Pathophysiology of sleep disturbances/unrefreshing sleep in pwME?

Hey guys.
I am wondering how much properly addressing sleep disturbances in pwME would help with symptoms. By properly I mean addressing the proposed mechanism that is out of whack in pwME, leading to unrefreshing sleep. From what I can tell from reading this review vertically (Table S3 for outcomes of trials included), the only consistent finding in studies that included MAI, is an increased MAI in pwME.

Has anybody stumbled upon studies where they look into this deeper? Try to elucidate the mechanisms behind this seemingly more fragmented sleep?

From own experience, without any medication I have sleep onset and sleep maintenance issues - and surely wake up feeling unrested despite sleeping for 7-9 hours.

As low as 300 mg of gabapentin (or pregabalin 75 mg) taken 1-2 h before sleeping (only 1-2 times a week to keep tolerance low) is the only medication I have tried that actually makes me feel more rested in the mornings and the whole day for that matter.

Other meds knocked me out, but did not subjectively improve my perceived sleep quality or gave me nasty side effects like migraines.

Besides countless supplements from minerals to amino acids to herbal extracts, I have tried H1-antagonists/inverse agonists (promethazine, hydroxyzine), SARI (trazodone - migraine city), benzodiazepines (alprazolam, diazepam) and modified-release melatonin (circadin). Probably more that I don't remember now.

In comparison to benzodiazepines for example, gabapentinoids (gabapentin and pregabalin) seem to increase SWS and reduce sleep fragmentation. Maybe this is why it seems to help me more than other drugs?

Other medication I will try are clonidine and baclofen. Both with different modes of action than gabapentinoids, but modes of action that in my view make sense to try out for pwME. Namely, a2 receptor agonism (clonidine), which could potentially address decreased HRV seen in pwME (at least during PEM) and GABA-B receptor agonism (baclofen).

Orexin antagonists are something I would like to try, unfortunately they are not available where I live.

Does anybody here have more knowledge on how exactly sleep is disturbed in pwME - and whether there have been trials to address exactly this?
I would assume that parts of the fatigue we feel could be alleviated by having some more restful sleep?

Edit: sorry if the post gets worse the longer it gets, my brainfog got worse by the minute.

 

I don’t have much information on the research side but I do have personal experience. There were definitely periods when I was getting as “perfect” sleep as I possibly could. The main thing that helped was a beta blocker (propranolol).

I’ve been using a sleep tracker app consistently, which probably isn’t the best data, but it has been very accurate in showing issues on the days when I wake up feeling even more crap than usual. It also showed that on the days I felt a little more “rested” (relatively), I got a lot more deep sleep. This was often preceded by days when I was active but not so active that it triggered PEM (I’m mild, it was still rare to strike this balance).

The main two things I noticed from getting better sleep quality is that I would recover from the negative effects of activity a little quicker, and that it helped a lot to wake up when my body naturally wanted to wake up with a consistent wake time, as opposed to getting ripped from sleep by an alarm.

Bad insomnia or an ability to get back to sleep after waking up at night would make me feel like an absolute zombie the next day, so good sleep helped to the extent that it prevented those extra awful days.

Because of the effect of beta blockers, I’m inclined to say that my own insomnia/sleep issues were probably due to some kind of sympathetic nervous system activation triggered after exertion. But even getting consistently good quality sleep didn’t alleviate my symptoms much overall, just made the very bad days with lack of sleep less frequent.

 

I used propranolol for POTS for a while and it definitely maybe me more sleepy, but I don't recall waking up more rested, unfortunately.

I see the exact same pattern for me, I am mild most days, used to be moderate.

100% agree. Makes me wonder how (1) how much of the fatigue we experience could be helped by improving sleep architecture longer term (let's say 6+ months of improved sleep architecture) and (2) if more severe people have worse sleep than mild/moderates.

Which surely is an improvement in quality of life! Happy to hear. What if your "very bad days" is a normal day for a more severe person and we could (at least regarding some symptoms) improve their QoL by regulating their sleep architecture?

I would really like to see a proper study on the mechanisms behind our unrestful sleep and follow up RCTs addressing those mechanisms.

 

I found that too. Gabapentin and melatonin helped me sleep more but not better, and the gabapentin caused weight gain. Sleeping pills made me feel awful and made no difference to sleep quality.

For me the best approach seems to be just living with it, because sleep that isn't naturally induced isn't really sleep. It's just a state of not-awake, and it does nothing to reduce fatigue and general awfulness.

Also, as meds always have some side effects, taking them seems to result a net loss in quality of life.

 

Thanks for sharing your experience. Do you remember how much you took, when you took it and for how long?

This is certainly the case with benzodiazepines, they do not improve deep sleep for example.

But I don't think it's necessarily true for all medication - I wouldn't know why it would be. They affect different stages of sleep.

Say a robust study finds out pwME have an altered EEG during a certain sleep stage that affects overall sleep architecture: If that person would take medication targeting that specific thing that makes their sleep unrestful, I would expect them to wake up more rested.

Sure do - proper dosing to maximize effects and minimize side effects would be imperative.




Orexin antagonists are something I would like to try, unfortunately they are not available where I live.

 

I had two phases on it, the first for pain (didn't work very well) and the second several years later for extreme menopause symptoms (absolute life-saver). I've taken pretty much all the normal doses in trying to find the optimal one, and exceeded it. None of them improved sleep quality, though, I remember that much because it seemed so counterintuitive.

Both phases lasted several years. I took it for drenching sweats for three years; first time round it was longer than that, but probably not more than four years.

 

My opinion is that ME's "unrefreshing sleep" symptom has nothing to do with duration or quality of sleep. I feel the same level of unrefreshedness regardless of how long or how well I slept, so I consider it a symptom that simply feels similar to lack of sleep.

I haven't noticed any significant correlation between my ME symptoms and sleep duration or quality. Maybe there is a difference, but it's so small that I can't tell. My sleep seemed normal when my ME started, and the increase in wakings and insomnia didn't occur until maybe 10 years into my ME, and my ME symptoms didn't seem to change in response to those changes in sleep.

 

Great that it at least helped for the menopause symptoms!

Interesting, thanks for contributing! How you you measure your "sleep quality"?
Using my smartwatch + Zepp/Notify for Amazfit and also my Polar verity sense armband + Sleep as Android, I can clearly see a stark increase in deep sleep and feeling more rested on mornings after having taken gabapentin at night.
For me (mild/moderate) more deep sleep absolutely translates to feeling more rested the next day. More in the sense of having less awful days though, similar to what @jnmaciuch said above, it's like peeling away one layer of symptom severity - if that makes any sense.

 

Personal judgement, no fancy devices. Bad quality (frequent wakings, slow to go back to sleep) is far easier to judge than superior quality.

For me, a night of poor sleep, or only a few hours due to insomnia, makes me feel like I didn't get enough sleep, but doesn't noticeably make my ME symptoms worse. It's hard to tell whether a response to a food trigger or whatever is affected by sleep, but there's no obvious correlation.

 

Alright. So what if your good quality night baseline (i.e. the nights that are not obviously bad) is full of microarousals that you don't perceive leading to fragmented sleep architecture (as has been shown in several studies for pwME)?

I am trying to dig through the literature, but too brain foggy today.

 

my personal view & experience is :

1) that good sleep will help symptoms (but not cure anything, except when you’re already on an upward spiral)

2) daily benzodiazepine help me sleep
- and help many PwME to relief symptoms, or shield PEM (think Whitney Dafoe)

3) pregabalin helps me better with sleep than benzo and relieves symptoms for the next day
– but may be because I only take it once weekly
- so no tolerance

so I think the effect pregabalin for sleeping is similar to benzo
- possibly specifically because it improves symptoms in general

 

Some quotes from this study from 2014:

I myself don't know what diagnostic criteria for ME are state of the art currently.

Results table:


The amount of SWS (slow-wave sleep) and sleep fragmentation (MAI) seem to be higher in CFS:

*excessive daytime sleepiness

However:

Interestingly, in this study on gabapentin they find a (non significant?) 13% increase in US delta power (delta-1) and (change of topic) a decrease in LF power and increase in HF power (indicating higher parasympathetic tone) during N3 (SWS).

Table.

Maybe these could be hints for why gabapentin seems to help me in terms of unrestful sleep?

 

Do you mean an inability to get back to sleep, @jnmaciuch?

 

Seems like this is a follow-up study of the EEG study I quoted in my previous post. Excerpts of the discussion sound interesting:

I like the sound of the idea regarding homeostasis. I wonder whether the increased amount of SWS seen in pwME is due to the body trying to counterbalance the increased microarousals.

Does anybody know if there have been any more studies, specifically looking into the changes in ultra-slow delta power and microarousals in sleep for pwME?

There's a meta-analysis on objective sleep measures in pwME, however they don't really touch upon the US delta and the MAI.

Here, they observed elevated delta power in awake EEG:

I am wondering if the higher MAI seen is due to increased sympathetic tone at night and if thus nightly clonidine (as mentioned earlier) could improve sleep architecture in ME. This paper seems to go deeper into microarousals. Will dig through when possible.
Will look for more data on gabapentinoids and baclofen or sodium oxybate (GABA-B receptor agonists).

Very interested in hearing more anecdotes!

 

Yes, sorry

 

I'd put that in the category of possibilities to consider if there was some reasonable evidence for it, but to ignore otherwise. I didn't notice any change in dreaming due to ME, or evidence of more movement during sleep, or any other such things. There could be changes in brain function that cause ME symptoms, but which don't register on present scanning technology, but that's the sort of thing that you can't prove or do anything about.

I view "unrefreshing sleep" as similar to the effects of a drug (benzos?). Take a pill and feel like you haven't slept for days. I take that as evidence that the feeling of inadequate sleep doesn't require inadequate sleep.

FWIW, 15-20 years into my ME, I started waking fully every 90 minutes, although able to fall asleep again. That didn't seem to have an effect on my ME symptoms. On the rare nights that I do sleep through some of those cycles, I don't wake feeling significantly more refreshed.

 

I was under the impression, that I provided several pieces of literature that indeed show evidence for an increased amount of microarousals (and reduced US delta power in SWS) during sleep in pwME. I thus don't fully understand what you are trying to tell me, sorry. Microarousals, as far as I understand, are not felt. I am specifically talking about changes in sleep architecture, not about all ME symptoms.

My previous "what if" question was not meant to speculate about some hypothetical possibility - it was meant to introduce the literature-based notion that your baseline might well not be a "healthy" (sleep architecture wise) baseline. Sorry for being unclear.

 

Sleep disturbance and unrefreshing sleep are probably separate things. Some patients suffer sleep disturbance as a part of their symptoms. Some (many?) don't. Unrefreshing sleep, on the other hand, is universal. As for me, sleep and symptoms are inversely correlated. I sleep better while suffering from PEM just as I sleep well when I'm suffering from a flu.

 

Interesting, thanks for sharing.

I don't think I perceive my sleep any better or worse when I have PEM or a flu. As in, I don't wake up more often or have any more insomnia. I wake up feeling less rested though.

With regards to separating unrefreshing sleep and sleep disturbances (I guess you mean sleep onset and maintenance insomnia) - I don't know but might well be different etiologies.
The literature I shared is specifically covering altered sleep architecture potentially leading to unrefreshing sleep in pwME and what some studies found is an increase in micro arousal index (unnoticed sleep "disturbances") and a decrease in ultra slow delta power in slow wave sleep (deep sleep).
Big question being "why is this happening?"

 

I'm questioning the claim that altered sleep pattern is the cause of unrefreshing sleep. Unrefreshing sleep is a hallmark/universal symptom (ME/CFS patients are constantly unrefreshed, after all) whereas altered sleep pattern is not. My take on it would be that it is one of plethora of anomalies in ME/CFS. One still could inquire why that is happening of course, just as one would about any other symptoms. And treating sleep difficulties may help just as it would in healthy people. But I just don't see it leading to refreshing sleep in ME/CFS. If it does, we may have found a solution to ME/CFS.