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This is part three in a multi-part sleep series on fibromyalgia and chronic fatigue syndrome (ME/CFS) dedicated to Darden Burns.

Health Rising’s ME/CFS and FM Sleep Series

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O sleep! O gentle sleep! Nature’s soft nurse, how have I frighted thee, William Shakespeare

Sleep. If only one could get more of it or better of it, how much of fibromyalgia (FM) or chronic fatigue syndrome (ME/CFS) would simply disappear? Good sleep is so rare in these diseases that Dr. Eleanor Stein starts off the sleep section in her online ME/CFS/FM course by reminding her patients what a good night’s sleep actually looks like.

Unrefreshing sleep is ubiquitous in fibromyalgia and chronic fatigue syndrome

Nobody knows the effects poor sleep has on FM in part because no ones been able to consistently get people with FM to get really good, deep sleep. There are certainly ways to improve sleep, but consistently getting really deep, healthy sleep is just beyond most of us.

That’s unfortunate, as the costs of poor sleep are many. Sleep, it turns out, is not the absence of activity. Some parts of the brain are actually more active during sleep. Memories get encoded; cognitive connections get established; in a very real sense, learning takes place; toxins and sewage get pumped out; immune enhancement occurs; hormonal changes happen.

Getting poor sleep on the other hand, actually activates the fear center of the brain (the amygdala) – leaving us edgy and emotionally reactive. Lactic acid piles up, aerobic energy production declines, blood oxygen levels drop, sympathetic nervous system activity (fight/flight) spikes, your ability to fight off pathogens decreases, inflammation soars, the rates of atherosclerosis and heart attack increase. It’s not surprising, given all that, that consistently poor sleep is associated with increased mortality.

Pain, Fibromyalgia and Sleep

It makes intuitive sense that being in pain would impact one’s ability to sleep – and that’s what the studies have found. Being in pain makes it hard to relax enough (pain increases the fight/flight response) to get to sleep and to stay asleep. Poor sleep is often found in chronic pain conditions such as rheumatoid arthritis, osteoarthritis, cancer pain and headaches.

It actually goes both ways. Getting poor sleep is also a really good way to notch up your pain levels. Numerous studies have shown that depriving healthy people of sleep increases their pain sensitivity. Totally depriving a person of sleep over 24 hours results in the same kind of pain hypersensitivity found in fibromyalgia.

Poor sleep increases one’s risk of coming down with a widespread pain disorder such as FM.

Temporal summation or “windup” – the process by which the nervous system gets put into a hypersensitive state – gets wound up. Controlled pain modulation – the process by which pain signals get ameliorated – gets impaired. Both these problems are found in FM.

A 2018 study that followed two cohorts of patients over five and 15 years found sleep problems (such as trouble getting to sleep, waking up in the middle of night, reduced sleep times, non-restorative sleep) approximately doubled one’s chance of coming down with chronic widespread pain. (Interestingly, fatigue also dramatically increased one’s risk of coming down with widespread pain.)

If you were getting poor sleep prior to coming down with fibromyalgia, it’s possible that poor sleep increased the risk of getting it. Adding the pain of FM to the equation probably made your sleep worse. A combination of poor sleep and pain may have increased your risk for yet another common problem in FM – depression.

How much easier it would all be if we could all just get better sleep. The list of sleep problems that studies have found in FM is not a short one.

The Sleep Disturbances in Fibromyalgia

The feeling of waking up unrefreshed (or even feeling worse than when one went to bed) is very common in both FM and ME/CFS. So is daytime sleepiness and the need to take naps. These are mostly subjective, but still telling, measures. Both indicate there’s a real problem with sleep in FM.

One possible cause that has been looked at concerns the spikes of high frequency alpha brain waves that pop FM patients out of slow wave sleep. This is an intriguing possibility as it could provide a finding that was more or less unique to FM and ME/CFS. Questions regarding alpha brain waves in fibromyalgia and ME/CFS date back an astounding 45 years.

Follow-up studies, however, had mixed results over time.  A 2000 review cast doubt on the alpha finding and concluded that while sleep problems were present in FM, it was not a sleep disorder per se. A recent meta-analysis of 25 FM sleep studies did not – to the author’s surprise – find evidence of increased alpha brain wave activity in FM. Nor did it find the significant increase in arousals during slow wave sleep that alpha intrusions would produce.

Slow wave sleep

What slow wave sleep looks like on an EEG. Slow wave sleep is reduced in FM

The analysis did find, however, a reduction in slow wave sleep – which has been associated with unrefreshing sleep, widespread pain, tenderness and fatigue, as well as reduced sleep efficiency, longer wake time after sleep onset, shorter sleep times, and light sleep. While a smaller recent study did not find alterations in total sleep time, time to go to sleep, time awake after going to sleep, or levels of alpha-delta sleep, a quite large 2016 study (n=132 FM patients) found decreased sleep times and slow wave sleep (SWS), more difficulty going into deep sleep and wake times during sleep. Those findings seem set.

With its long, slow, perfectly synchronized waves, Walker characterizes slow wave sleep as a “nocturnal cerebral meditation” or long, slow swells rippling across a placid ocean surface.  Emanating from the middle of our frontal lobes (about the middle of our forehead), the swells transfer data from our short-term to our long-term memory stores in the neocortex. This type of sleep occurs during the early night-time and is a good reason not to stay up too late.  Your ability to remember something from the past day  and learn from it is a function of early night, deep slow wave or NREM sleep.

Other study results have not been validated.  One study, for instance, found reduced spindle activity. Spindles help tranquilize the brain – allowing it to achieve restful but productive sleep without interference from the outside. By integrating short-term memories gathered during the day into long-term databases in the brain, they also facilitate learning.

in contrast to slow wave or NREM sleep, spindle activity occurs in the late morning. If you’re consistently waking up early you might miss some of it.  With just one 16-year-old FM spindle study, though, we can’t say that spindle activity is impaired in FM.

Sleep Pt. I: Why We Sleep (and What Happens When We Don’t)

Ironically, given its prevalence in the population, only one small 2013 study (n=40) has assessed the prevalence of sleep apnea in FM as well. (Another older study found a high occurrence of periodic breathing – which may be similar to sleep apnea.) Dr. Klimas has reported finding a high incidence of sleep apnea in her ME/CFS/FM patients. The 2013 study found that over 60% of male FM patients had a high “apnea-hypopnea index” and 32% of women did. (Males also had poorer sleep quality and slow wave sleep). While no one thinks sleep apnea is the cause of FM, a couple of studies on sleep apnea would be very helpful clinically.

When It’s Not All ME/CFS/FM: How a Sleep Study Turned One Chronic Fatigue Syndrome Patient’s Life Around

It may be that sleep researchers are so focused on finding the cause of fibromyalgia they haven’t looked at comorbidities such as sleep apnea, which we know aren’t causing it, but which could be making the symptoms of fibromyalgia worse.

While studies have found numerous problems with sleep in FM, nothing yet indicates any unique problems not found in other diseases are present. Instead the sleep issues may be be part and parcel of having a disease characterized by chronic pain.

The Gist

  • Poor sleep has been found to increase the risk of coming down with a widespread pain disorder such as fibromyalgia.
  • Poor sleep also increases pain sensitivity, causes cognitive problems, disrupts the autonomic nervous system, dysregulates the immune system, impacts the cardiovascular system and on and on.
  • Studies indicate that people with FM typically experience reduced amounts of slow wave sleep, reduced sleep overall, take longer to get into deep sleep and have reduced sleep efficiency.
  • People with FM do not, however, appear to have increased intrusions of alpha brain waves. It does not appear that the sleep problems found in FM are unique to the disease. Instead people with FM appear to have an amalgam of sleep problems similar to those experienced by others in chronic pain.
  • Poorer sleep is clearly associated with increased pain in FM: the worse sleep you have the more likely you are going to be in more pain.
  • Only one sleep apnea FM study has been done but it suggested that high rates of sleep apnea may be present – particularly in men.
  • Recent studies suggest that activation of the fight/flight (sympathetic nervous system (SNS)) in FM is implicated in the sleep problems. One paper suggested a vicious circle had occurred: chronic pain jacks up the SNS, which impairs sleep, which then causes more pain sensitization.
  • From problems with the opioid system to neurotransmitters (serotonin, norepinephrine, dopamine) to orexin to nitric oxide, to immune problems, etc. many other systems may be affecting sleep in FM.
  • Neuroinflammation could potentially be at the root of the sleep problems in FM. Given the amount of work focused at batting neuroinflammation down in other diseases that might be a very good outcome…

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The Sleep-Pain Connection

The connection between poor sleep and pain is clearer. A systematic review of FM sleep studies that examined whether sleep problems were increasing pain in FM and assessed study quality found, as expected, some holes. Only one study, for example, objectively assessed sleep duration. All the studies found that people with FM were sleeping less than normal. One found reduced sleep times were associated with increased pain levels, while another did not.

The results were more consistent with sleep quality. All 9 of the studies measuring sleep quality concluded that worsened sleep quality was associated with increased pain levels in FM. The few studies which measured “sleep efficiency” – the amount of time spent trying to sleep vs time spent actually sleeping – found that reduced sleep efficiency was associated with more pain as well.

Overall, nine of ten studies found that poorer sleep was associated with more pain in FM. Several studies also found, not surprisingly, that poorer mood was associated with poorer sleep. That brings up the question whether the depression found in some people with FM might be more a function of their not being able to get a good night’s sleep.

The Cause of the Sleep Issues in Fibromyalgia

Given that sleep issues have been identified in FM and other chronic pain conditions, the next step is identifying the biological cause. A recent review, “Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications“, provides a good, but rather disconcerting, overview of the many possibilities present.

The senior author of the paper, Janet Mullington, interestingly enough, applied for an NIH ME/CFS research center. Way back in 2001 she authored a paper suggesting that cytokines and inflammation may be disrupting sleep in ME/CFS.

Autonomic Nervous System

Mullington has been on the cutting edge of understanding the role the autonomic nervous system plays during sleep – an intriguing subject for people with ME/CFS. Darden Burn’s dramatic arousals shortly after going to sleep may have resulted from poor ANS control. Just last year, Mullington co-authored a study which showed that restricting the sleep of healthy volunteers resulted in reduced heart rate variability – a common finding in both FM and ME/CFS.

Reduced sleep results in increased blood pressure during sleep. Other autonomic nervous system factors may play a role as well.

In 2017, she showed that chronically reduced sleep durations in healthy people was associated with reduced “blood pressure dipping”. Our blood pressure usually declines by 10-20% as we enter into slow wave sleep, but when Mullington restricted sleep in healthy people, she found that their blood pressure tended to remain high – and likely impaired their sleep further. Plus, she speculated that increased sympathetic nervous system activity may have resulted in blood vessel vasoconstriction or narrowing – thereby providing a new way to possibly explain the low blood flows in ME/CFS. Interestingly, sodium excretion – a possible factor in the low blood volume found in ME/CFS – also increased – which brought up the renin-aldosterone-angiotensin which we know is impaired in ME/CFS and POTS. All told, Mullington was able to potentially link a rather remarkable array of factors in ME/CFS to poor sleep.

Several studies have linked autonomic nervous system dysfunction to poor sleep in FM. One suggested that simply being in pain was creating a vicious circle of increased flight/flight or sympathetic nervous system activity, poor sleep and more pain.

 “A vicious circle is created during sleep: pain increases sympathetic cardiovascular activation and reduces sleep efficiency, thus causing lighter sleep, a higher CAP rate, more arousals, a higher PLMI, and increasing the occurrence of PB, which gives rise to abnormal cardiovascular neural control and exaggerated pain sensitivity.”

Other Possibilities

Mullington listed a rather daunting list of other factors could be whacking sleep – several of which are certainly options for FM. Since the opioid system affects both pain and sleep, problems with that system, such as decreased opioid receptor availability, have been proposed. That’s an interesting idea given a study which found just that problem in FM. Since the serotonergic system regulates both pain and sleep/wake control, a pumped up serotonergic system (see Cortene) is a possibility. Norepinephrine and dopamine are two other duo sleep/pain neurotransmitters – both of which have been possibly implicated in FM and ME/CFS.

Nitrogen oxide, the orexin system, the  paraventricular nucleus in the HPA axis, the immune and endocannabinoid systems and others could play a role. Problems with each may be found in FM and ME/CFS.

While disentangling the sleep issues in FM may not be easy, it’s possible one central actor – inflammation – could be behind all of these problems. Mackay proposed that inflammation was dysregulation the paraventricular nucleus – an important sleep/wake center in the hypothalamus.

A Novel Neuroinflammatory Paradigm for Chronic Fatigue Syndrome (ME/CFS)

 

Mulligan pointed to some recent data suggesting that reducing inflammation with biologic drugs may be helpful with sleep. Plus, prominent FM researcher Daniel Clauw also recently proposed targeting the glial cells that produce inflammation in the brain to improve sleep in diseases like FM, which are characterized by central sensitization (i.e. central nervous system caused pain and sensory hypersensitivity).

If, in the end, it all came down to combating central nervous system inflammation, that could be very good news indeed – as funding into that issue has been ramping up in other diseases. One hopes for real movement in that area in upcoming years.

This is part three in a multi-part sleep series on fibromyalgia and chronic fatigue syndrome (ME/CFS) dedicated to Darden Burns.

Health Rising’s ME/CFS and FM Sleep Series

Coming up – projected

  • The Sleep issues in ME/CFS
  • Treating Sleep – What do the studies say?
  • Outside the lab – Other Treatment Options
  • The Future Sleep Drugs

 

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