Detailed guides to painful problems, treatments & more

Chronic, Subtle, Systemic Inflammation

One possible sneaky cause of puzzling chronic pain

Paul Ingraham • 55m read
Close-up photograph of hot coals, representing inflammation.

Do you seem to have more than your fair share of aches and pains? It’s probably not your imagination, and there are many possible explanations for chronic pain, but this article is about one of the most insidious and interesting. It’s most relevant to you if you’re struggling with your weight and/or severe chronic stress … or if you’re just getting older. So really quite a lot of people.

Everyone over 40 knows that it gets more uncomfortable to get out of beds and chairs as we age, and we’re plagued by ever more pains that come and go without much rhyme or reason. Most people chalk this all up to “arthritis,” but that’s rarely a significant factor until much later in life.1 Conditions like fibromyalgia and myofascial pain syndrome, as common as they are, can’t account for all of it. Some medications cause widespread sensitivity as a side effect,2 but that still doesn’t explain such a widespread problem either. So what’s going on?

A little bit of inflammation spread all over the place is one possible culprit. And I have to strongly emphasize that this is an unproven idea, and there is plenty of guessing in this article: well-informed and evidence-based guessing, but guessing. Nevertheless, it may be one of the major fundamental mechanisms of vulnerability to chronic pain, along with sensitization.

Chronic low grade inflammation is increasingly seen as a part of other orthopaedic conditions such as osteoarthritis — once considered a ‘cold’ wear and tear problem (as opposed to the far more overt and ‘hot’ inflammation of rheumatoid arthritis).

Summer is coming — Frozen Shoulder, Cocks (

Why would anyone be a little bit inflamed all over?

To some extent inflammation is just a part of life, the inevitable cost of having an immune system. Just like a society must balance police and military powers against civil liberties, evolution has had to juggle the pros and cons of a potent defense system. It is obviously not all bad, and it may have been excessively demonized in recent decades.3 There’s probably always some inflammation going on somewhere in the body, and it even fluctuates in natural daily rhythms. It’s suppressed at night, for instance, which has many clinical implications, such as why morning pain may be such a familiar annoyance for humans.4

For a variety of reasons, it can get a bit out of hand. Especially as we age.

Most chronic low-grade inflammation is probably an aging thing. This has a name: it is quaintly known as “inflammaging.”5 To be old is to be inflamed! And to be inflamed excessively may be synomous with premature aging … which is probably affected by both your genes and lifestyle. Things that are unhealthy (smoking, inactivity, stress, sleep deprivation) don’t so much make you feel old as literally age you.

Exactly why we get inflamed is where the mystery lives.

It’s not the years, honey. It’s the mileage.

Indiana Jones

Metabolic syndrome

A lot of inflammaging is probably a consequence of “metabolic syndrome,” a set of biological dysfunctions strongly linked to poor fitness, obesity, and aging. It is the roots of heart disease and diabetes. And we also know that metabolic syndrome is clearly associated with at least some common pain problems, like neck pain6 and back pain.7

Or maybe it’s the other way around, and chronic inflammation drives metabolic syndrome. Definitely maybe!8

Stress and metabolic syndrome

Metabolic syndrome in turn is probably linked to severe chronic stress … or even stress that happened long ago, during childhood.9 It’s also quite possible that stress is inflammatory independently of metabolic syndrome (if they can be separated). The role of stress is too complex, indirect, and long-term for clarity, but it’s a near certainty that it does have a role. I will return to this topic below, because it’s of great importance: it suggests that chronic low-grade inflammation might not be limited to the metabolic syndrome stereotype of “old, fat, unfit.”

From here, the waters only get muddier, the speculation thicker.

Menopause is probably inflammatory

This is an example that applies to only one phase of the lives of half the population — but even though it is limited to that context, I can hardly imagine a better example of what makes inflammaging work.10 And it is probably an excellent representative example as well: it highlights that there are a variety of ways for people to get more inflamed as they age.

For instance, men also go through roughly analogous hormonal changes, so-called “manopause.” Good chance that’s at least a little bit inflammatory too!

Chronic subtle infections

Inflammaging may worsen with time as we accumulate infections and their consequences. There are many pathogens and other invaders we know about that set up shop in the human body forever — “tenants” we cannot evict. The obvious ones are famous (e.g. herpes, measles, HIV, etc). For every obvious one, there might be several subtler ones that only mildly arouse our defenses, infections that will never be diagnosed, let alone treated. As we move through life, we encounter more and more of these pathogens, some tougher than others. Accumulate enough of them, et voila, “inflammaging.”

Another scenario: there’s good evidence that a weak immune system can also allow some common minor infections to “reactivate” after lying dormant in our cells for years or even decades.11

But we may carry on suffering from infections even when we successfully fight them off.


PainSci Member Login

Submit your email to unlock member content. If you can’t remember or access your registration email, please contact me. ~ Paul Ingraham, PainSci Publisher

Privacy & Security of this form This login is private and secure: the information you submit is encrypted, used only to search for matching accounts, and then discarded.

Members-only area unlocked. See your account page.

Autoimmunity and collateral damage: antibodies are forever

Autoimmune disease was originally thought of as a baffling biological blooper: the body mysteriously attacking itself, the “why are you hitting yourself?” school of pathology.12 Some autoimmune disease may indeed be perverse self-abuse, but there is a more modern perspective, a hypothesis that autoimmune disease is mostly the price of doing business: collateral damage from unavoidable, ongoing battles with pathogens.

Or, worse, it could be collateral damage from battles that ended long ago, like stepping on a land mine from an old war.14

We make new antibodies for every pathogen (and other antigens, like allergens). Sometimes, those antibodies are not a perfect match for their target alone: they might also be match for a few of our own proteins, causing our immune systems to spend the rest of our lives over-reacting to healthy tissues that “look” a little bit similar to that old nemesis. The more wee beasties we fight off, the more potential there is for random, on-going, low-grade inflammation here there and everywhere.


Interestingly, allergies often start in middle age. Hmmmm. The thot plickens.

Autoimmune disease is basically an allergy to yourself, an immune system reaction to a non-toxic foreign substance in the body, something harmless to one person but irritating or even deadly to the next. The immune system can be a terrible thing when incorrectly activated.

Inflammaging could also be the consequence of an escalating number of minor allergies — another kind of collateral damage. As we build up a collection of defenses against infection (antibodies), directly inspired by all the antigens we’ve “met” (both pathogens and allergens), those defenses almost certainly start reacting to a wider range of foreign substances in addition to some of our own proteins.


Pollutants are probably what most people hope to purge. Historically, the best specific candidates would be the persistent organic pollutants like pesticides, flame retardants, and polychlorinated biphenyls (PCBs, now banned, but formerly ubiquitous in many plastics). Lead is also an alarmingly common environmental poison, much in the news a lot lately.

And there are always new pollutants. Surgical implants are an interesting example: they can break down in the body, causing widespread inflammation to varying degrees, a complication that can be extremely serious, but which almost certainly exists in many other people to a less obvious degree. Awareness of this problem started with a surprisingly recent disaster with metal-on-metal joint implants that poisoned people,16 but that was the tip of the iceberg: poorly designed and regulated surgical implants are a major concern (especially textile/fabric meshes).

There may also be similar and subtler sources of pollutants, like the routine consumption of microplastics — microscopic particles of garbage plastic — a topic much in the news lately. They probably aren’t as dangerous as disintegrating surgical implants, but it’s unlikely that they are completely safe either.

So all of these things, and probably more, can indeed be found in our environment and our bodies, where they mostly get trapped in fat and otherwise sequestered — but they can also potentially be a source of chronic inflammation. We would certainly “detox” these pollutants if we could, but in most cases we probably cannot: the massive detox industry is almost pure bullshit, along with basically all popular beliefs about detoxing. For instance, we cannot sweat out toxins,17 or suck them out our bodies with Epsom salts baths.18

Can low-grade inflammation be diagnosed with blood tests?

A lot of inflammation is not easy to detect. It may hide effectively in specific tissues and systems, only detectable with complicated, expensive, invasive testing. This is one of the main reasons that some diseases have been so mysterious for so long.

There are more accessible blood tests that are quite sensitive to various signs of inflammation, but — because biology is messy — they are not super reliable, and even people with serious inflammatory diseases do not always get a clear result.

Many tests are not available as clinical tests for ordinary folks at all; they’ve just been used by scientists to show that:19

concentrations of inflammatory factors in these conditions are overall slightly higher than in healthy populations, but still remain in the healthy ranges. It is therefore hard to determine whether a specific patient exhibits ‘low-grade inflammation.’

Nevertheless, it’s worth asking your doctor. In particular, check your “CRP” (C-reactive protein). This is a common and easy test, and who knows: you might discover that you have not-so-low-grade inflammation.

Inflammation and fibromyalgia

The pain of fibromyalgia is an unexplained sensory dysfunction resulting in widespread oversensitivity to stimuli, exhaustion, and mental fog, among other things. It is stigmatized and both under and overdiagnosed,20 and all too often it is used as a way to dismiss the complaints of people who have unexplained pain, with the insinuation that they are “sensitive” or “dramatic” and don’t really have anything “real” wrong with their tissues. Of course this is great disservice to patients who don’t really have fibromyalgia and those who actually do.

But you’re not paranoid if they’re really after you, and you’re not “sensitive” if you’re actually inflamed. And fibromyalgia patients are probably actually inflamed!21 Inflammation may be why they are sensitized. Or perhaps even the other way around.

Fibromyalgia does routinely seem to involve sensitivity — the nervous system is over-reacting to stimuli — but inflammation constitutes an actual insult to tissues. Molecules produced by immune system activity, normally associated with infection and injury, are stimulating nerve endings (nociception). The information is sent to the spinal cord and brain for consideration, where the experience of pain may or may not be generated (but it probably will be).

Subjectively, it is nearly impossible to tell the difference between the pain of an oversensitive nervous system and the pain of a nervous system that is actually detecting inflammation all over.22 And yet the difference is enormous. For instance, Lasselin et al discovered in 2016 that chronic pain patients who are actually inflamed — confirmed with lab tests — are less responsive to behavioural therapy.23

Fibromyalgia may involve sensitivity and/or inflammation. Each of them might cause or aggravate the other, though it’s more likely that inflammation drives sensitization.

Inflammation and stress

The brain has a vast potential for sticking its nose into the immune system’s business.

Robert M Sapolsky, Why Zebras Don’t Get Ulcers, 2004, p. 144

There are strong but murky links between chronic pain and stress.24 We feel literally aged by adversity — we speak darkly of terrible events actually shaving time off our lifespans — and aging is nothing if not painful. We still don’t know if stress directly causes chronic pain and other health problems — though there are signs that it can25 — or if it “just” feeds back into it.26 It’s possible that low-grade chronic inflammation is one way that stress can become painful.

Inflammation is mostly27 immunity’s fingerprint, and we know (or strongly suspect) that “immunity is tuned by one’s emotions, personality, and social status as well as by other life style variables like sleep, nutrition, obesity, or exercise.”28 We know that nervous-wreck monkeys are inflamed, their immune systems a mess29 — and the same thing probably happens in humans. We suspect that rough childhoods may be a risk factor for several disorders that probably share inflammation as a mechanism.30

This is all a bit counterintuitive, because any smartypants “knows” that stress suppresses immunity, and that stress hormones — corticosteroids — are impressively anti-inflammatory.31 There are even viruses that monitor those hormones, waiting until we are weak to attack,32 or even meddling to trigger and exploit immunosuppression.33 Fascinating and horrible! This is specifically why certain kinds of viral flare-ups predictably occur when we are stressed.

So why would we worry about stress causing inflammation, which is nearly synonymous with immune function? The response changes over time. It’s insanely complicated, but prolonged and severe stress probably gets the immune system revved up, even to the point of causing autoimmune disease.

In the very short term (minutes), stress is an immune stimulator (inflammatory). But then, almost right away, that effect gets reeled in to prevent collateral damage: you don’t want sustained immune stimulation! This suppressive effect is robust, and it’s why stress/steroids suppress inflammation. But in chronic stress, the stimulatory phase keeps happening over and over again, and the suppressive phase never quite catches up, and so overall immune system activation gradually ratchets up and up and up. Ergo, long term stress is inflammatory.34

Chart showing a sawtooth pattern of immune function increasing and decreasing with repeated stressors, but never quite recovering before increasing again, producing a steady upward trend.

“A schematic representation of how repeated stress increases the risk of autoimmune disease,” adapted from Sapolsky’s Why Zebras Don’t Get Ulcers.

The relationship between metabolic syndrome and inflammation is clear, but there may also be a link between metabolic syndrome and stress,35 and is almost certainly a link with sleep disturbance (which overlaps with stress, obviously).36 If true, it means that metabolic syndrome could affect millions of people who would not otherwise be likely victims.

We know that sleep deprivation (one of the most common forms of chronic stress) actually ages us in an objectively measurable way,37 and we know that age is strongly linked to inflammation (inflammaging).

There’s evidence that suggests that various soothing forms of treatment — yoga, meditation — may reduce chronic low-grade inflammation.38 Disclaimer: this is a very complicated, conflicted area of the scientific literature, possibly polluted with a lot of wishful thinking.

It’s really quite a lot of “circumstantial” evidence, isn’t it? This is hardly a complete tour of inflammation-stress science, but three times as much wouldn’t change the punchline: there’s probably a very complicated link.

Neuroinflammation in particular

Any tissue or system in the body can get inflamed, with many possible consequences, but inflammation of the nervous system is of special interest for patients with chronic pain and other medically unexplained symptoms (MUS).

Inflammation is almost synonymous with immune function, but not entirely. The most dramatic exception is the phenomenon of widespread neuroinflammation, where the “side effects” of inflammation seem to be exploited for a purpose that has nothing to do with fighting off alien invaders.

If you’ve ever had a major illness or injury, you may have noticed that it’s exhausting. It even happens in a milder way with a good head cold. That feeling is the neuroinflammation talking. Whenever we face systemic threats, neuroinflammation kicks in and starts making us feel sicker than we actually are, forcing serious rest — “no foraging this week!” — by making us feel fatigued, fragile, and gross.

This is a lot like the way acute pain modifies behaviour to protect us from immediate tissue threats, just slower and less specific.

Being sick or injured is a double whammy: we get the symptoms of that illness/injury plus the general malaise that “encourages” us to retreat from life. In fact, this “sickness behaviour” is standard for all animals facing major health challenges, and always has been: it’s an old system.39

Neuroinflammation in response to perceived threats?

In humans, with our complex minds, sickness behaviour could conceivably be triggered by perceived threats to health: severe chronic stress, one big one or lots of little ones.

The symptoms of neuroinflammation seems to accompany all chronic and serious diseases and traumas, but — crucially for our purposes here — it might also occur without any substantive physical threat to the system, and thus may explain some cases of medically unexplained symptoms and chronic pain.40 For instance, it also might get triggered by an illness, and then persist after the illness resolves for unclear reasons: the feeling of illness outlasting the illness itself, a new kind of illness in its own right.

But this could also be reaching. Woodburn et al argues persuasively that the kind of neuroinflammation caused by major trauma or disease is just in another league, and it isn’t plausible that just being anxious and burned out could ever trigger anything like it.41 That doesn’t mean that milder neuroinflammation isn’t involved in pain (it probably is). I just want to be clear that serious neuroinflammation being driven by stress is highly speculative, and maybe not even plausible. It’s an idea to keep on the radar, but not super promising.

Neuroinflammation is probably a driver of sensitization. Lowering pain thresholds has an obvious functional role to play in sickness behaviour: what better way to force an animal to take it easy than to make everything hurt a bit too much? This link has not been firmly established yet, but science is closing in. We do already know for sure that chronic widespread pain is closely linked to sensitization. So sensitization bridges the gap between the clinical problem of chronic widespread pain and the biological mechanism of neuroinflammation, and so “neuroinflammation drives widespread chronic pain via central sensitization.”42


Leaky gut syndrome: not a real cause of inflammation

This is a fake disease, based on the “hypothesis” — it barely deserves that word — that our modern diets are so full of irritating substances that our bowel is literally full of holes. Those substances, and gut bacteria as well, seep out into the abdominal cavity and provoke an autoimmune reaction. Leaky gut syndrome has been nominated as the root cause of nearly every unexplained syndrome there is, anything that can be plausibly linked to “inflammation.”

The alleged cure? Usually it’s just to eat like a prehistoric human. The autoimmune protocol (AIP) diet, which is a strict version of the trendiest of all trendy diets, the “paleo” diet: basically anything humans have eaten since the stone age is considered risky. This is obviously just an elimination diet that casts a wide net over everything you can put in your mouth that has ever been demonized, from food additives to gluten to dairy to nightshades. It’s a classic example of the naturalistic fallacy at work.

The theory is much more full of holes than anyone’s gut. The whole thing is nasty faddish pseudoscience being profitably marketed by all the usual suspects. For serious debunking, see the Canadian GI Society. For a more whimsical and snarky one, which is probably all it really deserves, see Dr. Mark Crislip’s analysis.

What can you do about inflammation and inflammaging?

No one really knows, of course, and quite possibly nothing. But here are some ideas …

Exercise and fitness: You knew this was coming. Regular moderate exercise really is the closest thing we have to a miracle drug or a fountain of youth.43 The older you get, the more you should avoid the extremes: too much and too little are likely both a problem. But exercise in the Goldilocks zone is actually anti-inflammatory, in at least one noteworthy context.44 As clear as it is that exercise is healthy, there have been recent leaps in our understanding of exactly why — and it is increasingly clear that's in not just generally healthy but specifically anti-inflammatory. I'll get into considerable detail below.

Portrait of Isaac Newton with meme-style caption: “Brother, do you even attempt to raise heavy objects against the force of gravity?”

Do you even lift? You should! It’s not for everyone, but it is for many people who haven’t realized it yet. It’s a more well-rounded and efficient workout than most people realize.45 And weight lifting specifically fights metabolic syndrome46 and neuroinflammation.47

Anti-inflammatory nutrition: It’s also possible to some extent to eat an anti-inflammatory diet — but that isn’t nearly as promising as it sounds. Things like Dr. Weil’s “Anti-Inflammatory Food Pyramid” are full of wishful thinking and make the science of anti-inflammatory diets seem way more complete and tidy than it actually is. Or there’s the autoimmune protocol (AIP) diet for “leaky gut syndrome,” which is all nonsense (see the leaky gut syndrome section). The smart money is on a diet that is just generally healthy, mostly by being low in obvious junk food (especially the ones that are a challenge to blood sugar regulation). Supplements and anti-inflammatory “superfoods” are mostly a pipe dream and the stuff of marketing. But there are a handful of quitegoodfoods with a bit more evidence of health benefits than normalfoods: (well-known for good critical analysis of nutrition claims) votes for garlic, dark berries, spirulina, and leafy greens. I might add a couple foods rich in omega-3 fatty acids (mostly some fish and nuts/seeds).

Ketogenic diets and fasting: Just as scientifically sketchy as any other kind of anti-inflammatory dieting, but possibly worth experimenting with nevertheless. More below.

Reduce stress: Even though it’s really not confirmed that there is a link between stress and inflammation, stress management has so many benefits that it is well worth pursuing regardless. You don’t have to meditate or do yoga (unless you want to). Often the best place to begin is troubleshooting major sources of chronic stress, like insomnia or anxiety.

Quitting bad habits: Consider finally ditching habits that are putting a strain on your biology, especially smoking (of course, smoking is a well known independent risk factor for pain), or drinking too much too regularly (anything more than a couple per day). Any kind of “hard living” is suspect. Coffee in reasonable doses, mercifully, is not an obvious suspect (it doesn’t dehydrate you, for instance48) — but if you’re drinking so much that it’s aggravating emotional stress with caffeine-powered agitation and anxiety, that’s another matter.

Tickling your vagus nerve: vagus nerve stimulation, or just relaxation?

The vagus nerve is the “relaxation” nerve, deep in the neck, passing through a hole in the bottom of your skull. Relaxation involves several physiological changes stimulated by vagus nerve activity. If you could stimulate your vagus nerve by any means, it would relax you, and a lot of people get excited by the idea of a shortcut to profound relaxation, a calming “switch.” It’s not really in doubt that this is possible in principle, but it is very much in doubt whether it’s practical, or meaningfully better than just, you know, relaxing.

So how do you stimulate a vagus nerve? Well, mostly you don’t, not without an implant (more on that below). In a self-help context, some people have argued that relaxing is how you “stimulate the vagus nerve,” and that meditation is basically just focused, “formal” relaxation. The simplistic rationale is just that, if the vagus nerve induces relaxation, then relaxation must “stimulate” the vagus nerve. That’s doubtful. And, if you’re already relaxed, why stimulate the vagus nerve anyway?

Well, vagus nerve stimulation might go beyond just “relaxing” us. It might also reduce inflammation — or fail to do so.

The vagus nerve regulates immune system activity by detecting and responding to signs of inflammation — the “inflammatory reflex.” Immune regulation is insanely complex, but the inflammatory reflex is a major component of that system, and it’s a simple enough idea in itself. Too much inflammation? Vagus nerve does its thing. The inflammatory reflex may be impaired in people with excessive inflammation.49

So what if we could kick-start a dysfunctional inflammatory reflex artificially? Stimulate your vagus nerve with an implant, et voila, less systemic inflammation? Ji et al: “Increasing evidence suggests that neuromodulation such as vagus nerve stimulation can powerfully regulate inflammation.” Evidence like a 2016 test on humans, with results that “establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans.”50 Established, eh? Not without replication! That’s overconfident for sure — this badly needs replication before celebration.51 As of late 2019, there’s still no other clinical research on this topic, so “increasing evidence” also seems like an optimistic overstatement.

Still genuinely interesting topic, though.

You can’t pay for vagus nerve stimulation yet, even if it is a great idea. So how else could vagus nerve stimulation be achieved? Pavlov and Tracey devote dizzyingly complex passages to “novel therapeutic approaches” that might achieve “cholinergic suppression of inflammation” either by inspiring the vagus nerve to do it, or by doing it directly by other means. Mostly it’s about exotic drugs, and there’s a passage about implanted vagus nerve stimulators (none of which is practical or accessible). There’s some discussion of the effects of nutrition (much more accessible).

What they do not discuss is how normalization of the inflammatory reflex might be achieved by extra relaxation — that is certainly implied, and seems well worth exploring. It is possible that some kind of artificial stimulation or simulation might constitute some kind of a kick-start for a glitchy inflammatory reflex, but it’s also possible that a big boost in relaxation — a new meditation habit, for instance — is actually easier and better. No one really knows.

Reducing inflammation with a ketogenic (very low carb) diet

Diets that force you to mainly burn fat for energy, instead of carbohydrates — like the infamous Atkins diet — may be anti-inflammatory and/or otherwise metabolically salubrious. This also includes fasting and intermittent fasting, discussed more below, but I’ll start with low-carb diets, which have been popular for much longer.52

Ketogenic diets are low enough in carbohydrates (sugars) that they force the body to burn an alternate fuel source, ketone bodies. This state is known to treat epilepsy surprisingly effectively in some children,53 and we can infer from that success story that the biology of this treatment might also have an effect on some kinds of inflammation and pain (especially neuropathic pain, the pain of damaged nerves54). Although speculative, there are some reasons to think this might work, and some indirect (animal) evidence that it does.55 Like seizures, some kinds of pain may involve “overexcited” neurons, and can be treated with anticonvulsant drugs. Ketone metabolism “produces fewer reactive oxygen species,” a contributor to inflammation; and it produces adenosine signalling, which is a suspected pain-killer in other contexts (exercise, possibly acupuncture).

This is an experimental treatment. However, just like an anti-inflammatory diet (AKA “healthy”), it has a non-crazy rationale, and it’s safe and inexpensive to dabble in. As long as you don’t get extreme, the worst-case scenario is putting up with a fussy and unpleasant change in eating habits. Nevertheless, I am obliged to suggest that you run this by your physician and/or a nutritionist.

You should probably spend at least two to four weeks in a ketogenic state to be sure that you’ve given it an adequate chance to work its magic. If you see a clear reduction in symptoms, that’s a strong sign that it’s working. In a spirit of moderation, I do not recommend trying to stay in a ketogenic state for any more than a several weeks at a time, and you should probably take breaks — give your system a rest from ketogenesis once every week or two.

Is intermittent fasting anti-inflammatory?

Atkins is so 2005. These days, the cool kids are inducing ketogenesis with some intermittent fasting — also known as “skipping some meals.” This practice has achieved Hype Factor 10, and almost everyone seems to believe that it has substantial general health benefits, a special metabolic sauce that improves us. Not-eating as actual medicine. “Would you like to not eat this? It’s good for you! 🎶”

I’m focusing on the more specific claim that fasting is anti-inflammatory.56

In late 2019, intermittent fasting was given a huge publicity boost by a widely cited New England Journal of Medicine paper, basically a fancy opinion piece,57 and their opinion is: “fasting is probably great!” The paper contains an on-the-nose assertion for our purposes here: “intermittent fasting reduces markers of systemic inflammation.” That statement is supported by four references. That seems like plenty. But are the references persuasive? Not so much. Did a stoned undergrad pick those out? Do peer reviewers even look at the footnotes?58

As far as I know, there is literally only one solid study showing clear evidence of an anti-inflammatory effect in humans.59 (It is even more recent that the NEJM paper, so it wasn’t cited there.)

So the “growing body of evidence” has been exaggerated by everyone, surprise surprise, and fasting has not yet been shown to be “anti-inflammatory” per se. Yet. That’s the bad news. The good news…

I believe (opinion alert) that there’s actually a decent chance that an anti-inflammatory effect of fasting will be confirmed in time. It’s actually quite plausible, based on lots of indirect evidence — animal, cell, more general research, and so on — which truly is accumulating.

It’s also just a reasonable diet. The worst-case scenario for any non-extreme attempt is just getting pretty hangry (angry from hunger). And it’s probably perfectly good as a weight-loss diet if nothing else. You’ll even save time and money, making it a great rarity in rehab — even the most harmless treatment experiments usually take some money/time.

And here’s a simple idea to end on: it may not be that fasting is anti-inflammatory, but rather that long-term overeating is inflammatory, and fasting is just a rather dramatic way of swinging the pendulum away from that metabolic trap. So we’re back to the idea that the only “anti-inflammatory” diet is just one that isn’t inflammatory.

Some further reading on intermittent fasting: Martin Berkhan’s (start with his myths of fasting), and Dr. Bojan Kostevski’s thesis paper, “The Effects of Intermittent Fasting on Human and Animal Health.”

Massaging the inflammation away

Basically there isn’t a shred of evidence that any kind of massage can reduce any kind of inflammation in a clinically meaningful way. However, you see this claim touted surprisingly often, because of course it sells massage tools and services, and it’s suitably non-specific and technical sounding — even better than “increasing circulation.”

Although it’s not crazy to check for an anti-inflammatory massage effect, all such scientific efforts thus far have failed. There are two particularly notorious examples of over-hyped research on this score:

  1. In 2012, Crane et al very elaborately studied changes in the proteins that cells constantly make (“gene expression”).60 They compared muscle tissue samples with and without massage and concluded that “massage therapy appears to be clinically beneficial by reducing inflammation and promoting mitochondrial biogenesis.” Unfortunately, this was quite misleading, and the results of this study were really quite negative: the data showed that massage has no significant effect on gene expression in muscle cells. There were several major problems with the study. For very detailed analysis, see Massage Does Not Reduce Inflammation.
  2. A much more recent hype-storm formed around the work of Seo et al, who made this extraordinary claim in 2021: “robotic” massage of mice supposedly helped their little muscles heal.61

    This was another overly elaborate and technical study, this time massaging injured mouse muscles with high doses of vibration, again purporting to find evidence that massage is “antinflammatory” and “regenerative.” While some of the findings are intriguing, it’s extremely unlikely that they are replicable or clinically relevant in people. The study is a classic example of a “fishing” expedition: a search for meaningful signals in a lot of complex data. You can read my detailed analysis here: “Robotic Mouse Massage: Is It ‘Regenerative’ and ‘Anti-Inflammatory’?”

More ordinary clinical tests of massage for exercise-induced soreness have showed either nothing or only trivial benefits. I report on that research at length in A Deep Dive into Delayed-Onset Muscle Soreness.

Hyperventilation + cold exposure = anti-inflammatory (maybe)

Meditation, breathing, and cold exposure have all been touted as anti-inflammatory, often by gurus with dubious credibility. There’s a long history of half-arsed science about all of these things, and it’s disheartening to try to get anything useful out of that literature. But we do have good reasons to believe that something in that mess seems to have some “anti-inflammatory” effects (to oversimplify). So I was quite happy to see an interesting 2022 experiment that focused specifically on trying to identify the “active ingredients.”

Zwaag et al. observed a clear anti-inflammatory effect from hyperventilatory breathing exercises both alone and when combined with cold exposure. Cold exposure alone had no effect, but it did seem to enhance the effect of the breathing exercises.62

This experiment was impressively gruelling for the participants: the researchers put a few dozen healthy young men through several days of intense breathing and/or cold exposure training, for hours at a time, and then artificially cranked up their systemic inflammation with injections of bacterial lipopolysaccharides. Serious business! Lots of care and ethical oversight required to do a study like this safely.

The breathing exercises mainly consisted of extensive hyperventilation. Most people would find the full protocol prohibitively challenging and exhausting. Happily, the researchers also tested easier methods… and were convinced by their data that a much tamer and simpler protocol had the same effect. Yahtzee.

The cold exposure protocol was even more intense, and impractical for most people to even attempt.

All of the hyperventilating certainly seemed to reduce objective signs of endotoxemia (assuming no statistical jiggery-pokery, which is always possible of course).

The simplest practical implication is that hyperventilation exercises alone might reduce some systemic inflammation in ways that could be helpful for some kinds of chronic pain … and that breathing probably works better with a bunch of added cold exposure. There’s plenty of uncertainty here, and in particular the required dosage might just be too much for a lot of people, but the data clearly shows that there is potential in principle. The word “promising” gets overused in this business, but I think it might actually be applicable in this case.

For additional perspective on this paper, see the blog post “Anti-inflammatory hyperventilation: I’ll huff and I’ll puff and I’ll blow my pain away.”

Hungry, hungry humans balance the energy budget by … cutting inflammation?! The detailed case for exercise as anti-inflammatory medicine

Photo of a runner’s legs on a road with a brightly lit but indistinct background.

The bad news? You have to be burn quite a few calories. The good news? We know better than ever exactly why it’s so good for you.

There is lots of decent indirect evidence that fitness is anti-aging and anti-inflammatory (summarized earlier with several citations), but new science emerged in 2021 and 2022 that daily physical activity is linked to meaningful reductions in generalized inflammation. Yes, we are still learning!

It turns out that maybe exercise can convince our body to spend a bit less energy on defence: reduced immune system activity, AKA inflammation, that holy grail of general health. Optimistic, science-based life hacks are not my usual style, but I think this one’s cromulent (wouldn’t publish it if I didn’t). It takes some proper splainin’, but the journey is interesting, and the destination useful: an excellent new scientific justification for exercise as medicine for chronic pain.

PainSci Member Login

Submit your email to unlock this audio content (and any other stuff for members). If you can’t remember or access your registration email, please contact me. ~ Paul Ingraham, PainSci Publisher

Privacy & Security of this form This login is private and secure: the information you submit is encrypted, used only to search for matching accounts, and then discarded.

First you need to know that humans are unusually fuel-hungry critters. We burn through calories much faster than any other primate. The old idea was that homo sapiens uses energy like other animals, but that reasonable assumption was knocked over surprisingly recently, by evolutionary anthropologist Herman Pontzer.63

In fact, humans need quite a lot of fuel, probably because of all the brains. Brains are expensive.

Pontzer et al. used the most new-fangled methods to measure energy usage in people of all ages — 8 days to 95 years. Highlights:

That’s all “fun facts,” but another result might be a little more consequential.

Animated GIF of a realistic looking brain wobbling.

All brains are metabolically “expensive,” but this one burns extra calories from all the wiggling.

Homo sapiens is also amazingly good at balancing the energy budget

Human also keep our high total cost of activity surprisingly consistent over time. If we exercise more, our clever biology starts to actually cut back on other metabolic expenses — so we don’t burn as much extra fuel as we expect.

This does not mean that the exercise is futile! Despite some hype to contrary (doubling down on the idea that “you cannot outrun your diet”), exercise is still a valuable part of any weight loss plan, for instance.

But every calorie counter knows all too well how much harder it is to get rid calories than it is to shovel them into our pie holes in the first place … and this new data means the deck is even more stacked against us than we thought.

So: the body tends to actually reduce overall metabolic spending, the better to afford extra exercise. That budgeting adjustment is cool, and not especially controversial as far as I know. (Although saying that is like casting a magic spell that summons an expert to put me in my place: “experto correctium!”) Now for the cool part…

Where exactly these metabolic spending cuts happen?

What gets sacrificed? This is where this all plugs into the world of pain science. Pontzer postulates (as quoted by Gibbons):

“I think we’re going to find these adjustments lower inflammation, lower our stress reaction. We do it to make the energy books balance.”

That is quite a thought. Is Pontzer nuts? No, it’s just legitimate speculation. If true, it would be a tidy new way to explain why exercise is such good medicine.

The need to conserve fuel for exercise may reduce how “seriously” the body takes its stress — how much energy we invest in maintaining better-safe-than-sorry levels of immune system function.

Fresh evidence that exercise does indeed tame inflammation

While this post sat in my drafts folder for a while, Pontzer’s team published the results of a test of this hypothesis.64 Bravo! Nice timing!

They crunched the numbers in a big health database to find a long-term relationship between energy expenditure and inflammation, and found it: sustained daily physical activity was linked to reductions in the several major biomarkers for systemic inflammation, like C-reactive protein (CRP) and white blood cells. Cool.

So this intriguing idea is now at least partially evidence-based, and relevant to chronic pain — which is often more about biology than biomechanical strain and tissue failure.

About Paul Ingraham

Headshot of Paul Ingraham, short hair, neat beard, suit jacket.

I am a science writer in Vancouver, Canada. I was a Registered Massage Therapist for a decade and the assistant editor of for several years. I’ve had many injuries as a runner and ultimate player, and I’ve been a chronic pain patient myself since 2015. Full bio. See you on Facebook or Twitter., or subscribe:

Related Reading

What’s new in this article?

Twenty-seven updates have been logged for this article since publication (2016). All updates are logged to show a long term commitment to quality, accuracy, and currency. more When’s the last time you read a blog post and found a list of many changes made to that page since publication? Like good footnotes, this sets apart from other health websites and blogs. Although footnotes are more useful, the update logs are important. They are “fine print,” but more meaningful than most of the comments that most Internet pages waste pixels on.

I log any change to articles that might be of interest to a keen reader. Complete update logging of all noteworthy improvements to all articles started in 2016. Prior to that, I only logged major updates for the most popular and controversial articles.

See the What’s New? page for updates to all recent site updates.

May 31, 2023 — Added big new section about the role of exercise in reducing inflammation: “Hungry, hungry humans balance the energy budget by … cutting inflammation?! The detailed case for exercise as anti-inflammatory medicine.”

March — Added short new section, “Hyperventilation + cold exposure = anti-inflammatory (maybe).”

2022 — Added new section, “Massaging the inflammation away.”

2022 — Removed some excessively speculative claims that serious neuroinflammation might be driven by perceived threats (stress), as opposed to actual ones (serious injury and illness).

2020 — Small new section, “Menopause is probably inflammatory,” based on some new science.

2020 — Minor science update — added citations and detail about the anti-inflammatory potential of exercise/activity.

2020 — More upgrades to the intermittent fasting section.

2020 — Added a new section on the alleged anti-inflammatory effects of intermittent fasting. Bottom line: plausible but far from proven, safe and cheap to experiment with. This section will expand and may even be spun-off into its own article.

2019 — Added disclaimer and acknowledgement of reader concerns about the topic of leaky gut syndrome as a cause of systemic inflammation.

2019 — New section with much more detail about vagus nerve stimulation and the inflammatory reflex.

2019 — Added a couple of particularly interesting (but minor) points about the effect of stress on immunity. Also added a primer on neuroinflammation.

2019 — Added a small section about pollutants and their potential contribution to inflammaging.

2019 — Added quite a bit of speculation about factors that might contribute to inflammaging, mainly related to immunity.

2019 — New section: “Leaky gut syndrome: not a real cause of inflammation.”

2018 — Summary of Sapolsky’s explanation for why chronic stress is inflammatory, plus a nice new chart. Good stuff! Answers to questions I have had myself for a looong time.

2018 — Added a bit more detail on anti-inflammatory foods and dieting.

2017 — Science update based a nice bit of good news about weight lifting reducing the risk of metabolic syndrome (Bakker et al).

2017 — Added interesting citation to Hussain et al, showing evidence of the metabolic/inflammatory roots of back pain.

2017 — Added interesting citation to Bäckryd et al, the first evidence of extensive inflammation in fibromyalgia patients.

2017 — Science update, added a citation about the link between metabolic syndrome and sleep disturbance (as a proxy for stress).

2017 — Revision and upgrades to the link between stress and inflammation: more citations, more ideas, more clarity.

2016 — New section devoted to exploration of the link between stress and inflammation.

2016 — Science update, mostly concerning the relationship between inflammation and stress.

2016 — New treatment option reviewed: vagus nerve stimulation.

2016 — Added mobile summary, and a “perspective” sidebar warning against snake oily imposters.

2016 — Added another plausible explanation for inflammaging: the reactivation or dormant common infections. Also added a citation link metabolic syndrome to neck pain.

2016 — Many miscellaneous minor improvements.

2016 — Publication.


  1. Not many middle-aged people have enough arthritis to account for the sheer number of variety of aches and pains that they often report. Arthritic pain is typically well localized to specific joints, and usually not serious in middle age (unless the joint is vulnerable to early arthritis due to an injury).
  2. The main ones to watch out for are the bisphosphonates (Alendronate, risedronate, Actonel, Atelvia) and statins (Lipitor, Crestor, Mevacor, Zocor, Lescol). For more information, see 35 Surprising Causes of Pain.
  3. Gauldie J. Inflammation and the aging process: devil or angel. Nutr Rev. 2007 Dec;65(12 Pt 2):S167–9. PubMed 18240542 ❐

    This is a short and technical exploration of reasons not to demonize inflammation. There is some evidence that it might actually be a relatively innocent bystander to the some pathologies it has been blamed for. Otherwise, the article is mainly just a reminder that inflammation is synonymous with immune function and dazzlingly complex, and suppressing it in general is best avoided unless absolutely necessary (which is not wrong, but also so obvious I wonder if it actually needed to be said).

  4. Hand LE, Hopwood TW, Dickson SH, et al. The circadian clock regulates inflammatory arthritis. FASEB J. 2016 Aug. PubMed 27488122 ❐
  5. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014 Jun;69 Suppl 1:S4–9. PubMed 24833586 ❐ PainSci Bibliography 53291 ❐ “Human aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as "inflammaging." Inflammaging is a highly significant risk factor for both morbidity and mortality in elderly people, as most if not all age-related diseases share an inflammatory pathogenesis. Nevertheless, the precise etiology of inflammaging and its potential causal role in contributing to adverse health outcomes remain largely unknown.”
  6. Mäntyselkä P, Kautiainen H, Vanhala M. Prevalence of neck pain in subjects with metabolic syndrome—a cross-sectional population-based study. BMC Musculoskelet Disord. 2010;11:171. PubMed 20670458 ❐ PainSci Bibliography 53456 ❐ This study found that neck pain is prevalent in people with metabolic syndrome. The relationship is definitely not necessarily causal, but it certainly might be. This evidence certainly suggests a need for more research to find out.
  7. Hussain SM, Urquhart DM, Wang Y, et al. Fat mass and fat distribution are associated with low back pain intensity and disability: results from a cohort study. Arthritis Res Ther. 2017 Feb;19(1):26. PubMed 28183360 ❐ PainSci Bibliography 52908 ❐

    This important paper shows evidence of the metabolic roots of back pain, and perhaps other kinds of chronic pain as well. The majority (82%) of 5000 Australians reported back pain on a questionnaire, and in 27% of them it was bad enough to be disabling. When compared to their fat mass fat distribution — known indicators of metabolic disorders — a clear pattern emerged: back pain intensity and disability go up with measures of fat mass and distribution. This data does not suggest that weight is a “mechanical” problem — greater weight causing greater stress on spinal joints. Instead, it suggests that “systemic metabolic factors associated with adiposity play a major role in the pathogenesis of LBP.” The weight isn’t the problem, but the biochemistry of being out of shape.

    This is a particularly excellent example of what I mean when I argue that we need to look beyond trivial physical stresses and biomechanical factors to the messy “wet” factors in chronic pain, the things that make us more vulnerable to pain.

  8. Esposito K, Giugliano D. The metabolic syndrome and inflammation: association or causation? Nutr Metab Cardiovasc Dis. 2004 Oct;14(5):228–32. PubMed 15673055 ❐
  9. Burke NN, Finn DP, McGuire BE, Roche M. Psychological stress in early life as a predisposing factor for the development of chronic pain: Clinical and preclinical evidence and neurobiological mechanisms. J Neurosci Res. 2016 Jul. PubMed 27402412 ❐ “Early-life adversity increases the risk of developing a number of disorders, such as chronic pain, fibromyalgia, and irritable bowel syndrome.”
  10. McCarthy M, Raval AP. The peri-menopause in a woman's life: a systemic inflammatory phase that enables later neurodegenerative disease. J Neuroinflammation. 2020 Oct;17(1):317. PubMed 33097048 ❐ PainSci Bibliography 51940 ❐
  11. Bennett JM, Glaser R, Malarkey WB, et al. Inflammation and reactivation of latent herpesviruses in older adults. Brain Behav Immun. 2012 Jul;26(5):739–46. PubMed 22155500 ❐ PainSci Bibliography 53327 ❐ “Persistent pathogens such as latent herpesviruses and chronic bacterial infections can act as a source of inflammation. Herpesviruses, including Epstein-Barr virus (EBV) and cytomegalovirus (CMV), establish latent infections following primary infection and reactivate when the cellular immune system is compromised.” In this study of 222 older adults (~64), activity of these two viruses was associated with more inflammatory markers (CRP and IL-6). “Thus, reactivation of multiple herpesviruses may drive inflammation and could contribute to poorer health among older adults.”
  12. Autoimmune disease is inflammatory by definition, and is extremely unpredictable. Even full-blown autoimmune diseases are notoriously difficult to diagnose, because they tend to erratically affect many systems. It’s likely that some people have minor autoimmune disease, effectively undiagnosable. It’s not even a case of having “early” autoimmune disease: AD is so unpredictable that it might back off before getting severe enough to be diagnosed.
  13. [Internet]. Quirks & Quarks. Have researchers been wrong about Alzheimer’s? A new theory challenges the old story; 2018 Dec 8 [cited 19 Jun 16]. PainSci Bibliography 52274 ❐ The infamous brain plaques of Alzheimer’s have always been a mystery. Evidence increasingly suggests that they are actually “nets” of a sophisticated infection-fighting strategy, designed to trap a common pathogen — but at a price that gets steeper over the years.
  14. [Internet]. Proal A. Re-evaluating the theory of autoimmunity; 2019 June 6 [cited 19 Jun 19]. PainSci Bibliography 52273 ❐

    This is a clear and concise summary of an intriguing and plausible hypothesis: that autoimmune disease is not caused by the body’s immune system “attacking itself,” but by collateral damage when the immune system fights infections with antibodies that also happen to match our own proteins. This may also be the explanation for “inflammaging”: as we accumulate antibodies from infections over the years, we basically start to get mild “autoimmune disease.”

  15. [Internet]. Williams C. How to extinguish the inflammation epidemic; 2017 July 18 [cited 19 Jun 17]. PainSci Bibliography 52866 ❐

    This article was really hot for a while. It has superficial credibility, but actually offers just a lot of oversimplified wishful thinking about inflammation as the one true cause of all of our problems, and a few unremarkable treatment suggestions. The author aggressively demonizes stress and “modern living” as the major cause of systematic inflammation (far beyond what the evidence can support), and gives only token attention to the devil in the details.

    In particular, she gets carried away with the idea that “inflammation has an off switch,” acknowledging too late that one of her expert sources, Dr. Derek Gilroy, “warns against getting too carried away with the resolvin story.” Dr. Gilroy’s quote (too little, too late) reads like a desperate attempt to undermine the story the author is hell-bent on telling:

    “The inflammation that we have in diseases like Alzheimer’s, cancer, autoimmune diseases like osteoarthritis, all of these are very different inflammatory processes,” he says. “It is hard for me to understand, given that there are many ways that a disease occurs, that they can resolve by the same mechanism.”

    Despite all of Williams’ optimism, the article coughs up a ridiculous list of five tepid inflammation-fighting recommendations: lose weight, relax, take aspirin in low doses, and — facepalm — stretch (a particularly desperate item, unwisely based on a scrap of evidence from Berrueta et al). These aren’t completely meritless, but they are blatantly a very weak sauce.

  16. Cohen D. How safe are metal-on-metal hip implants? BMJ. 2012;344:e1410. PubMed 22374741 ❐ PainSci Bibliography 53447 ❐
  17. Imbeault P, Ravanelli N, Chevrier J. Can POPs be substantially popped out through sweat? Environ Int. 2018 Feb;111:131–132. PubMed 29197670 ❐
  18. Epsom salt in your bath is cheap and harmless and it makes the water feel “silkier,” but it’s unlikely that it has a therapeutic effect on aches and pains. Magnesium supplementation might be helpful for some patients with some kinds of pain, but not many others, and it’s doubtful that it can soak through the skin, and it definitely doesn’t “detox” anything. The soothing heat of a nice bath is probably the main source of health benefits. The case for the healing powers of Epsom salt is mostly made by people selling the stuff, or recommending it as casually and imprecisely as an old wives’ tale. See Does Epsom Salt Work? The science and mythology of Epsom salt bathing for recovery from muscle pain, soreness, or injury.
  19. Lasselin, J. Low-grade inflammation and the brain. Accessed 2016-12-08.
  20. Walitt B, Katz RS, Bergman MJ, Wolfe F. Three-Quarters of Persons in the US Population Reporting a Clinical Diagnosis of Fibromyalgia Do Not Satisfy Fibromyalgia Criteria: The 2012 National Health Interview Survey. PLoS One. 2016;11(6):e0157235. PubMed 27281286 ❐ PainSci Bibliography 53271 ❐The majority of clinically diagnosed fibromyalgia cases in the US do not reach levels of severity necessary and sufficient for diagnosis. The clinical diagnosis of fibromyalgia is disproportionally dependent on demographic and social factors rather than the symptoms themselves. Diagnostic criteria for fibromyalgia appear to be used as a vague guide by clinicians and patients, and allow for substantial diagnostic expansion of fibromyalgia.”
  21. Bäckryd E, Tanum L, Lind AL, Larsson A, Gordh T. Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. J Pain Res. 2017;10:515–525. PubMed 28424559 ❐ PainSci Bibliography 53589 ❐

    Although inflammation has been suspected in fibromyalgia, it has been poorly studied to date. This experiment went much further, employing “a new multiplex protein panel enabling simultaneous analysis of 92 inflammation-related proteins.” They looked for these markers in the cerebrospinal fluid and blood of 40 fibromyalgia patients and compared with healthy controls, finding an “extensive inflammatory profile.”

  22. In theory, the way to tell the difference would be the absence of other classic fibromyalgia symptoms like poor quality sleep, fatigue, memory and mood issues — the infamous “fibrofog.” In practice, those are common, messy, and overlapping sensations (even more so in people who’ve had a lot of aches and pains for years). The sensations in an inflamed person could strongly resemble those in someone with fibromyalgia.
  23. Lasselin J, Kemani MK, Kanstrup M, et al. Low-grade inflammation may moderate the effect of behavioral treatment for chronic pain in adults. J Behav Med. 2016 Oct;39(5):916–24. PubMed 27469518 ❐ PainSci Bibliography 53548 ❐

    Forty-one patients with chronic pain (at least six months, many much longer) were tested for signs of systemic inflammation. They all had stable medications, and no major complications. Then they were provided with two kinds of behavioural treatments for several weeks, measuring their progress in several ways.

    Unfortunately, no one did well: “No substantial overall effect of behavioral treatment on pain intensity and pain-related variables was found in the present study.” So that’s a sad result for these behavioural therapies.

    However, there is a scrap of backwards good news here: the patients with more inflammation “were more resistant to the improvement in pain intensity and in psychological variables contributing to pain.” Note that the mechanism of that effect is probably not that inflammation directly makes pain harder to treat, but actually modifies mental state and behaviour and that makes the pain harder to treat.

    The authors believe that this data tentatively “suggests that the inflammatory state may be one of the mechanisms of the persisting behavioral alterations in patients who do not respond to treatment, corresponding to previous studies on treatment resistant depression.”

  24. And all its cousins: anxiety, insomnia, depression, weak social connections and low social status, and so on. When I refer to “stress” here, I’m talking about any and all of them.
  25. Thompson T, Correll CU, Gallop K, Vancampfort D, Stubbs B. Is Pain Perception Altered in People With Depression? A Systematic Review and Meta-Analysis of Experimental Pain Research. J Pain. 2016 Dec;17(12):1257–1272. PubMed 27589910 ❐

    Although “clinical studies suggest depressed patients may be more vulnerable to pain,” it’s far from proven. It’s not clear, and it still isn’t after this meta-analysis of 32 studies. The only real finding here was that there’s so much variety in the results of studies that “it depends” in a big way, on many variables.

    This analysis actually found that in some ways depressed patients were less vulnerable to pain — a “small but significant” higher mean sensory threshold and pain threshold — which is interesting but probably not meaningful, given the complexity of the data.

  26. Elbinoune I, Amine B, Shyen S, et al. Chronic neck pain and anxiety-depression: prevalence and associated risk factors. Pan Afr Med J. 2016;24:89. PubMed 27642428 ❐ PainSci Bibliography 53545 ❐
  27. Not exclusively. There are inflammatory mechanisms that have nothing directly to do with immunity. A major example of this is neuroinflammation, discussed further along.
  28. Lasselin J, Alvarez-Salas E, Grigoleit JS. Well-being and immune response: a multi-system perspective. Curr Opin Pharmacol. 2016 Aug;29:34–41. PubMed 27318753 ❐
  29. Dr. Robert Sapolsky, regarding a study of low-status monkeys (Snyder-Mackler et al), who have hard lives:

    At the end of the day, being a chronically subordinate nonhuman primate and being a human mired at the bottom of the socioeconomic scale are similar in the most fundamental ways. You have remarkably little control and predictability in your life, your outlets for frustration are limited, and it’s relatively hard to access social support. That’s the prescription for chronic, stress-related maladies.

  30. Burke 2016, op. cit.
  31. Corticosteroids are potent anti-inflammatory agents (and not the same thing as the anabolic steroids taken by bodybuilders), but their potency also means they have a lot of side effects. Oral steroids can be invaluable for management of severe widespread inflammatory conditions — like rheumatoid arthritis, say — but they are also overkill for almost any painful “hot spot,” because they are a bit of a bull in a biological china shop. And so injection is preferred for its precision wherever it makes sense… though even then there are major caveats (e.g. see Okike).
  32. More Sapolsky (p. 170):

    The next clever thing that viruses have done? They don’t reactivate at any old time. They wait until the immune system of the host organism is lousy, and then gun for some quick rounds of replication. And when are immune systems often at their lousiest? You got it. It’s been endlessly documented that latent viruses like herpes flare up during times of physical or psychological stress in all sorts of species. It’s the same thing with some other viruses that go latent, like Epstein-Barr virus and varicella-zoster (which causes chicken pox and shingles).

    Herpes doesn’t measure how your immune system is doing. It measures something else that, for its purposes, gives it the information it needs—it measures your glucocorticoid levels. Herpes DNA contains a stretch that is sensitive to elevated glucocorticoid signals, and when levels are up, that DNA sensor activates the genes involved in coming out of latency. Epstein-Barr and varicella-zoster contain this glucocorticoid-sensitive stretch as well.

  33. And still more Sapolsky (continuing from last note):

    And now for something even more fiendishly clever. You know what else herpes can do once it infects your nervous system? It causes your hypothalamus to release CRH which releases ACTH which raises glucocorticoid levels. Unbelievable, huh? So you don’t even need a stressor. Herpes infects you, artificially pushes you to step 2 with your elevated glucocorticoid levels, which gets you to step 3, and allows the virus to come out of latency. Moreover, elevated glucocorticoid levels impair your immune defenses against activated herpes. This leads to step 4—a cold sore flare-up. And we think we’re so clever with our big brains and opposable thumbs.

  34. Sapolsky RM. Why Zebras Don’t Get Ulcers. 3rd ed ed. New York: Times Books; 2004. Chapter 8: Immunity, Stress, and Disease; p. 144–185. Sapolsky goes deep on this topic, and I am completely relying on him for this point. I hope I’ve boiled it down to the essentials correctly. His bottom line: “The system apparently did not evolve for dealing with numerous repetitions of coordinating the various on-and-off switches, and ultimately something uncoordinated occurs, increasing the risk that the system becomes autoimmune [inflammatory].”
  35. Gohil BC, Rosenblum LA, Coplan JD, Kral JG. Hypothalamic-pituitary-adrenal axis function and the metabolic syndrome X of obesity. CNS Spectr. 2001 Jul;6(7):581–6, 589. PubMed 15573024 ❐ Prolonged chronic stress can probably contribute to metabolic syndrome by messing with the hormonal balance of the hypothalamic-pituitary-adrenal axis (HPA-axis).
  36. Koren D, Dumin M, Gozal D. Role of sleep quality in the metabolic syndrome. Diabetes Metab Syndr Obes. 2016;9:281–310. PubMed 27601926 ❐ PainSci Bibliography 53564 ❐
  37. Carroll JE, Cole SW, Seeman TE, et al. Partial sleep deprivation activates the DNA damage response (DDR) and the senescence-associated secretory phenotype (SASP) in aged adult humans. Brain Behav Immun. 2016 Jan;51:223–9. PubMed 26336034 ❐ PainSci Bibliography 53312 ❐ “Age-related disease risk has been linked to short sleep duration and sleep disturbances…”
  38. Bower JE, Irwin MR. Mind-body therapies and control of inflammatory biology: A descriptive review. Brain Behav Immun. 2016 Jan;51:1–11. PubMed 26116436 ❐ PainSci Bibliography 53640 ❐

    This is a qualitative review of 26 randomized controlled trials of the biological effects of mind-body therapies like Tai Chi, Qigong, yoga, and meditation. The studies show “mixed effects” on inflammation (CRP, IL-6, stimulated cytokine production, etc), and more consistent results for “genomic markers.” Based on this evidence, it seems likely that these activities are meaningfully good for you, and probably helpful for some kinds of chronic pain.

  39. Lyon P, Cohen M, Quintner J. An evolutionary stress-response hypothesis for chronic widespread pain (fibromyalgia syndrome). Pain Med. 2011 Aug;12(8):1167–78. PubMed 21692974 ❐ This paper explores a striking similarity between fibromyalgia and “sickness behaviour” in animals.
  40. Albrecht DS, Forsberg A, Sandström A, et al. Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation. Brain Behav Immun. 2019 Jan;75:72–83. PubMed 30223011 ❐ PainSci Bibliography 52325 ❐ This study provides the first in vivo evidence of neuroinflammation in fibromyalgia patients.
  41. Woodburn SC, Bollinger JL, Wohleb ES. The semantics of microglia activation: neuroinflammation, homeostasis, and stress. J Neuroinflammation. 2021 Nov;18(1):258. PubMed 34742308 ❐ PainSci Bibliography 52006 ❐ When I read this paper, I realized I had gone too far promoting the role of stress as a driver of neuroinflammation, and I wrote this very silly blog post about my mistake. It’s silly but also substantive and worthwhile if you want to learn more about this.
  42. Ji RR, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology. 2018 08;129(2):343–366. PubMed 29462012 ❐ PainSci Bibliography 52332 ❐
  43. It has been said that exercise is the closest thing there is to a miracle cure. “All the evidence suggests small amounts of regular exercise (five times a week for 30 minutes each time for adults) brings dramatic benefits,” we “age well” when we are active (Gopinath): less anxiety (Schuch), prevention of dementia (Smith) and a laundry list of other diseases (Pedersen), and as little as just 10 minutes per week might push back death itself (Zhao).

    But why is it so awesome? Exertion mobilizes extensive networks of biological resources that are relatively dormant while we’re watching Netflix. It’s biologically “normalizing,” pushing systems to work the way they are supposed to work. Exercise cannot normalize everything, but it does stimulate an incredibly broad spectrum of biological function — way more than any medicine, supplement, or superfood.

  44. Fu S, Thompson CL, Ali A, et al. Mechanical loading inhibits cartilage inflammatory signalling via an HDAC6 and IFT-dependent mechanism regulating primary cilia elongation. Osteoarthritis Cartilage. 2019 Jul;27(7):1064–1074. PubMed 30922983 ❐ PainSci Bibliography 52660 ❐

    This is a highly technical petri-dish study of the effect of “exercise” (mechanical loading) on the inflammation signalling of cartilage cells. Basically, they mechanically stressed samples of excised cartilage and cartilage cells. The surprising, good-news result was that the researchers reported that moderate loading actually reduced inflammation. That is, fewer inflammatory signals were produced by the cells.

    While it is a near certainty that too much loading would increase inflammatory signalling, it is nifty that mechanical loading in the “just right” Goldilocks zone might actually be anti-inflammatory. This implies a specific and substantive way in which “exercise is medicine.”

  45. Research shows strength training is a much more efficient form of exercise than most people realize, and almost any amount of it is much better than nothing. You can gain strength and all its health benefits fairly easily. For more information, see Strength Training Frequency: Less is more than enough: go to the gym less frequently but still gain strength fast enough for anyone but a bodybuilder.
  46. Bakker EA, Lee DC, Sui X, et al. Association of Resistance Exercise, Independent of and Combined With Aerobic Exercise, With the Incidence of Metabolic Syndrome. Mayo Clin Proc. 2017 Aug;92(8):1214–1222. PubMed 28622914 ❐ PainSci Bibliography 52977 ❐ “Participating in resistance exercise, even less than 1 hour per week, was associated with a lower risk of development of metabolic syndrome, independent of aerobic exercise. Health professionals should recommend that patients perform resistance exercise along with aerobic exercise to reduce metabolic syndrome.”
  47. Liu Y, Chu JMT, Yan T, et al. Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer's disease mice. Journal of neuroinflammation. 2020 01;17(1):4––4. PubMed 31900170 ❐ PainSci Bibliography 52495 ❐

    Lifting weights: good for Alzheimer’s? Good chance. This study clearly showed a neuroprotective effect from resistance training in mice. Compared to mice who were not given cute little barbells!

    It has been clear for many years now that exercise in general is neuroprotective — that is, it has an anti-inflammatory effect in the brain and slows down Alzheimer’s disease progression — but that insight mostly comes from studies of aerobic exercise. This study extends that effect to resistance training. Specifically: “improved cognitive performance and reduced neuropathological and neuroinflammatory changes in the frontal cortex and hippocampus of mice… [and] inhibition of pro-inflammatory intracellular pathways.”

    Obviously a human study would be more persuasive, but it’s still early days for studying neuroinflammation. Lots of what we now know about exercise physiology we learned from mice initially. It’s likely that the effect will be confirmed in humans as well.

    And now, just for fun… how exactly do you strength train mice? A ladder with a treat at the top, and teensy weights attached to their tails! I am not even joking: that really is how they did this. “The mice were motivated to climb up the ladder to a total of 15 times, with progressively heavier weights attached to their tails and a 2-minute rest in between each climb.”

  48. Killer SC, Blannin AK, Jeukendrup AE. No evidence of dehydration with moderate daily coffee intake: a counterbalanced cross-over study in a free-living population. PLoS One. 2014;9(1):e84154. PubMed 24416202 ❐ PainSci Bibliography 53892 ❐ “These data suggest that coffee, when consumed in moderation by caffeine habituated males provides similar hydrating qualities to water.”
  49. Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nat Rev Endocrinol. 2012 Dec;8(12):743–54. PubMed 23169440 ❐ PainSci Bibliography 52724 ❐ This paper discusses the role of the inflammatory reflex in obesity specifically, but frequently mentions the potential relevance to other conditions associated with chronic inflammation. The paper is all about “the intriguing possibility that dysregulation of vagus nerve-mediated signalling might contribute to the pathogenesis of obesity and its related comorbidities.”
  50. Koopman FA, Chavan SS, Miljko S, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016 Jul;113(29):8284–9. PubMed 27382171 ❐ PainSci Bibliography 53670 ❐
  51. All kinds of data hijinks could be hiding in a study that technical. My main concern is the use of the word “significantly” in the abstract, without any details (effect size in particular). All too often that wording, without clarification, means there was a statistically significant but clinically trivial result. With many treatment trials I can go digging for the effect size to confirm, but not here, the reading is too difficult for me to form any meaningful impression without spending an hour, and even then it might not be clear. And even if the paper does indicate a clinically meaningful result it’s still got “too good to be true” written all over it and may well prove to be difficult to reproduce.
  52. Atkins started in 1989, if you can believe that — practically ancient history now — though it didn’t achieve fad-diet status until the mid 2000s.
  53. Kossoff EH, Zupec-Kania BA, Rho JM. Ketogenic diets: an update for child neurologists. J Child Neurol. 2009 Aug;24(8):979–88. PubMed 19535814 ❐
  54. There are two main kinds of pain: nociceptive and neuropathic, or the more familiar pain of tissue damage and the more exotic pain caused by a damaged nervous system. Some pain isn’t easy to classify (fibromyalgia). For more information, see The 3 Basic Types of Pain: Nociceptive, neuropathic, and “other” (and then some more).
  55. Masino SA, Ruskin DN. Ketogenic diets and pain. J Child Neurol. 2013 Aug;28(8):993–1001. PubMed 23680946 ❐ PainSci Bibliography 53476 ❐


    Ketogenic diets are well established as a successful anticonvulsant therapy. Based on overlap between mechanisms postulated to underlie pain and inflammation, and mechanisms postulated to underlie therapeutic effects of ketogenic diets, recent studies have explored the ability for ketogenic diets to reduce pain. Here we review clinical and basic research thus far exploring the impact of a ketogenic diet on thermal pain, inflammation, and neuropathic pain.

  56. If fasting really does have general health benefits, there are all kinds of metabolic pathways to that happy ending, but it’s extremely likely there’s an anti-inflammatory effect in there somewhere. It’s the most likely specific example of how it would work as a broad metabolic tonic. While it’s conceivable that fasting could be good for us without an inflammatory effect, it’s unlikely.
  57. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. N Engl J Med. 2019 12;381(26):2541–2551. PubMed 31881139 ❐
  58. Two are underpowered studies that damn with faint praise; two are (sigh) actually a bit negative, true citation backfires. Tch tch: the NEJM authors didn’t read the fine print in what they were citing! So it’s truly a poor selection of citations to support the assertion that “fasting is anti-inflammatory.”
  59. Jordan S, Tung N, Casanova-Acebes M, et al. Dietary Intake Regulates the Circulating Inflammatory Monocyte Pool. Cell. 2019 Aug;178(5):1102–1114.e17. PubMed 31442403 ❐
  60. Crane JD, Ogborn DI, Cupido C, et al. Massage therapy attenuates inflammatory signaling after exercise-induced muscle damage. Sci Transl Med. 2012 Feb;4(119):119ra13. PubMed 22301554 ❐
  61. Seo BR, Payne CJ, McNamara SL, et al. Skeletal muscle regeneration with robotic actuation-mediated clearance of neutrophils. Sci Transl Med. 2021 Oct;13(614):eabe8868. PubMed 34613813 ❐
  62. Zwaag J, Naaktgeboren R, van Herwaarden AE, Pickkers P, Kox M. The Effects of Cold Exposure Training and a Breathing Exercise on the Inflammatory Response in Humans: A Pilot Study. Psychosom Med. 2022 May;84(4):457–467. PubMed 35213875 ❐ PainSci Bibliography 52067 ❐
  63. Pontzer H, Yamada Y, Sagayama H, et al. Daily energy expenditure through the human life course. Science. 2021 08;373(6556):808–812. PubMed 34385400 ❐ PainSci Bibliography 51994 ❐
  64. Klasson CL, Sadhir S, Pontzer H. Daily physical activity is negatively associated with thyroid hormone levels, inflammation, and immune system markers among men and women in the NHANES dataset. PLoS One. 2022;17(7):e0270221. PubMed 35793317 ❐ PainSci Bibliography 51450 ❐


linking guide

12,000 words