insomnia hyperarousal

Do people with ME/CFS and FM have the type of insomnia characterized by “hyperarousal”.

Insomnia may be common but much is still unknown about it. We know, for instance, that different types of insomnia exist, but the authors of a recent paper “Effects of trazodone versus cognitive behavioral therapy in insomnia with short sleep duration phenotype: a preliminary study” report that attempts to define them based on whether they are primary or secondary, age of onset, or even objective sleep findings have, for the most part, failed.  The answer, they believe is to go beyond the ordinary sleep findings and look deeper at what’s going on in the body.

Interestingly, they’ve turned to a subject of interest in chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) – the stress response system in order to better understand insomnia.

Check out the 4th part of an ongoing sleep series:

Two Types of Insomnia

ISS – the Stress Response Insomnia –  Not many studies have been done but the authors believe the results have allowed them to identify two distinct types of chronic insomnia: one called ISS (insomnia with short sleep and stress activation) produces insomnia and shortened sleep is associated with “physiological hyperarousal“; i.e. activation of the stress system and potentially a host of negative side-effects (hypertension, diabetes, cardiovascular disease, increased mortality.

INS – The Anxious Insomnia –  Insomnia with normal sleep duration (INS) is not associated with increased mortality, etc. but is associated with anxiousness and a tendency to ruminate. Note people with INS have normal sleep duration – they just have trouble falling asleep. That probably does not fit most people with ME/CFS/FM.


ISS (Stress Response Insomnia) Treatment – ISS (the stress response sleep disorder) is treated with drugs aimed at decreasing the hyperarousal, in particular, the HPA axis activation the authors believe is occurring during sleep. The two drugs they’ve focused on – doxepin elixir and trazodone – have long been used in ME/CFS/FM. Doxepin elixir was a favorite of Dr. Cheney – who years ago lauded its histamine-reducing properties. (Trazodone is a weaker histamine blocker.)

Doxepin Elixir (Sinequan, Silenor) for ME/CFS and Fibromyalgia

Trazodone, the second-most prescribed drug for insomnia, is also known to downregulate HPA activity. Trazodone has long been a go-to drug for sleep among ME/CFS/FM doctors. Other sleep drugs such as benzodiazepines and benzodiazepine receptor agonists do not downregulate the HPA axis.

Trazodone (Desyrel) For Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia

INS- Anxious Insomnia – INS is usually treated with cognitive behavioral therapy for insomnia (CBT-I). According to the authors, CBT-I – a management tool – can produce insomnia remission rates of 50%–60% and significant symptom reductions in 75%–80% of patients. Interestingly, it does not appear to be particularly good at improving sleep duration in people who get too little sleep. It’s more able to help people get to sleep and reduce symptoms.

Whether or not people with ME/CFS/FM have hyperarousal sleep patterns or not, CBT-I  might be something worth trying given the anxiety and changes to sleep times and rhythms that accompany poor sleep in these diseases.

Given that ISS is associated with an activated stress response system and CBT-I attempts to reduce anxiety it perhaps stands to reason that it might help with ISS. These authors believe, though, that more aggressive treatment is needed to get at the pathologically activated stress systems in people with ISS. Studies have found that CBT-1 is more effective in people with insomnia and normal sleep duration than in people with insomnia and shortened sleep.

The Study

The authors tested their hypothesis that HPA axis inhibiting drugs work better in insomniacs with ISS than in insomniacs with INS in a quite small, preliminary study (n=15) study which was randomized but also open-label (everyone knew what treatment they were getting) The treatments (drugs vs CBT-I) were randomized and actigraphy (done for several 2-week periods), salivary cortisol (five time-points during three periods), and the insomnia severity index assessments were done.

The CBT-I treatment included de-catastrophizing, constructive worry, and cognitive restructuring techniques. Trazodone (25-100 mg) was taken for 9 months.



Trazodone reduced cortisol levels during sleep by a whopping 36%.

Trazodone “significantly and markedly” lengthened objective sleep duration by about 50 minutes both at the post-treatment time point and at long-term follow-up. It also reduced cortisol levels by a whopping 36% “in a clinically meaningful manner”.  That the cortisol reduction was only “marginally significantly associated” with the increased sleep duration pointed to the possibility that upregulated cortisol during sleep was reducing sleep times but did not nail it.

The authors noted, though, that the HPA axis reduction/increased sleep time made sense as studies have shown that activating the HPA axis by intravenously injecting corticotrophin-releasing hormone produces increased wake times and reduced sleep times.

One fly in the ointment did possibly show up during the long-term assessment. A reduced drop in cortisol levels (from 36%-21%) suggested that long-term use of trazodone might result in tolerance. The study was so small, though, that other variables may have come into play, and ME/CFS doctors suggest the drug maintains its effectiveness long term.

ME/CFS and Fibromyalgia – Does the hyperarousal HPA axis sleep pattern apply?

HPA Axis

With regard to the HPA axis, salivary morning cortisol levels tend to be reduced (not increased) in ME/CFS.  Cortisol in fibromyalgia, on the other hand, appears to be increased including at nighttime. Unfortunately, sodium oxybate (Xyrem) did not get FDA approval for FM, but this alpha-wave reducing drug also apparently reduces morning cortisol levels. A couple of studies, though, have found low cortisol levels in FM.

The Gist

  • The authors propose that two different kinds of insomnia exist. One – called ISS – is driven by a pathological hyperarousal of the HPA axis which results in shortened sleep times and increases the risk of several serious conditions. The other – called IND –  is a more anxiety-driven type of insomnia that does not result in shorter sleep times overall or negatively affect health overall.
  • The first – which fits ME/CFS/FM better – is best treated, they believe, by drugs that tamp down the stress response. The second type of insomnia is best treated by cognitive behavioral therapy for insomnia (CBT-I).
  • The reduced parasympathetic nervous system activity found during slow wave (deep) sleep in ME/CFS and increased cortisol levels in fibromyalgia suggest that hyperarousals could be affecting sleep in these diseases. (Note, though, that low morning salivary cortisol is found in ME/CFS.)
  • Two sleep medications (low-dose trazodone, and Doxepin elixir) were proposed to reduce central nervous system hyperarousal and improve sleep. The small study assessed trazodone’s effectiveness in doing so and found that it substantially reduced cortisol levels, significantly improved sleep times by 50 minutes, and improved sleep overall. It was more effective in almost all ways than CBT-I.
  • Trazodone has been recommended by ME/CFS experts before and may be the least likely drug to lose effectiveness over time. It may also be able to reduce neuroinflammation. Doxepin elixir, on the other hand, appears to have better histamine-reducing properties.
  • Some time ago, a drug repurposing company proposed that trazodone + low dose naltrexone might prove particularly helpful in ME/CFS.



Autonomic Nervous System

A 2012 review noted that sleep study results in ME/CFS tend to be all over the map. For instance, some people with ME/CFS sleep too little while others sleep too much. Some studies have found evidence of alpha-delta intrusions that interrupt sleep while others have not. The amount of slow-wave, or deep, sleep may or may not be reduced. (One study found it was increased.) The heterogeneous nature of these diseases, the heterogeneous diagnoses used in study criteria, the inadequate state of testing, or other factors may contribute.

Interestingly, one finding that has seemed to hold up is a state of autonomic nervous system hypervigilance (reduced parasympathetic nervous system activity). One study found that low heart rate variability (HRV) was the best predictor of subjective sleep quality. Personally, my Oura ring and Garmin watch at times show remarkably high sympathetic nervous system activity (i.e. stress) levels during sleep.

Several studies suggest that the other stress response system – the autonomic nervous system – may be aroused during sleep as well. Several have found reduced parasympathetic nervous system activity during the deep stages of sleep (and NREM2) in ME/CFS, which is associated with reduced self-reported well-being and sleep quality. The authors of the most recent study in 2020 suggested that the reductions in parasympathetic nervous system activity may be inhibiting “the energy recuperation” that normally occurs during slow-wave sleep.

They proposed that even people getting normal amounts of slow-wave sleep may not be getting the benefits their sleep apps might suggest they are getting. They suggested that treatments designed to inhibit sympathetic nervous system activity and plump up parasympathetic nervous activity during deep sleep could be helpful.


Trazodone is a triazolopyridine derivative that is structurally more closely related to other triazolopyridine-derived drugs than the drugs that make up major classes of antidepressants.

By inhibiting the reuptake of serotonin and blocking the histamine and alpha-1-adrenergic receptors, trazodone reduces levels of neurotransmitters (serotonin, noradrenaline, dopamine, acetylcholine, and histamine) that are associated with arousal.

Trazodone is also classified as a “weak histamine antagonist”, but its histamine-blocking effects could conceivably be helpful in people with mast cell activation syndrome (MCAS). It may also inhibit neuroinflammation.

Some limited evidence suggests that trazodone may be able to regulate autonomic nervous system functioning as well. Trazodone reportedly helped with a disease called Barré-Lièou Syndrome (BLS), which sounds like a close cousin to ME/CFS and FM. BLS is characterized by autonomic and other symptoms including muscle stiffness, tinnitus, dizziness, insomnia, and widespread pain. It’s believed to be caused by hyperactivation of the autonomic nervous system due to trauma. Trazodone was found to “safely and effectively” treat it.

Mathew Walker has inveighed against the use of sleep drugs because he reports that they don’t improve sleep architecture and are associated with detrimental long-term effects. A recent review of trazodone (and other antidepressants as well as anticonvulsants and antipsychotics) reported that it and the other drugs had “a beneficial effect on sleep architecture” but may suppress REM sleep.

An interesting 2008 study suggested that trazodone may enhance the benefits of mindfulness practices such as cognitive-behavioral therapy (CBT) in some people. A small 2008 study found CBT plus trazodone resulted in greater increases in deep, slow-wave sleep in people with depression.

Trazodone For Chronic Fatigue Syndrome and Fibromyalgia

The IACFS/ME Primer for Clinical Practitioners states trazodone may be the sleep drug “least likely to lose effectiveness over time”.

2011 open-label FM study found that trazodone had the greatest effect on sleep, markedly improved sleep quality, sleep duration, and sleep efficiency, and also had moderate effects on other symptoms such as anxiety and depression scores and pain interference with daily activities. The authors called the improvement of sleep quality ‘striking’.

Another 2011 open-label FM study by the same group found that trazodone helped with “global fibromyalgia severity, sleep quality, and depression, as well as pain interference with daily activities”. When Lyrica (pregabalin) was added, there were further improvement improvements in morning stiffness, pain (body pain and pain severity), and anxiety. An interesting placebo-controlled 2018 study found that in Vit. D deficient fibromyalgia patients, trazodone (25 mg) given at bedtime + vitamin D 50 000 IU (international units) weekly significantly improved pain and sleep scores.

Spanish FM study suggested that low doses can effectively enhance sleep but that higher doses are needed to affect depression and FM symptoms.

Dr. Lapp reports that he has “excellent luck” with Trazodone, and Dr. Bell states that “Trazodone is one of my most favorite medications for sleep. Trazodone doesn’t cause dry mouth or stimulate the appetite (no weight gain) and puts you into deep stage three or four sleep.”

Since it works best in the early morning hours it is a good medication for those who wake early and can’t get back to sleep. It also helps with anxiety. Men may find that it may help with erections.

Trazodone + Low Dose Naltrexone for ME/CFS?

Trazodone has been recommended by several ME/CFS experts, but the most interesting part of the trazodone saga in ME/CFS concerns the hunt for a repurposed drug for ME/CFS that occurred about a decade ago. The CFIDS Association of America (now Solve M.E.) funded a firm called Biovista to analyze mounds of data and come up with an already approved drug/drug combo that could help people with ME/CFS.

Biovista identified a two-drug combo: trazodone plus low-dose naltrexone (LDN) – that it proposed could tamp down neuroinflammation. The findings were interesting because neither the trazodone nor the low-dose naltrexone drug trials had been published – yet Biovista pegged this drug combination as promising.

Low Dose Naltrexone Drug Combination Proposed for Chronic Fatigue Syndrome (ME/CFS)

Dose – Trazodone should be taken at least an hour before bedtime to treat sleep-onset insomnia. Dr. Bell starts at 25 mg (taken ½-2 hours before sleep) and works his way up (50-150 mg). Dr. Lapp recommends 50 mg.

Side Effects – Tachycardia is not normally associated with trazodone, but it was experienced by 32% of patients in a fibromyalgia study and was the most common reason for discontinuing trazodone in a Spanish FM study. That led the authors to suggest that autonomic nervous system abnormalities in FM may leave some patients more susceptible to tachycardia. Other possible side effects that might be particularly pertinent for ME/CFS/FM patients include low blood pressure, dizziness, light-headedness, and fatigue.

Trazodone (Desyrel) For Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia


The authors of this interesting study propose that two different kinds of insomnia exist. One is driven by a pathological hyperarousal of the HPA axis which results in shortened sleep times and increases the risk of several serious conditions. The other is a more anxiety-driven type of insomnia that does not result in shorter sleep times overall or negatively affect health overall. The first – which fits ME/CFS/FM better – is best treated, they believe, by drugs that tamp down the stress response. The second is best treated by cognitive behavioral therapy for insomnia (CBT-I).

Given the evidence of reduced parasympathetic nervous system activity during slow wave (deep) sleep in ME/CFS, and the findings of increased cortisol levels in fibromyalgia, the idea that hyperarousals are affecting sleep in these diseases makes sense. On the other hand, the low morning salivary cortisol levels found in ME/CFS, suggest the opposite might be happening with in the HPA axis. Clearly, more study using more fine-tuned assessments is needed concerning sleep in these diseases.

The two sleep medications (low-dose trazodone, and Doxepin elixir) proposed by the authors of this study to reduce central nervous system hyperarousal are, interestingly, in fairly common use in ME/CFS/FM and appear to be commonly used overall. Trazodone was found to reduce cortisol levels by about a third and was associated with substantially long sleep and better sleep overall. Trazodone may also be able to reduce neuroinflammation. Doxepin elixir, on the other hand, appears to have better histamine-reducing properties.





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