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The Proteins of Pain: Part 3, Spice Therapy (Member Post)

 •  • by Paul Ingraham
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This is part three of what has turned out to be a three-part series about the smallest functional units of sensation: the proteins that help us feel threatening extremes of temperature and pressure, the discovery of which (about 20 years ago) recently won a Nobel prize.

Today I will zoom in on the TRPV1 receptors, which react not only to scalding heat, but also spice, inflammation, and cannabinoids — which is what makes them super interesting at the least. But can this knowledge help pain as well as tickle your brain? Maybe.

Illustration of three colourful chili peppers: red, green, and yellow.

The capsaicin in chili peppers stimulate TRPV1 receptors. So does heat. So do some molecules of inflammation. This overlap produces some fascinating implications.

Spice therapy: mild, medium, hot!

There are, of course, many possible clinical implications of the “proteins of pain,” and this could turn into an eight-part series if I’m not careful. But for now we’ll just consider the big one, spice therapy, the use of capsaicin to manipulate sensation mediated by TRPV1 receptors.

The general idea here is that capsaicin can trigger TRPV1 receptors with a strong but relatively harmless stimulus. That main idea breaks down into four more specific ones that have been used to explain capsaicin as a pain medication. They correspond roughly to dosage and the intensity of burning pain produced:

  1. 🌶 Mild — Small doses of capsaicin can feel pleasantly warm, simulating a heating pad with biochemistry. This is the most basic rationale for spicy body rub products like A535: they just feel nice. Heat you can apply wherever you like and walk around with easily is just more convenient that stuffing a hot water bottle into your shirt.
  2. 🌶🌶 Medium — Capsaicin in a dose high enough feel to like a mild burn — and we know from part 2 of this series that this is literally what it feels like — may be a particularly good way to “distract” the nervous system because of the unique combination of safe but intense sensation.
  3. 🌶🌶🌶 Hot — Capsaicin in substantial and repeated doses may “burn out” TRPV1 receptors, reducing their population and sensitivity, which in turn reduces the amount of signalling they can produce in response to other noxious stimuli — like inflammation.
  4. 🌶🌶🌶🌶 Insane! — Capsaicin in large doses is a mild neurotoxin, which may produce a more profound effect, shrivelling TRPV1-containing nerve endings like salted slugs.

All of these mechanisms have been used to justify spice therapy over the years, but they all have the same basic form: applying capsaicin to the skin.

Review: the proteins of pain so far

Before we dig into the details, let’s recap some of the most relevant highlights from the last two posts in the series:

  • “Transduction” is the conversion of physical forces into nerve impulses, and proteins are the main transducers.
  • “Noxious stimuli” are, critically, not usually noxious — just potentially noxious, depending on the degree and context of the stimulus.
  • The TRPV1 protein triggers nerve impulses in response to scalding heat, acidic conditions, inflammatory molecules, and spice. The Piezo1 and Piezo2 do it for pressure and stretch.
  • These proteins produce lots of data about harmless warmth and pressure, but they also react to dangerous extremes of temperature and force, which are nearly always experienced as painful.
  • TRPV1 detects heat that is around the threshold of what’s threatening (40˚C) but the exact amount of stimulation required to trigger an alarm varies with context and variables like the source, extent, and rate of exposure.
  • What constitutes threatening mechanical force is even more dependent on context and complex variables, but we are “optimized” for detecting puncture threats: rapidly applied focal pressure is very painful, often out of proportion to any actual danger (e.g. stepping on a Lego piece in the night).
  • People have wildly variable pressure tolerance in massage, probably because there are so many complex biological and contextual variables involved. Massage therapists need to understand that many people are “super pressure feelers” (for reasons we don’t understand).
  • Capsaiscin, the molecule that makes chili peppers spicy, also triggers TRPV1 receptors. In high doses, it can “convince” your nervous system that you have actually been severely burned, despite all contextual clues to the contrary. This has a variety of fascinating implications.
  • I had a bizarre personal experience with capsaicin: no effect for hours, and then strong burning in the middle of the night! This emphasizes the potential hazard.

And now for the spicy details of using capsaicin therapeutically.

Heat in a tube: mild spice therapy 🌶

Ointments and balms like Tiger Balm, RUB A535, Deep Heat, Zostrix and many others are not actually hot, but literally feel like it, because they stimulate the TRPV1 receptors that also respond to scalding heat.

Other than contextual clues, our nervous systems literally have no way of telling the difference. A little capsaicin feels like a mild burn, like the early stages of a sunburn.

That can feel “nice” to us.

These burning sensations are widely regarded as therapeutic! The rationale for this is not immediately obvious, and the popularity of these remedies precedes our comprehension of TRPV1 ion channels by most of human history. But it’s also still not clear that we understand if or why they are helpful.

They can feel nice though. They are indeed “warming.” And humans do like a bit of that. Heat rarely works miracles for any kind of pain… but I would also never want to give it up as an option. Mild spice therapy is perfectly justifiable in that spirit.

Red rub, red rub! The rubefaciants

These nostrums are sometimes classified as “rubefaciants” (and there’s your word-of-the-day) because many of them cause reddening of the skin. Not all them. In fact, this is not actually due to capsaicin, which — surprisingly — does not actually turn the skin red.

I put a good dose of pure capsaicin on my arm an hour ago just to make sure. It’s completely invisible. I can feel it, but I cannot see it. Higher concentrations will certainly do it (photo), but not OTC products.

However, many of these products contain other compounds that do increase superficial circulation, for whatever it’s worth. It’s also worth noting that many of them do not actually contain capsaicin at all, including classic Tiger Balm (although the company does make other products that contain it).

Is red skin worth anything? Probably not. “Increasing circulation” is tediously overused explanation for why all kinds of treatments work (like massage), but a lack of circulation is rarely the problem, and increasing circulation to a meaningful degree is rarely possible in any case.

Counterstimulating with capsaicin: medium spice therapy 🌶🌶

“Distracting” the nervous system from pain is another classic rationalization for how therapy works, much like increasing circulation. It’s probably more legitimate, however.

“Sensory distraction” is a common oversimplified way of splainin' how this works.

The underlying mechanism is that one sensation can “pre-empt” another one to some degree. This is known as counterstimulation, and it is certainly a real thing — it is firmly based on the well-known neurological principle of “gate control” (see the classic paper, Melzack 1965). The canonical example is the way we instinctively rub tissue around acute minor injuries.

If we counterstimulate with a noxious stimuli, it’s counter-irritation.

Counterstimulation is a real thing, but not an especially potent thing. You could call it another tool for the pain treatment toolbox, but it’s not an impressive tool. Maybe just like a small screwdriver or a tack hammer.

But counterstimulation with capsaicin might be different.

Potent but safe? Premium counter-irritation

There are lots of potent but hazardous sources of counter-irritation. Hitting your hand with a hammer would also be an impressively effective counter-irritant, but I don’t recommended it.

The discomfort of capsaicin overdose can be shockingly intense while remaining almost perfectly safe (another weird thing about capsaicin, discussed in more detail in the last post). That combo of a strong source of sensation that is also actually safe might make capsaicin a more premium counter-irritant than other options — more irritating! More countering!

If capsaicin is a good counter-irritant, it strongly suggests a promising usage strategy: don’t just apply capsaicin to the body part that hurts. Apply it in in patches nearby, as well as other patches distributed around your body. Give your body multiple “burns” to process. I think it’s quite likely that this strategy would be more efficacious. Naturally this hypothesis has never been tested.

Down-regulation station: hot spice therapy 🌶🌶🌶

We can become more or less sensitive to stimuli by a variety of mechanisms. Nerves fire in response to specific chemicals. The number of receptors they have for specific chemicals is “regulated,” and they can be regulated “up” or “down.” If you flood a nerve with too much with a specific chemical, it will get “numb” to it — by downregulating the number of receptors for it.

Clever system.

TRPV1 receptors can be downregulated if persistently drenched in capsaicin. Nerve cells exposed to lots of capsaicin start reacting to it less over time. And if the nerve cells have downregulated their populations of TRPV1 receptors… then they have also become numb to scalding heat. And that works, which we have known for decades (see Simone). But it's also not very useful.

But if that works, then they may also get numb to inflammatory triggers — and that might be extremely useful (but has never been demonstrated, as far as I know).

It’s not clear how long it takes, but it’s quite a while.

And it’s not clear how much capsaicin this takes, but it’s more than just a little. Simone et al. used 0.075%, three times more than the concentration I struggled with. And low-dosages might actually backfire and cause sensitization — an effect that has been demonstrated! See LaMotte et al.

And there are probably many unknown and unknowable variables affecting all of that in different ways for different people at different times.

But the general principle is sound: it’s almost impossible not to downregulate TRPV1 receptors if you just throw enough capsaicin at them.

And there’s another interesting mechanism that’s probably at work: a lot of capsaicin probably also changes how the TRPV1 protein behaves, making it less responsive to more capsaicin — just pure biochemistry, a quirk in how the protein changes in response to a lot of capsaicin. So they can probably be downregulated and desensitized.

An example: how capsaicin might help a problem like tendinitis

This is how I rationalized using capsaicin on my own Achilles tendinitis recently:

  1. My tendons are persistently inflamed. (Yes, they are: inflammation has been demonstrated in chronic tendinitis, despite the popular contrary view that they are “not inflamed.”)
  2. At least part of the reason that they hurt is that my TRPV1 receptors are responding to the presence of molecules of inflammation. (There is undoubtedly more to it, of course.)
  3. If I flood that superficial tissue with capsaicin, I might reduce the population of TRPV1 receptors and desensitize the remainder — and so I might also not feel the inflammation as intensely.

But the burning of the capsaicin was just too severe — and too weird with it’s timing, surging in the middle of the night — so I gave up after only a couple of days. I probably didn’t get to the “downregulated” and “desensitized” part. 🤷🏻‍♂️

Barfing interlude: what does capsaicin have to do with violent vomiting?

Cannabis can cause a severe and surprisingly non-rare serial vomiting problem called “cannabinoid hyperemesis syndrome.” (Seriously. See Marijuana for Pain.)

It probably does this by “burning out” TRPV1 receptors (downregulation again)… which are sensitive to cannabinoids! (In addition to scalding heat, capsaicin, and inflammation!) No one knows for sure, but that’s the most likely reason. Widespread downregulation of TRPV1 receptors causes vomiting! Maybe. The details are hazy.

These tragic patients — it really is an awful thing — habitually self-treat with the hottest showers and baths they tolerate. They may be trying to compensate for the lack of TRPV1 receptor activity with a different and strong source of stimulation for them.

So… how about capsaicin? That’s another source of strong stimulation for TRPV1 receptors! Gold star if you saw this coming. See Moon et al for a good technical summary of the rationale (there’s a nice diagram I can’t use, because copyright).

The logic is simultaneously based on some seriously advanced biology … and yet it kinda boils down to “well, let’s try to give those TRPV1 receptors a good kick,” like Fonzi bashing an appliance.

Alas, it doesn’t seem to work terrible well, despite the clever rationale (see McConachie et al). But it is, at least, a really interesting idea.

Insane spice therapy (actually a thing) 🌶🌶🌶🌶

“I say we take off & nuke the entire site from orbit. It’s the only way to be sure.”

Ellen Ripley, Aliens

Earlier I called over-the-counter topical capsaicin a tool, but an unimpressive one, “maybe a small screwdriver.” But the dosage makes the poison. If the dose is small enough dose to feel mild, it’s probably not doing much; and if it’s doing something, it probably doesn’t feel mild! So, how much capsaicin to make it into a crowbar?

High-dose capsaicin has actually gotten some high fives and thumps on the back from science (Derry) specifically for treating neuropathic pain with disturbingly high doses. How much are we talking about?

8% capsaicin. Compare that to .025% capsaicin in a typical over-the-counter product — like the one that I put on my Achilles tendinitis. 8% is three hundred and twenty times more.

Even far saner dosages can be extremely intense sensory experiences. It’s important to understand that this will make you feel as if you’ve been badly burned. This isn’t user-friendly medicine. It isn’t something you can do for yourself, or would want to: “It must be applied under highly controlled conditions, normally under local anaesthetic, due to the initial intense burning sensation it causes.” For pity’s sake, why?

You have to be desperate.

Post-herpetic neuralgia as the perfect target for high-dose capsaicin

Shingles is notoriously painful, but do you know what’s worse? Shingles pain that keeps going, long after the rash and blisters are gone: post-herpetic neuralgia, one of the most vicious of all chronic pain syndromes. Of course it varies in severity, but for some patients it really is just like the shingles never really ended. 😱

Despite all the misery I have endured from fibromyalgia (unexplained chronic widespread pain), I know that it’s nothing compared to “infinite shingles.” People with post-herpetic neuralgia are willing to do almost anything to try to shut those nerves up. Including a third degree burn. “Kill it with fire”!

Or at least something that feels like that. Like high-concentration capsaicin.

Capsaicin as a neurotoxin

The idea with high-concentration capsaicin is to shoot past mere “downregulation” and have a more profound effect on the neurons — downright neurotoxic in fact, poisoning them, actually making their tips shrivel and retreat from the insane stimulus. This does happen (see Kennedy et al). Interesting stuff.

But does it work clinically? Does poisoning those nerve endings translate into a reduction of neuralgia?

It actually does for a select few. According to Derry et al, some people do quite well with this approach — while most do not. There’s probably some genetic or biological x-factor, something we can’t identify in advance.

This is not promising for the average mediocre pain problem. But, if I had post-herpetic neuralgia, I’d probably roll that dice.

Do tolerable doses achieve anything for typical aches and pains?

Clinical efficacy of non-insane spice therapy

We’ve discussed multiple plausible and interesting mechanisms for pain relief from mild, medium, hot, and insane dosages of spice therapy. But we have half decent efficacy data only for the insane dosages.

Welcome to the science of pain, where hardly anything that normal people actually do for their pain is ever properly tested.

The same folks who reviewed high-concentration capsaicin also reviewed low-concentration and found the evidence to be “very low quality and typically limited to single studies or comparisons with sparse data” (see Derry et al).

Notably, even low concentration capsaicin caused lots of adverse events and withdrawals of study subjects compared to placebo. That’s what happened to me with my heels. If I’d been in a study, I would’ve dropped out, because yikes. And that was with .025% capsaicin.

A 2018 review was slightly more optimistic, concluding that capsaicin seems to be roughly as good for as common over-the-counter medications, but also noted the “limited and poor quality evidence” (Persson et al).

If you don’t mind risking feeling a bit burned, capsaicin is probably worth a shot, and real harm is unlikely if you exercise any caution at all — capsaicin’s bark is way worse than its bite. But it’s also not likely to deliver much relief, and I’ll wager it’s just going to be a clean miss with lots of types of pain.

And that concludes our 6600-word whirlwind tour of protein-inspired pain science.
My article about therapeutic heat has had only very basic coverage of the topic of spice therapy for many years now, and yet I have always known that it was biologically intriguing subject matter — and the whole point of PainScience.com content is to delve into stuff like this. Really wrapping my head around this topic was long overdue, and the Nobel prize finally pushed it to the top of my writing list.

And now it is done. I “grok” TRPV1 proteins, sorta, finally! Achievement unlocked.

Sort of? Each of these posts took me about 6-8 hours of studying and writing and processing shower brainstorms. I looked at dozens of scientific papers. I estimate that I now know at least three percent of everything there is to know about the TRVP1 and Piezo1 and Piezo2 receptors, their many cousins, and how they relate to pain experiences and treatments.

It’s a start…