Can someone help explain the neurobiology of pain and what all interventions work on it from a biological POV

In My Humble Opinion
1

Both my parents have/had bad chronic pain due to their health issues. I have mild chronic pain. So its something I’m interested in.

If anyone has any books or scientific papers they feel are educational, feel free to post them. I’m more interested in chronic pain, but I’m also open to learning more about acute pain too.

However on the subject of pain, its best that the books and articles be as recent as possible. Science is advancing fast and what was cutting edge 10 years ago is going to leave a lot of new information out.

So here is my understanding as a general overview:

Damage occurs to the tissue. This causes immune cells to rush to the injury site and produce prostaglandins. prostaglandins trigger a pain response in nociceptive receptors, this travels along sensory neurons to the spinal cord. At the spinal cord, neurotransmitters like substance P transmit the pain message from the periperhal nervous system to the central nervous system in the spinal cord. The spinal cord takes the message up to the brain where it is processed by the somatosensory cortex, limbic system and thalamus as pain.

There are various ways to stop pain at various points along this process.

NSAIDS can prevent the creation of prostaglandins

Drugs or gene therapy that can block the NaV1.7 or NaV1.8 Nociceptors can prevent the transmission of pain signals along sensory neurons. There is work on both drugs and gene therapy to disable these sodium channels. However as a risk, if you take an oral drug you could theoretically lose all pain sensation abilities all over your body, which would put you at high risk of accidental injury.

Medications that disable the TRPV1 channel which allows calcium ions to transmit pain signals along neurons. There is a new injectable drug being worked on called RTX that overwhelms the TRPV1 channel, causing an overflow of calcium ions that basically deadens the nerves ability to send pain signals for 3-6 months. Every 3-6 months you just get a new injection to deaden the nerve again.

Anticonvulsants like gabapentinoids (lyrica or gabapentin) can inhibit substance P in the spinal cord (I think). However this doesn’t explain why other anticonvulsants like topamax or trileptal help with pain. Is any anticonvulsant that tamps down on excess neural signaling going to work to treat chronic pain?

How exactly do opioids help control pain? I know they attach to opioid receptors, but how does that translate into pain control?

What role does the mesolimbic pathway play in pain? It was my understanding that almost all euphoric and recreational drugs end up increasing dopamine transmission in the mesolimbic pathway. However almost all recreational and euphoric drugs also have analgesic properties. Alcohol, opioids, marijuana, NMDA antagonists, ether, inhalants, etc. Cocaine was originally used as a topical anesthetic and things like lidocaine and novacaine are similar to cocaine. What is the connection between recreational drugs and analgesics, is it the mesolimbic pathway or something else?

What role does heat play in treating pain? Why does applying a heat pack sometimes help? My understanding is it could be because it increases blood flow and increases lymphatic drainage, but wouldn’t that only help with acute pain, not chronic pain?

Also how would neuropathic pain work as opposed to chronic pain due to bone or tissue damage? Would NSAIDS help at all with neuropathic pain?

As far as electrical stimulation of nerves, there seem to be various devices. TENS units are OTC, but spinal cord stimulators are a medical implant.

There are various ways to disable sensory nerves. Botox, radioablation, cryoablation. Like I mentioned earlier, injection of RTX may be on the market in a few years too. But this seems like it would only help with localized pain. Conditions of overall chronic pain like CRPS or fibromyalgia probably wouldn’t benefit from this.

How does the gate control system in the spinal cord work? Are there drugs, medical implants or ways to activate this? The impression I get is that its mostly psychological methods to activate the gate control system to prevent pain signals from traveling to the brain.

What about the nerves that send inhibitory signals from the brain back to the spinal cord to suppress pain? Are there ways to activate this?

Why do drugs like clonidine help with pain? Aside from clonidine, tricyclic antidepressants and anticonvulsants, are any other prescription medications used off label for pain (aside from the on label usage of things like opioids and NSAIDs?)

Why do topical creams like methol help with pain?

Why do tricyclic antidepressants help with pain? I’ve heard of them both being used as oral medications as well as ingredients in topical creams for pain. Do they work better than other serotonin agents like SRAs or SSRIs?

2

I have only a tiny understanding of pain, but what I read was that since pain is technically inside one’s head, it unfortunately often persists long or permanently after the initial injury itself is over because the brain has become accustomed to pain and now programs itself to feel pain. At that point, it’s no longer an issue of the nerves or wound, it’s a matter of the brain’s own internal wiring, and unfortunately, that can be near-impossible or impossible to unscramble. (The specific example I read was of corneal neuralgia - one patient who did LASIK but then their body took pain signals from the eyes, made it permanent, and now the brain was programmed to feel pain 24/7 even when the eye wound had long since healed.)

I have read that, in a few instances, people were able to get relief from chronic pain by using psychedelic drugs since such drugs introduce neuroplasticity and can have sort of a CTRL+ALT+DELETE effect on a brain that’s suffering something chronic, but this approach is extremely unpredictable and risky.

3

Thanks for that info. I found this article, i can look through it.

https://www.sciencedirect.com/science/article/pii/S0028390823001181

It does add yet another recreational drug that helps treat pain though. It seems like almost all recreational drugs also act as analgesics including benzodiazepines and hallucinogens too. I wonder if there is a universal mechanism or if its just a coincidence.

4

These are all excellent questions to which you will find incomplete, speculative, and often contradictory answers in the literature, and effective chronic pain management is one of the most problematic areas in medicine from a practical standpoint.

The book below is a summary of current research and understanding of pain from both a neurophysiological, medical pathology, and treatment standpoint; I haven’t yet read the book but at just over two hundred pages it is pretty short, written for the reasonably well-informed layperson, and covers all of the various aspects of research that I’m aware of. The technical literature often delves in the arcana of neuroscience and physiology of sensory and neuropathic pain and generally offers a limited scope with necessarily incomplete conclusions.

The Brain and Pain: Breakthroughs in Neuroscience

Stranger

5

My system does weird things on opioids. It never relieves the pain, really.
If the pain is mild and my head has convinced me it’s worse than it really is a mild opioid will convince brain it helped. It doesn’t really.
I’ve sat and considered this, at the moment it seemed to have helped. I realized the injury was still painful. But I just didn’t feel the distress. Not exactly euphoria, just ok.

I probably don’t need to take opioids at all. I’m too susceptible to addictions. Well, really fetishes.
Which is fine for foods that I’m allowed. But not for real addictive drugs.

Then I think, what’s the reality. I doubt I’ll live another 5 years with all my afflictions. Who cares if I’m addicted. It would be a mild addiction. It’s not like they are easy to get, legally.

I had a procedure done a few days ago, afterward I had a massive headache and they gave me fentanyl. I was kinda alarmed for a few minutes.
Then I thought, what’s the worse that might happen?
I told my daughter where my will was, crossed my fingers and got the injection.
Went to sleep quickly. I dreamed my head was still hurting. It was nightmarish til I finally went into a black hole sleep.
When I woke, my head was still sore, not achey. More muscle sore.
I decided the sleep relieved the headache. The injection just put me there.

Pain is a fickle friend. It lets you know you’re not dead. Then it bites you hard and you wish you were dead.

When you live with pain everyday you get to know it’s schedule, it’s variety, it’s idiosyncrasies and try really hard to catch it unawares.

I have no studies or papers to offer you. Just my experience.

6

I have neuropathy in both feet, my left more than my right. I feel the burning/stabbing/pins and needles is attached to a squished disc in L4-L5 via my sciatic nerve. I take gabapentin for the neuropathy and hydromorphone for my back. For years now. It helps quite a bit, but I have to stay in front of it. If I let it go too long, it takes extra medicine to calm the pins and needles.

Neuropathy is the weirdest thing. Your feet feel numb, yet also burning and like they’re waking up from being asleep. It’s very uncomfortable and distracting. I can’t wear shoes because the upper part touches my feet. NOTHING should touch the tops of my feet. I can wear flip-flops. I have to time getting a pedicure just right, because I’m liable to involuntarily kick the salon girl if she touches me wrong. I’m extremely ticklish.

I wish to subscribe to your newsletter. :slight_smile:

7

I have intermittent neuropathy in my feet. I find binding socks are the best help. Isn’t it weird how different things help different people?

I feel for you. It is the strangest kind of pain.

8

On the subject of neuropathic pain in your extremities, these articles have some useful into about topical pain creams and oral supplements.

However its for diabetic neuropathy, I don’t know how much would apply to other forms of neuropathy.

Also I’ve heard mixed things about the effectiveness of compounded topical creams for neuropathy.

https://www.hmpgloballearningnetwork.com/site/podiatry/compounding-meds-diabetic-neuropathic-pain-can-they-have-impact?amp

9

Yep. YMMV, but I’ve never gotten any help from the Voltaren or other creams.

I can’t take gabapentin. I think that’s the go-to pill.

It’s hard to treat, your neuropathy pain is not my neuropathy pain…
The spasms and shocking cramps are terrible. I have itching too. It’s an itch you can’t scratch.

Altho’ I am T1 diabetic my neuropathy is postherpatic neuropathy or maybe the damage I did to my feet as young person. Or all of them together.

10

Yes but both gabapentin and pregabalin are available as topical creams too, which should avoid a lot of the side effects you’d get from taking them orally.

When you say you cant take gabapentin, do you mean you’re allergic to all forms, or you get side effects from the oral versions of it?

11

Damn, this is a good book. Its only 200 pages but its very dense so I’ve only gotten through 1/3 of it so far. But its very informative. I’m hoping the later chapters which deal with treatment will be good too.

But in the book he mentions how targets of the NaV1.7 and NaV1.8 channels aren’t really showing promise yet for treating pain, but there are clinical trials in phase 2 and 3 of various drugs designed to block these channels to treat pain.

12

Mine is diabetic neuropathy. I’ll check out the creams, and the book. Thanks, guys.

13

Looking into it further, I think there are at minimum 9 different electromagnetic ways to control pain. Obviously a lot of pain research is new and more research needs to be done, but its interesting that so many different ways to use EM to treat pain already exist.

TENS unit

Transcranial magnetic stimulation (TMS)

Vagus nerve stimulation

Deep brain stimulation

Spinal cord stimulator

Electroconvulsive therapy

Pulsed electromagnetic field therapy

https://www.sciencedirect.com/topics/medicine-and-dentistry/pulsed-electromagnetic-field-therapy#

Electromagnetic induction

Infrared and near infrared light therapy

I’m not a physicist so I don’t know if some of these technologies are the same thing. But its interesting. I mean I understand that neurons use voltage gated ion channels to transmit signals so its unsurprising that electromagnetism can be used to treat pain. But I had no idea there were at minimum 9 different kinds of EM methods to treat pain.