10/21/2018 Chronic, Subtle, Systemic Inflammation

Chronic, Subtle, Systemic Inflammation

A possible insidious cause of mysterious chronic pain
updated Feb 19, 2018 (first published 2016)

by Paul Ingraham

SUMMARY
Chronic, subtle, systemic inflammation is a possible factor in stubborn musculoskeletal pain. It can have many underlying causes, from bad genes to

mild autoimmune disease (including allergies), smoking or other severe biological stresses, chronic infections, and even just getting old (known as

“inflammaging”). The greatest culprit is metabolic syndrome: a set of biological dysfunctions strongly linked to poor fitness, obesity, aging, and likely

emotional stress and sleep disturbance as well.

full article 4500 words

Ivanushkin

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 it, but this article is about one of the most insidious and interesting (of the many
insidious and interesting causes of pain). 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.

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 (Noijam.com)

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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. 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. 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. 3

Chronic low-grade inflammation might happen as a consequence of

“metabolic syndrome,” [NIH] a set of biological dysfunctions strongly
Aging seems to be inflammatory — no matter how fit,
linked to poor fitness, obesity, and aging. We know that metabolic
syndrome is clearly associated with at least some common pain skinny & calm you are.

problems, like neck pain 4 and back pain. 5

Much less speculative: aging itself seems to be inflammatory, no matter how fit, skinny, and calm you are. This is known as
“inflammaging.” 6 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.

Metabolic syndrome and/or inflammation may also be linked to severe chronic stress… or even stress that happened long ago,
during childhood. 7 The connection is speculative and poorly understood at best, but plausible. I’ll go into more detail below.
It’s of great importance, however, because it suggests that chronic low-grade inflammation might not be limited to the
metabolic syndrome stereotype of “old, fat, unfit.”

Another possibility, more speculative still — but still plausible — is that chronic low-grade inflammation could be a symptom
of mild autoimmune disease — diseases where our immune systems attacks our own tissues, the “why are you hitting
yourself?” diseases. 8 This could also have something in common with metabolic syndrome and aging, but it’s unknown.

Finally, there’s now good evidence that inflammaging is probably related to

Perspective! Many people get overzealous about
the gradual weakening of the immune system, which slowly allows some ideas like this. Quacks and cranks love to blame all
common minor infections to “reactivate” after lying dormant in our cells for or most health problems on subtle, speculative
years or even decades. 9 causes like low-grade inflammation or infection (and
of course they always believe they have the cure).
If you’re on the far side of middle age, or you’re younger but struggling with Don’t get carried away: these ideas are possible
your weight and/or major long-term stress, chronic inflammation could be factors, not holy grails.
your issue.

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: 10

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.’

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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 [Mayo] 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, 11 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
You’re not paranoid if they’re really after you & you’re
probably actually inflamed! 12 Inflammation may be why they are
sensitized. Or perhaps even the other way around. not “sensitive” if you’re actually inflamed.

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. 13 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. 14

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

There are strong but murky links between chronic pain and stress. 15 We feel literally aged by adversity — we speak darkly of
terrible events 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 can 16 — or if it “just” feeds back into it. 17
It’s possible that low-grade chronic inflammation is one way that stress can become painful. It might even be the way.

Inflammation is immunity’s fingerprint, and we know (or strongly

suspect) that “immunity is tuned by one’s emotions, personality,
We know that nervous-wreck monkeys are inflamed,
and social status as well as by other life style variables like sleep,
nutrition, obesity, or exercise.” 18 We know that nervous-wreck their immune systems a mess & the same thing probably

monkeys are inflamed, their immune systems a mess 19 — and the happens in humans.

same thing probably happens in humans. We know that rough

childhoods are a risk factor for several disorders that probably share
inflammation as a mechanism (Burke et al again).

The relationship between metabolic syndrome and inflammation is clear, but there may also be a link between metabolic
syndrome and stress, 20 and is almost certainly a link with sleep disturbance (which overlaps with stress, obviously). 21 If

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true, it means that metabolic syndrome could affect millions of people who would not otherwise be likely victims. But this is
quite speculative.

We know that sleep deprivation (one of the most common forms of chronic stress) actually ages us in an objectively
measurable way, 22 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. 23 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.

What can you do about inflammation and inflammaging?

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

Fitness: Undoubtedly critical! Regular moderate exercise really is the closest thing we have to a miracle drug or a fountain of
youth. The older you get, the more you should avoid the extremes: too much and too little are likely both a problem.

Do you even lift? You should! Weight lifting specifically is linked to a lower risk of metabolic syndrome. 24 It’s a more well-
rounded and efficient workout than most people realize. 25

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. 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.
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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 not confirmed that there is a link between stress and inflammation, stress management has
so many benefits that it is well 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.

Predictably, these treatment options look suspiciously similar to common treatment recommendations for fibromyalgia.

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 instance 26 ) — but if you’re drinking so much that it’s aggravating emotional stress with caffeine-
powered agitation and anxiety, that’s another matter.

Vagus nerve stimulation sure sounds great (maybe a little too great): stimulate your vagus nerve with an implant, et voila,
less systemic inflammation. There’s broad biological plausibility here, but almost no evidence. So far this hinges only on the
results of Koopman et al , who tested it on humans and reported that “these results establish that vagus nerve stimulation
targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans.” 27 Established, eh? Not
without replication! That’s overconfident for sure — this badly needs replication before celebration. 28 But it’s a genuinely
interesting topic, I think.

Reducing inflammation with a ketogenic (very low carb) diet

Diets that force you to mainly burn fat for energy, instead of carbohydrates — a “ketogenic” diet, like the infamous Atkins diet
— may be anti-inflammatory and/or de-sensitizing.

Ketogenic diets are so low in carbohydrates (sugars) that they force the body to burn fat for fuel, a novel metabolic state,
which is well-known to treat epilepsy in some children. 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 nerves 29 ). Although highly speculative, there are some reasons to think this might work, and some indirect
(animal) evidence that it does. 30 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 a completely experimental treatment. However, 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
Important: you can get “keto sticks” from a drugstore to
sure that you’ve given it an adequate chance. If you see a clear reduction in
verify that you are in a ketogenic state. It’s hard to tell
symptoms, that’s a strong sign that it’s working. In a spirit of moderation, I do otherwise.
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.

Fasting (or intermittent fasting)

Actual fasting might work simply because it includes ketogenesis, but it’s also harder and not as safe — so I’m less inclined to
recommend it. But if you are keen on the idea fasting for whatever reason (e.g. meditative, emotional, spiritual reasons) it’s

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another possibility to consider. Of course, the subject of fasting is rife with pseudoscience and big claims, but here are two
good sources to start with: Martin Berkhan’s LeanGains.com (start with his myths of fasting), and Dr. Bojan Kostevski’s thesis
paper, “The Effects of Intermittent Fasting on Human and Animal Health.”

About Paul Ingraham

I am a science writer, former massage therapist, and I was the assistant editor at ScienceBasedMedicine.org for several years. I

have had my share of injuries and pain challenges as a runner and ultimate player. My wife and I live in downtown Vancouver,

Canada. See my full bio and qualifications, or my blog, Writerly. You might run into me on Facebook or Twitter.

Related Reading

Why Does Pain Hurt? — How an evolutionary wrong turn led to a biological glitch that condemned the animal
kingdom — you included — to much louder, longer pain.

Surprising Causes of Pain — Trying to understand pain when there is no obvious explanation.

Trigger Points & Myofascial Pain Syndrome — A guide to the unfinished science of muscle pain, with reviews of
every theory and self-treatment and therapy option.

The Basic Types of Pain — Nociceptive, neuropathic, and “other”.

What’s new in this article?

Twelve updates have been logged for this article since publication (2016). All PainScience.com updates are logged to show a
long term commitment to quality, accuracy, and currency.

February — 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.
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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.

Notes

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). BACK TO TEXT

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 Surprising Causes of Pain. BACK TO TEXT

3. Hand LE, Hopwood TW, Dickson SH, et al. The circadian clock regulates inflammatory arthritis. FASEB J. 2016 Aug.
PubMed #27488122. BACK TO TEXT

4. 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 #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. BACK TO TEXT

5. 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 #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 — but rather that “systemic metabolic
factors associated with adiposity play a major role in the pathogenesis of LBP.”

Great example of what I mean when I say that we need to look beyond—way beyond—biomechanics to the messy “wet” factors
in chronic pain.
BACK TO TEXT

6. 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 #53291. “Human aging is characterized by a chronic,
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low-grade inflammation, and this phenomenon has been termed as "inflammaging." Inflammaging is a highly significant risk
factor for both morbidity and mortality in the 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.” BACK TO TEXT

7. 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.” BACK TO TEXT

8. 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 well permanently back off before getting severe enough to be diagnosed. BACK TO TEXT

9. 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 #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.” BACK TO TEXT

10. Lasselin, J. Low-grade inflammation and the brain. www.bodyinmind.org. Accessed 2016-12-08. BACK TO TEXT

11. 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 #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.” BACK TO TEXT

12. 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 #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 spinal fluid and blood of 40 fibromyalgia patients and compared with healthy
controls, finding an “extensive inflammatory profile.”
BACK TO TEXT

13. 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. BACK TO TEXT

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14. 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 #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.”
BACK TO TEXT

15. 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. BACK TO TEXT

16. 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.
BACK TO TEXT

17. 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 #53545. BACK TO TEXT

18. 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. BACK TO TEXT

19. Dr. Robert Sapolsky, regarding a study of low-status monkeys (Snyder-Mackler et al ), who have really 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.
BACK TO TEXT

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20. 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). BACK TO TEXT

21. 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 #53564. BACK TO TEXT

22. 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 #53312. “Age-related disease risk has been linked to short sleep duration and sleep disturbances…” BACK TO TEXT

23. 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 #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.
BACK TO TEXT

24. 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 #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.” BACK TO TEXT

25. Research shows strength training is 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. BACK TO TEXT

26. 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 #53892. “These data suggest that coffee,
when consumed in moderation by caffeine habituated males provides similar hydrating qualities to water.” BACK TO TEXT

27. 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 #53670. BACK TO TEXT

28. 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. BACK TO TEXT

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10/21/2018 Chronic, Subtle, Systemic Inflammation

29. 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 Basic
Types of Pain: Nociceptive, neuropathic, and “other”. BACK TO TEXT

30. Masino SA, Ruskin DN. Ketogenic diets and pain. J Child Neurol. 2013 Aug;28(8):993–1001. PubMed #23680946. PainSci #53476.

ABSTRACT
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.
BACK TO TEXT

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