Insomnia Until it Hurts

We are used to thinking of insomnia as a symptom of stress — and it is.12 However, it is also hazardous in its own right. In this article I’ll discuss what little is known, and what we might reasonably guess, about the relationship between sleep disturbance and pain, especially the murky concept of muscle pain.3

“Answers”

xkcd #1345 © xkcd.com by Randall Munroe

The general biological importance of sleep

Certainly serious insomnia is nothing to mess around with. Insomnia is not generally fatal, of course, because there are all kinds of self-preservation mechanisms that kick in. But unchecked sleep deprivation is so serious that it can actually kill. Laboratory animals subjected to extreme sleep deprivation can die relatively swiftly of unknown causes — exactly what goes wrong is not clear, but their body temperatures start to drop and then they suffer rapid and widespread physiological failure. So sleep is actually required for life — for all life, in fact. Virtually every living organism sleeps — even simple ones without brains or nervous systems, or extremely simple ones, have circadian rhythms with distinct rest phases.

This strongly suggests that sleep-deprivation is potentially dangerous stuff, even when it isn’t lethal. A poison at a non-fatal dosage is still poisonous.4 And in fact there is a considerable amount of science confirming this general hypothesis. In his 1996 book, Sleep Thieves: An eye-opening exploration into the science and mysteries of sleep, Dr. Stanely Coren describes sleep deprivation studies in humans showing a number of ominous effects, and he generally makes a strong case that everyone needs to take sleep deprivation much more seriously than we generally do. Here are some other examples from much more recent scientific research:

• Insomnia causes migraines. A study of 1869 migraines clearly showed that “sleep obviously protects against [migraine] attacks rather than provokes them,” while a whopping 29% were actually caused by insomnia. I don’t know about you, but anything that protects against migraine attacks is good and I don’t want to lose much of it.5
• Insomnia makes you vulnerable to infections. We know that immunity is “tuned” by sleep6 (among other things). A 2009 paper shows that people with even minor sleep problems (less than 7 hours per night) get almost three times as many head colds.7 Even in healthy young people who generally sleep well, having a couple rough nights before flu vaccination appeared to impair their ability to produce antibodies.8 A statistical analysis of insomnia’s relationship to absences from work caused by illness clearly found that there’s a connection: insomnia is followed by periods of increased absenteeism from illness and disease.9 Yikes. Even more disturbing? The evidence shows that the effect is prominent up to two years after insomnia! •shudder•
• Insomnia makes you sick in the long term, too. Sleep disturbance is associated with “a wide array of perturbations spanning from obesity, insulin resistance, type 2 diabetes, the metabolic syndrome, and cardiovascular disease risk and mortality in both adults and children.”10 Metabolic syndrome does its dirty work via subtle systemic inflammation, which may be a driver of chronic pain in some people (although normally associated with obesity and inactivity, metabolic syndrome also occur in fitter people as well, due to factors like insomnia, stress, anxiety, depression).

• Insomnia can wreck your mood. 40% of psychiatric mood disorders are preceded by insomnia, and insomnia sets in at the same time as another 20% of mood disorders.1112
• Insomnia impairs athletic performance, getting more sleep boosts it,13 and injury rates and recovery are probably affected too.14

And still more! Roth et al. summed some of this up: “Chronic insomnia is associated with absenteeism, frequent accidents, memory impairment, and greater health care utilization. The most consistent impact of insomnia is a high risk of depression.”15

So sleep deprivation involves some ominous potential hazards. But what about pain?

Is insomnia painful?

Yes. “According to the majority of the studies, sleep deprivation produces hyperalgesic changes.”16 Here’s a persuasive selection of many research examples:

In early 2019 (surprisingly late in history), we finally have the first proper brain study of sleep deprivation, one of those studies that looks at what parts of the brain “light up.”17 Although pain doesn’t happen in just one area of the brain, there are specific areas responsible for certain major features of pain. Sleep deprivation boosts responses to pain “within the primary sensing regions of the brain’s cortex,” and — more sinister — suppresses activity in the areas we use to “fine tune” pain experiences (“regions that modulate pain processing-the striatum and insula”). And that is a hellish cocktail: louder pain alarms, and less ability to mute them.

To anyone who has lost a lot of sleep, that sounds very familiar. Stepping on Lego in your bare feet is just a lot worse when you’re exhausted.

As if that wasn’t bad enough, the same study also found that even “subtle” sleep disruptions can cause “consequential” changes in pain. It doesn’t take much.

A major driver of chronic pain is sensitization, basically turning up the “volume” on all pain.18 The phenomenon is well-known, but how it works is still a mystery, and its relationship with sleep has barely been studied. A 2016 experiment looked carefully at 133 patients with knee arthritis, comparing those who slept well versus those who did not. They found, with a high degree of certainty, that “sleep fragmentation may strongly affect the pain and CS relationship; consequently, these results underscore the importance of considering and treating sleep in patients with chronic pain.”19

The issue with fragmentation came up in a 2007 study: Smith et al. experimentally messed with the sleep of 32 innocent women, and found that they were significantly more pain-sensitive, finding that the effect was caused by sleep discontinuity, not deprivation alone (most insomniacs face both problems).20

What about the chicken/egg thing: which comes first, pain or sleeplessness? Once you have both insomnia and pain, they surely do cause each other, but one side of that equation is probably more important than the other, like a cyclist pushing much harder on one pedal than the other. In 2017, Gerhart et al. studied the which-came-first question of pain and insomnia in 105 chronic low back pain patients. The answer was decisive: pain followed sleeplessness much more than the other way around.21

An internet survey of over 2,500 people with fibromyalgia (a chronic pain condition) showed that insomnia was one of the most commonly identified aggravating factors.22 Whatever fibromyalgics find uncomfortable may be moving healthier people in the direction of increased sensitivity as well — they are a canary in the neurological mine. Simply put, if sleep deprivation does hurt, then fibromyalgics will notice it more readily than other people, and this is at least consistent with the fact that fibromyalgics believe that sleeplessness aggravates their symptoms.

Another survey found the fairly spectacular statistic that 53% of chronic low back pain patients had insomnia, compared with only 3% in pain-free controls.23 Critical thinkers might suggest that it’s most likely that low back pain that is keeping these people awake, but I don’t think that’s obvious at all. The jury must remain out for me. My clinical experience suggests that it’s just the opposite: chronic low back pain patients are often poor sleepers, and insomnia may routinely precede episodes of pain! All of this is also discussed in advanced low back pain tutorial.

And fortunately I’m not alone in this fairly counterintuitive idea. Kundermann et al. write, “Although it is well documented that subjects with different pain syndromes suffer from sleep disturbances, the direction of cause and effect in this relationship is still a matter of debate.”24

There hasn’t been much data on this topic outside of wealthier populations. A 2018 study went further abroad and looked at links between pain and severe sleep problems in many poorer populations.25 The data set was humungous, and the results were vivid: pain and sleep problems were strongly linked, and it is definitely not just a case of the “worried well” sweating the little stuff in our relatively cushy lives. The sleep-health link matters no matter where you’re from.

People who hurt cannot sleep and vice versa — and that’s true globally.

If insomnia does cause pain, the costs are even more serious

Can pain shorten your life? It’s a plausible and disturbing possibility.

A large study of four million Swedes looked for a correlation between increased mortality and work absenteeism due to painful musculoskeletal conditions.26 They found the first ever evidence that people who have musculoskeletal pain may have “an increased risk of premature death.” The researchers adjusted their data for “several potential confounders.” The costs of pain are often expressed in terms of hair-raising stats on the economics of work absenteeism — but they may be much greater still.

Pain and insomnia are clearly the perfect ingredients not only of a vicious cycle, each one worsening the other, but potentially a dangerous one. The stakes are high.

Sleep loss is inflammatory, and inflammation makes us lose sleep (and all of that is bad for our biology)

Sleep loss is probably terrible for our health in general because it’s inflammatory… and, because life is unfair, inflammation probably also makes it harder to sleep. Ugh.

The link between sleep and pain is partly based on some superficially simple inflammatory biology: bad sleep is inflammatory… and inflammation makes it harder to sleep, which is not so widely appreciated. That means that sleeping badly can actually make it harder to sleep well!27 This is a vicious cycle every extremely frustrated insomniac is all-too familiar with: being exhausted from a sleepless night is not a guarantee that you will sleep well the next night.28

So inflammation and sleep deprivation reinforce each other, and that vicious cycle is obviously in turn relevant to every kind of health problem that is mediated by inflammation, which appears to be most of them.

Do things really hurt more? Or does it just seem that way?

This is a thorny question, almost a philosophical one. It is well agreed in pain science that “seeming” is the whole ball of wax, the only thing that really matters: if something seems painful, it is. But we can still observe that some seemingly painful things are associated with measurable changes in tissues, while other seemingly painful experiences seem to occur in the absence of any such changes, and this difference is obviously of interest, and we’d like to identify it if we can. For instance, we mostly know about trigger points because they hurt, but only relatively recently in medical history have we begun to identify the tissue changes associated with that pain!

The lack of such signs in the tissues does not indicate an imaginary or hysterical pain, but either that we simply can’t identify an associated change in the tissues, or the difference exists in the complex functioning of the central nervous system itself — not so much a pain that’s “all in the your head” in the psychological sense, but a pain that’s “all in your brain and spinal cord.”

And all pain is also mediated by psychology. There is no such thing as pain that is “all in your body” — it’s impossible. See Pain is Weird for more about that interesting idea.

In 2004, Kundermann et al. tried specifically to approach this question of whether or not pain associated with sleep deprivation involves an “organic” change in the tissues, or is simply a difference in how painful things seem. They tested whether or not sleep deprivation changed perception in general or only pain perception. The result was definitely the latter. Pain sensitivity was increased without any other general effects on physical sensations, strongly suggesting that something “actually” hurt more, as opposed to just “seeming” that way (“without alteration of somatosensation in general”).

The authors concluded, “Because this suggests an effect truly specific for pain, research may now focus on its underlying mechanisms of action.”29

Such as …

The case for insomnia as an aggravator of trigger points specifically

Insomnia doesn’t just cause pain in general, and it doesn’t do it just by mucking with the volume of all your nerves. It probably causes “musculoskeletal pain” specifically. We’ve already given the examples of the effects on fibromyalgia patients and migraine sufferers. But insomnia is also a likely cause of increased muscle pain in normal, healthy people.

Moldofsky et al.’s sleep deprived subjects “reported more musculoskeletal symptoms” and “a significant increase in muscle tenderness.”30 The same researchers repeated those results in a second study.31 In 1999 Lentz et al. found in their sleep-deprived subjects a whopping “24% decrease in musculoskeletal pain threshold.”32 That’s tenderness in the muscles specifically — sensitivity to poking or “mechanical” stimualtion — as opposed to sensitivity to cold or heat as is the case in many of the studies mentioned previously.

Another sleep-deprivation study of nine men in 2001 showed that pain sensitivity increased 8% with a “sleep debt” of 40 hours (40 hours of lost sleep with no opportunity to recover). Even more interesting, letting them catch up actually had a much greater pain-relieving effect — “greater than the analgesia induced by level I analgesic compounds.” Cool!33

And so on.

We are still a long way from proving that insomnia affects trigger points specifically or directly. None of these studies even begin to try to correlate pain sensitivity and musculoskeletal symptoms with trigger points specifically. And how could they? A lot of the scientific know-how needed to reliably measure the presence and severity of trigger points is barely any older than this sleep research, and only a few people on Earth have it.

But there is plenty of reason here to make an educated guess that a lot of that increased sensitivity is related to trigger point formation. If we pull back from the science for a moment and think about our subjective experience, if we know that most pain and stiffness is caused by trigger points, then we also know that sleep loss makes them worse: who hasn’t had the experience of having a bad night and feeling distinctly stiffer, achier, more sensitive to pressure? Who hasn’t noticed that it is precisely such a morning when you are most likely to suffer from at least a tension headache, if not a migraine as shown in one of the studies mentioned earlier? Who hasn’t wished especially hard for a good shoulder squeeze after sleeping badly?

These common experiences are definitely consistent with trigger point aggravation. It is likely that there is a whole mess of physiology and psychology that produces those effects, numerous factors above and beyond trigger points alone. But it is also quite reasonable to imagine that the effect is dominated by a straightforward worsening of the same pain and stiffness caused by trigger points that we feel even when we’ve slept perfectly well. And this would be a good use of Occam’s razor (Wikipedia) — let’s not make this too much more complicated than it has to be!

A personal example: acute sleep deprivation causes extra muscle soreness after sports (quite a lot extra)

Ultimate is an intense Frisbee sport that can make almost anyone wicked sore.

The first ultimates games of the season have always been an ordeal. They are followed by 3-5 days of harsh delayed-onset muscle soreness. But in 2011 I started the season in unusually good physical condition, thanks to months of sprint intervals and strength training. For the first time ever I was not sore after my first games of the summer. And my DOMS-immunity continued in week two, so it didn’t seem to be a fluke.

That was then followed by some nasty sleep deprivation and jet lag. I suffered a great deal of it for two weeks — before, during and after a holiday to Amsterdam. When I returned to Vancouver and played ultimate again, I was really blasted sore. Quite extreme!

Coincidence? I think not. The scientific evidence is strong that sleep deprivation and disruption are major factors in chronic pain. This is the best example I’ve observed in the laboratory of me!

More personal perspective

I turned to a career in massage therapy in the late 90s largely because I was (and still am) an unusually “triggery” person. I am one of those people who just seems to have more than his fair share of trigger point discomfort. I relate well to my patients. I have been highly motivated to study the phenomenon of muscle pain.

In 2005, when I suffered from a particularly long and severe bout of insomnia, sleeping less than 4 hours per night for many weeks at a time, I experienced an inexorable increase in pain of all kinds, but especially trigger point pain. Every familiar old knot became loud and then vicious, and without question these sensations became the single most debilitating consequence of my insomnia.

Like Carl Sagan famously suggested, I try not to “think with my gut” and patiently wait for science to clarify the situation, one study at a time — it is okay to be uncertain. But if there is a topic in musculoskeletal health care that I have a “hunch” about, it’s this: insomnia is probably food for trigger points!

About Paul Ingraham

I am a science writer in Vancouver, Canada. I was a Registered Massage Therapist for a decade and the assistant editor of ScienceBasedMedicine.org 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:

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Notes

1. Knutson KL, Van Cauter E, Rathouz PJ, et al. Association Between Sleep and Blood Pressure in Midlife: The CARDIA Sleep Study. Arch Intern Med. 2009 Jun 18;169(11):1055–1061. PubMed 19506175 ❐ PainSci Bibliography 55440 ❐

   Bad sleeps — quantity and quality, probably especially if caused by stress — are associated with elevated blood pressure, according to a side project of the big CARDIA study of coronary artery disease. They used wrist gadgets to monitor sleep and blood pressure in more than 500 adults in their 30s and 40s. The authors say the sleep-BP link is supported by previous research and “laboratory evidence of increased sympathetic nervous activity as a likely mechanism underlying the increase in BP after sleep loss.”

2. U.S. Department of Health and Human Services. Perceived Insufficient Rest or Sleep Among Adults — United States, 2008. Morbidity & Mortality Weekly Report. 2009 Oct 30;58(42):1175–1179. PainSci Bibliography 55373 ❐ People unemployed or unable to work were at increased risk of sleep loss — likely due to the stress. And sleep insufficiency is most prevalent among those aged 25 to 34 and least among those 65 and older, which I think is also probably related to stress: people tend to suffer a lot more stress earlier in their careers.
3. Based on clinical observations and unpleasant personal experience, I have long believed that the pain and stiffness of myofascial trigger points — muscle knots — is probably aggravated by insomnia or even mild but chronic sleep deprivation. There is no direct scientific evidence to support this (to the best of my knowledge), but there is plenty of indirect evidence.
4. Actually, many astute readers will know that this is crap: most medicines are toxic in high dosages, and many so-called “poisons” are actually used as medicines in low dosages. But this is a case of “you know what I mean” — a lot of sleep deprivation is a bad thing, and a smaller amount of sleep deprivation is still a bad thing, just less of it.
5. Alstadhaug K, Salvesen R, Bekkelund S. Insomnia and circadian variation of attacks in episodic migraine. Headache. 2007 Sep;47(8):1184–8. PubMed 17883523 ❐

   This study of 1869 incidents of migraine clearly showed that “sleep obviously protects against [migraine] attacks rather than provokes them,” while a whopping 29% were actually caused by insomnia. I don’t know about you, but anything that protects against migraine attacks is good and I don’t want to lose much of it.

6. 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 ❐ “immunity is tuned by ones emotions, personality, and social status as well as by other life style variables like sleep, nutrition, obesity, or exercise.”
7. Cohen S, Doyle WJ, Alper CM, Janicki-Deverts D, Turner RB. Sleep Habits and Susceptibility to the Common Cold. Arch Intern Med. 2009 Jan 12;169(1):62–67. PubMed 19139325 ❐ PainSci Bibliography 56092 ❐ For a good summary of this research, see Sleepless Nights Equal More Colds In U.S. Study.
8. Prather AA, Pressman SD, Miller GE, Cohen S. Temporal Links Between Self-Reported Sleep and Antibody Responses to the Influenza Vaccine. Int J Behav Med. 2020 Mar. PubMed 32236831 ❐

   This study showed that antibody production in response to flu vaccination may be reduced by sleep loss — even in healthy people, even when the sleep loss is minor.

   83 healthy young people kept a sleep diary for two weeks, starting three days before a flu vaccination. The ones who slept the best for the two nights before their jab produced more antibodies to one of three kinds of vaccine, one and four months later. And, if sleep helps our immune systems respond more robustly to vaccination, it’s a safe bet that it probably helps with actual infection too. (And much else, no doubt.)

   Maybe a small effect on only one kind of vaccine is not a clinically meaningful result. The authors do acknowledge that they “did not find strong effects of sleep” but also emphasized that they were also measuring the effect of minor sleep loss in healthy young people. In subjects like that, a strong effect would have been quite surprising. The fact they could measure any drop in antibody production seems highly suggestive of what would happen in more vulnerable subjects.

   So the “just one study” caveat is needed, of course, but it’s exactly the kind of thing we have been seeing from other sleep research constantly for years. It plugs into the body of evidence quite neatly, and it seems like (yet another) reasonable incentive to emphasize rest.

9. Akerstedt T, Kecklund G, Alfredsson L, Selen J. Predicting long-term sickness absence from sleep and fatigue. J Sleep Res. 2007;16(4):341–345.

   This is a statistical analysis of insomnia’s relationship to absences from work caused by illness. They identified a clear connection and concluded that “disturbed sleep and fatigue are predictors of long-term absence [from work due to sickness] and it is suggested that impaired sleep may be part of a chain of causation, considering its effects on fatigue.”

10. 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 ❐
11. Ohayon MM, Roth T. Place of chronic insomnia in the course of depressive and anxiety disorders. J Psychiatr Res. 2003;37(1):9–15.
12. Neckelmann D, Mykletun A, Dahl AA. Chronic insomnia as a risk factor for developing anxiety and depression. Sleep. 2007;30(7):873–880.

    The results of this large and well-conducted survey are “consistent with insomnia being a risk factor for the development of anxiety disorders.”

13. Bonnar D, Bartel K, Kakoschke N, Lang C. Sleep Interventions Designed to Improve Athletic Performance and Recovery: A Systematic Review of Current Approaches. Sports Med. 2018 Jan. PubMed 29352373 ❐ Just getting more sleep at night “had the most beneficial effects” on athletic performance, compared to napping, sleep hygiene, and post-exercise recovery strategies for young athletes.
14. Watson AM. Sleep and Athletic Performance. Curr Sports Med Rep. 2017;16(6):413–418. PubMed 29135639 ❐
15. Roth T, Roehrs T. Insomnia: epidemiology, characteristics, and consequences. Clin Cornerstone. 2003;5(3):5–15. PubMed 14626537 ❐
16. Kundermann B, Krieg JC, Schreiber W, Lautenbacher S. The effect of sleep deprivation on pain. Pain Res Manag. 2004;9(1):25–32.
17. Krause AJ, Prather AA, Wager TD, Lindquist MA, Walker MP. The pain of sleep loss: A brain characterization in humans. J Neurosci. 2019 Jan. PubMed 30692228 ❐
18. Pain itself often modifies the way the central nervous system works, so that a patient actually becomes more sensitive and gets more pain with less provocation. This is called “central sensitization.” (And there’s peripheral sensitization too.) Sensitized patients are not only more sensitive to things that should hurt, but also to ordinary touch and pressure as well. Their pain also “echoes,” fading more slowly than in other people. See Sensitization in Chronic Pain: Pain itself can change how pain works, resulting in more pain with less provocation.
19. Burton E, Campbell C, Robinson M, et al. Sleep mediates the relationship between central sensitization and clinical pain. The Journal of Pain. 2016 2016/05/03;17(4):S56. PainSci Bibliography 53398 ❐
20. Smith MT, Edwards RR, McCann UD, Haythornthwaite JA. The effects of sleep deprivation on pain inhibition and spontaneous pain in women. Sleep. 2007;30(4):494–505. PubMed 17520794 ❐
21. Gerhart JI, Burns JW, Post KM, et al. Relationships Between Sleep Quality and Pain-Related Factors for People with Chronic Low Back Pain: Tests of Reciprocal and Time of Day Effects. Ann Behav Med. 2017 Jun;51(3):365–375. PubMed 27844327 ❐ PainSci Bibliography 51845 ❐

    This experiment was all about the chicken/egg question of pain and insomnia in 105 chronic low back pain patients, who bravely filled out five questionnaires per day for two weeks, tracking and rating many aspects of their pain and sleep quality. The main goal was to study “lagged temporal associations”: what happens after what? Are bad sleeps followed by bad days with back pain? Are rough days with back pain followed by lousy sleeps?

    Yes and no to those two questions.

    Poorer sleep was strongly linked to everything being worse — which is about as surprising as a dog barking at a squirrel. It’s the timing of that relationship that this study zoomed in on, and not only did a bad night clearly herald trouble across the board the next day — more pain, more disability, more doom and gloom (“catastrophizing”) — but “especially during the early part of the day.”

    The relationship did not flow the other way. That is, bad nights were likely to be followed by bad days… but bad days were not followed by bad nights.

    Gerhart et al. shines a nice bright light on a simple old question. The answer isn’t much of a shock to anyone who struggles with both back pain and insomnia, but it’s important and surprisingly rare to confirm this stuff with a good study.

22. Bennett RM, Jones J, Turk DC, Russell IJ, Matallana L. An internet survey of 2,596 people with fibromyalgia. BMC Musculoskelet Disord. 2007;8:27.
23. Tang NKY, Wright KJ, Salkovskis PM. Prevalence and correlates of clinical insomnia co-occurring with chronic back pain. J Sleep Res. 2007;16(1):85–95.
24. Kundermann B, Spernal J, Huber MT, Krieg JC, Lautenbacher S. Sleep deprivation affects thermal pain thresholds but not somatosensory thresholds in healthy volunteers. Psychosom Med. 2004;66(6):932–937. PubMed 15564360 ❐
25. Stubbs B, Vancampfort D, Thompson T, et al. Pain and severe sleep disturbance in the general population: Primary data and meta-analysis from 240,820 people across 45 low- and middle-income countries. Gen Hosp Psychiatry. 2018 May;53:52–58. PubMed 29807277 ❐
26. Jansson C, Mittendorfer-Rutz E, Alexanderson K. Sickness absence because of musculoskeletal diagnoses and risk of all-cause and cause-specific mortality: A nationwide Swedish cohort study. Pain. 2012 May;153(5):998–1005. PubMed 22421427 ❐
27. Rohleder N, Aringer M, Boentert M. Role of interleukin-6 in stress, sleep, and fatigue. Ann N Y Acad Sci. 2012 Jul;1261:88–96. PubMed 22823398 ❐

    The most pertinent passage from this wide-ranging review:

    In addition to the well-documented consequences of low-grade inflammation on the cardiovascular system, for example, the literature summarized here further shows that stress-induced IL-6 increases are closely linked to fatigue and reduced sleep quality. Since sleep is important also for recovery from psychological stress, long-term or repeated stress-induced activation of inflammation is a maladaptive response.

    For inflammatory conditions in particular, these findings add important insights to the well-understood effects of anemia and nighttime pain through inflammation, which is also mediated by IL-6. Evidence clearly suggests that changes in circulating IL-6 can cause changes in sleep quality. Conversely, reductions in sleep duration, quality, or efficiency are capable of increasing peripheral IL-6 concentrations. These results are probably related to the fact that IL-6 increase can also be observed in chronic stress, as a consequence of long-term changes in stress system activity. Taken together, these findings, from various fields of research, underscore the close relationship between IL-6 signaling with CNS processes, thereby making IL-6 a promising candidate for linking adverse CNS states with physical disease.

28. One might reasonably wonder how insomnia could ever end! Just like many other positive feedback cycles in biology, it is self-limiting. There are other factors involved, and eventually one of them dominates and we finally get a decent night’s sleep.
29. Kundermann B, Spernal J, Huber MT, Krieg JC, Lautenbacher S. Sleep deprivation affects thermal pain thresholds but not somatosensory thresholds in healthy volunteers. Psychosom Med. 2004;66(6):932–937. PubMed 15564360 ❐
30. Moldofsky H, Scarisbrick P. Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosom Med. 1976;38(1):35–44. PubMed 176677 ❐
31. Moldofsky H, Scarisbrick P, England R, Smythe H. Musculosketal symptoms and non-REM sleep disturbance in patients with "fibrositis syndrome" and healthy subjects. Psychosom Med. 1975;37(4):341–351. PubMed 169541 ❐
32. Lentz MJ, Landis CA, Rothermel J, Shaver JL. Effects of selective slow wave sleep disruption on musculoskeletal pain and fatigue in middle aged women. J Rheumatol. 1999;26(7):1586–1592.
33. Onen SH, Alloui A, Gross A, Eschallier A, Dubray C. The effects of total sleep deprivation, selective sleep interruption and sleep recovery on pain tolerance thresholds in healthy subjects. J Sleep Res. 2001;10(1):35–42. PubMed 11285053 ❐