNS therapy? If so, do you have any resource recommendations? I have a bit of thoracic rotation I'm trying to fix and this DNS stuff is appealing. I've had some success with Original Strength which shares a similar principle of copying infant to child movements for body restoration.

I bought the original resource by Dr Kolar -- Clinical Rehabilitation textbook

It's a long book that acts as a reference, and not a prescription. It is recommended that you find a practitioner who knows what they are doing. eg: I got to hang out with Mark McGrath and Josh Lamaro down in the Southern Surf Coast some time ago, and talk about everything from movement patterns to spirituality, as well as get a demo of a mini treatment ;) -- http://www.markmcgrath.com.au/

But I don't personally see a practitioner (because of where I live). All I do is personal application of basic principles to particular movement patterns.

.....
 

michael94

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Low dose naltrexone alone is a great case for tlr4 antagonism, but the dose and timing has to be right. More is not better. Niacinamide and astragalus are also good for these purposes, but not as potent as Ldn i dont think. All have an immune boosting effect.

Edit immune normalizing would be a better description
 

jaa

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I bought the original resource by Dr Kolar -- Clinical Rehabilitation textbook

It's a long book that acts as a reference, and not a prescription. It is recommended that you find a practitioner who knows what they are doing. eg: I got to hang out with Mark McGrath and Josh Lamaro down in the Southern Surf Coast some time ago, and talk about everything from movement patterns to spirituality, as well as get a demo of a mini treatment ;) -- Mark McGrath — BodyBalance | Functional Movement | Postural Stability | Sports Performance | Therapeutic Yoga | Ontological Coaching

But I don't personally see a practitioner (because of where I live). All I do is personal application of basic principles to particular movement patterns.

.....

Cool. Thanks for the direction :hattip
 

kaybb

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Low dose naltrexone alone is a great case for tlr4 antagonism, but the dose and timing has to be right. More is not better. Niacinamide and astragalus are also good for these purposes, but not as potent as Ldn i dont think. All have an immune boosting effect.

Edit immune normalizing would be a better description
This also got me thinking of LDN. I am starting it as treatment for chronic pain (fivromyalgia) hoping to get off pain meds. Does anyone know how it actually works or fits into this study?
 
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There is also an excellent theory that Doidge talked about in his book The Brain's Way of Healing (exceptional book). The theory is that our brains acclimate to pain and recruit more neurons to feel pain. That the brain can gateway "off" pain actually, but painkillers chronically used habituate the brain to accepting and feeling pain and as more neurons are recruited to the pain, to accentuate pain.

I dealt with this by trying some things out and I believe there is truth to it. That's why chronic pain often gets worse and worse even when someone takes painkillers.

I've found great success with Open Focus by Dr. Fehmi, in dealing with pain myself without medication, and basically making it go away. It doesn't always work 100% but it often does, and the more you do it, the easier it gets.
 

kaybb

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There is also an excellent theory that Doidge talked about in his book The Brain's Way of Healing (exceptional book). The theory is that our brains acclimate to pain and recruit more neurons to feel pain. That the brain can gateway "off" pain actually, but painkillers chronically used habituate the brain to accepting and feeling pain and as more neurons are recruited to the pain, to accentuate pain.

I dealt with this by trying some things out and I believe there is truth to it. That's why chronic pain often gets worse and worse even when someone takes painkillers.

I've found great success with Open Focus by Dr. Fehmi, in dealing with pain myself without medication, and basically making it go away. It doesn't always work 100% but it often does, and the more you do it, the easier it gets.
I want to look into this. Sounds interesting, thanks
 
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I want to look into this. Sounds interesting, thanks

interestingly in the Doidge book, the exemplar (a doctor who had a terrible accident) insisted on opiods immediately so as not to acclimate his brain to pain, then used his techniques to basically close the gateway of pain into his brain. Shut this down, and the brain feels no pain. The gateway to pain can be shut down completely, apparently. But once you get into a pain cycle, not so easy.

However, my own experience now with Open Focus is that this is pretty easy to learn and it works even if you are feeling pain. In fact I discovered we carry emotional and physical pain ALL the time in very specific parts of our bodies. Our approach is to distract, ignore and try to live life without attending. But that approach doesn't work to a great degree becuase the pain exerts its impact on us. With Open Focus, I look directly at the pain, encourage it, try to increase it, and it fades away because its job (alerting the mind/body to something in an alarm state) has been done, I suppose. But Open Focus lets you bring pain into your world and it disappears as soon as you do.
 

kaybb

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interestingly in the Doidge book, the exemplar (a doctor who had a terrible accident) insisted on opiods immediately so as not to acclimate his brain to pain, then used his techniques to basically close the gateway of pain into his brain. Shut this down, and the brain feels no pain. The gateway to pain can be shut down completely, apparently. But once you get into a pain cycle, not so easy.

However, my own experience now with Open Focus is that this is pretty easy to learn and it works even if you are feeling pain. In fact I discovered we carry emotional and physical pain ALL the time in very specific parts of our bodies. Our approach is to distract, ignore and try to live life without attending. But that approach doesn't work to a great degree becuase the pain exerts its impact on us. With Open Focus, I look directly at the pain, encourage it, try to increase it, and it fades away because its job (alerting the mind/body to something in an alarm state) has been done, I suppose. But Open Focus lets you bring pain into your world and it disappears as soon as you do.
Are your pain issues still better ? Your feet pain? I am about to look for this book.
 

TubZy

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If one use opiates for a certain period of time and stopped, could it be possible that the TLR4 receptor is still "upregulated" per say?
 

dilantinoid

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@ Haidut - Opiateblock, new product?

I had a complete remission from my Bipolar depression with Dilantin (no longer works, maybe P-GP resistance)

Ray hypothesized Dilantin was protective against endogenous opiates.

No fatigue, zero naps, immune to depression, extremely resisant to stress, feelings of joy and joie de vivre

Any possible topical Opiate product?
 

Amazigh

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I just looked up the results of this study. Apparently it didn't work as they had hoped, but it did increase cognitive function:
Minocycline does not affect experimental pain or addiction-related outcomes in opioid maintained patients.
Minocycline does not affect experimental pain or addiction-related outcomes in opioid maintained patients. - PubMed - NCBI

RESULTS:
Minocycline treatment did not change pain threshold or tolerance on the CPT. Similarly, minocycline did not change severity of pain, opioid craving, withdrawal, or serum cytokines. Minocycline treatment increased accuracy on a Go/No-Go task.

CONCLUSIONS:
While these findings do not support minocycline's effects on OIH, minocycline may have a potential use as a cognitive enhancer for individuals with opioid use disorder, a finding that warrants further systematic studies.
 
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