Methylnaltrexone bromide (Relistor) may reverse OIH/tolerance

[drusso]

http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4262.html

https://med.stanford.edu/news/all-n...nd-to-limit-opioids-side-effects-in-mice.html

Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia

• Gregory Corder,
• Vivianne L Tawfik,
• Dong Wang,
• Elizabeth I Sypek,
• Sarah A Low,
• Jasmine R Dickinson,
• Chaudy Sotoudeh,
• J David Clark,
• Ben A Barres,
• Christopher J Bohlen
• & Grégory Scherrer

• Affiliations
• Contributions
• Corresponding author

Nature Medicine

(2017)

doi:10.1038/nm.4262

Abstract

Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia and drive dose escalation. The cell types and receptors on which opioids act to initiate these maladaptive processes remain disputed, which has prevented the development of therapies to maximize and sustain opioid analgesic efficacy. We found that μ opioid receptors (MORs) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA sequencing and histological analysis revealed that MORs are expressed by nociceptors, but not by spinal microglia. Deletion of MORs specifically in nociceptors eliminated morphine tolerance, OIH and pronociceptive synaptic long-term potentiation without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, was sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support the idea that opioid agonists can be combined with peripheral MOR antagonists to limit analgesic tolerance and OIH.

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[epidural man]

How can they say microglia doesn't express MORs? ( I didn't read the article by the way - just your post).

 

[drusso]

How can they say microglia doesn't express MORs? ( I didn't read the article by the way - just your post).

"Working in mouse models, Scherrer and his colleagues found that tolerance and increased sensitivity to pain may be specifically caused by opioids’ effect on peripheral pain neurons in the body, not those in the spinal cord or brain. They also established that contrary to the prevailing view in the field, microglia — non-neuronal cells found in the spinal cord and brain — are not initiating opioids’ side effects because they lack the gene that forms the receptors necessary to cause them."

 

[epidural man]

"Working in mouse models, Scherrer and his colleagues found that tolerance and increased sensitivity to pain may be specifically caused by opioids’ effect on peripheral pain neurons in the body, not those in the spinal cord or brain. They also established that contrary to the prevailing view in the field, microglia — non-neuronal cells found in the spinal cord and brain — are not initiating opioids’ side effects because they lack the gene that forms the receptors necessary to cause them."

well here we go!

 

[Ducttape]

so the implication is that just by adding Relistor, we can eliminate OIH, and patients by default should see improvement in those symptoms?

will we be giving Relistor to high dose opioid therapy patients as a means of justifying maintaining people on these doses due o OIH?

 

[EtherBunny]

so the implication is that just by adding Relistor, we can eliminate OIH, and patients by default should see improvement in those symptoms?

will we be giving Relistor to high dose opioid therapy patients as a means of justifying maintaining people on these doses due o OIH?

In principle, the relistor could be administered when tolerance comes into play and (fingers crossed) PREVENT escalation in dosage that leads to OIH. Also, the patients on high dose opioid therapy may be able to taper to lower daily requirements if the tolerance issue is mitigated. Interesting findings!

 

[drusso]

so the implication is that just by adding Relistor, we can eliminate OIH, and patients by default should see improvement in those symptoms?

will we be giving Relistor to high dose opioid therapy patients as a means of justifying maintaining people on these doses due o OIH?

I think that the problem one is trying to fix/prevent is OIH. Escalating doses cause OIH. This, of course, needs to be studied in a control fashion in humans. Relistor could be opioid-sparing and reduce the unwanted side-effect of OIH.

 

[Ducttape]

so far, I am not finding that patients that get put on Relistor are that much better off from their pain standpoint.

course, I use it on limited circumstances (mostly cancer pain patients) otherwise - opioid reduction surprisingly enough works much better at reducing constipation.

 

[lobelsteve]

Dose reduction for any side effects makes more sense.

 

[PainDrain]

"Working in mouse models, Scherrer and his colleagues found that tolerance and increased sensitivity to pain may be specifically caused by opioids’ effect on peripheral pain neurons in the body, not those in the spinal cord or brain. They also established that contrary to the prevailing view in the field, microglia — non-neuronal cells found in the spinal cord and brain — are not initiating opioids’ side effects because they lack the gene that forms the receptors necessary to cause them."

So first off, not to get particular, but this isn't true. It isn't that they lack the gene but they do not express the gene according to what he is stating. Having not read the article, I would have hoped they did either northern or western blot analysis or perhaps microarray analysis to show the lack of gene expression.

Second, I attended a talk by a researcher regarding chronic pain and microglial activation. In one of the slides they showed microglia become hyperactive when exposed to long term doses of opiates and that this effect was blunted and reversed by administration of intrathecal naltrexone. I believe the current hypothesis is that microglial activation is initiated by a secondary messanger produced by cells which express the opioid receptor and have been exposed.

 

[drusso]

So first off, not to get particular, but this isn't true. It isn't that they lack the gene but they do not express the gene according to what he is stating. Having not read the article, I would have hoped they did either northern or western blot analysis or perhaps microarray analysis to show the lack of gene expression.

Second, I attended a talk by a researcher regarding chronic pain and microglial activation. In one of the slides they showed microglia become hyperactive when exposed to long term doses of opiates and that this effect was blunted and reversed by administration of intrathecal naltrexone. I believe the current hypothesis is that microglial activation is initiated by a secondary messanger produced by cells which express the opioid receptor and have been exposed.

"Glia as bad guys" was the article that changed everything, but clearly there is so much more we need to learn about treating/preventing OIH. I think precision-medicine and regenerative medicine interventions will point us in the right direction.

http://www.thblack.com/links/rsd/brainbehavimmun2007_21_131_improveopioidutility.pdf

http://www.nature.com/articles/srep32096