Wakefulness-promoting agents for severe fatigue: to use or not to use? 2024 De Wit et al

Abstract

About 20% of adults experience excessive daytime sleepiness or severe fatigue. Causes include somatic conditions, psychiatric disorders, and medication or drug use. Treatment depends on the underlying cause. If sleepiness persists despite optimal treatment of the underlying condition, exclusion of other causes, and behavioral interventions, wakefulness-promoting agents may be considered. However, no established pharmacological strategy exists for symptomatic treatment. Modafinil and stimulants like methylphenidate may offer some benefit based on experiences with narcolepsy or idiopathic hypersomnia. Studies in specific patient groups (e.g., multiple sclerosis, Parkinson's disease, traumatic brain injury, cancer-related fatigue) show variable results. The use of wakefulness-promoting agents is discouraged for addressing unexplained fatigue, as seen in the context of chronic fatigue syndrome.

English abstract only, https://pubmed.ncbi.nlm.nih.gov/38630073/
Account-walled article, in Dutch, https://www.ntvg.nl/artikelen/medicatie-tegen-ernstige-aanhoudende-vermoeidheid

 

Many years ago, when modafinil first came out, my consultant was running a trial using it for MS. He asked me if I wanted to try it, and I decided it was worth a go despite the potential drawbacks.

It gave me a lot more Mental energy in particular. Eventually, it led to relapse. Several years later, when I was doing really well (oh, happy days), I asked him if I could try it again as I was feeling more robust. he said no, because my previous experience with It was not uncommon (I’m not sure if he was referring to or MS or ME).

 

The abstract suggests a confusion between fatigue and sleepiness.
My understanding of ME/CFS is that sleepiness is not the problem.

I have experienced fatigue after Covid. I also experience sleepiness from time to time - often early afternoons. The two things seem to be quite unrelated. Sleepiness is not unpleasant, just irritating when one feels one should be getting on with something.

 

Yes, that sounds familiar.

But the abstract suggests that the authors genuinely do not distinguish fatigue from sleepiness.

 

My experience with modafinil is that it did help with fatigue (presumably the reason it was being trialled for MS). But it pushed me to doing more than my body could handle, though I did enjoy a few good weeks on it. Before I crashed, the biggest problem was that it would interfere with my sleep, so I would take it very first thing.

 

For many years I coped with 3 pots of coffee every day. I always wondered why I could drink a full pot and then go to bed an hour later.

I tried modafinil for quite some time. I felt almost driven. Eventually I started doubling the dose, eventually getting to the highest dose allowed.

My analogy is one of being a castaway on an island. When a ship goes by the castaway gets elated, jumping up and down and using energy. Even when the ship sails last the horizon the castaway is elated and energetic for days. Eventually one ship is unexciting but two ships a day result in energy. Even having many ships a day pass by is ineffective.

I was in hospital at the end of last year for a week. Forced bed rest and no opportunity to complete my autistic daily exercise routines. The month afterwards was delightful with large amounts of energy.

For the last five years I've abandoned all stimulants. I also recognize mental stimulation as draining energy, so an hour driving someone to the airport leaves me exhausted for a couple of days.

I tell people that I can do everything they do, but the cost is 20 times greater. I can walk a kilometer but it is like walking 20 kilometers.

The best solution for me is to recognize that the recovery time for any activity can be very long. Stacking up other activities without recovery is a big problem. I have learned to go into a dark, totally quiet room and lie down until I'm sufficiently recovered. Sometimes that means excusing myself for an hour or two. Sometimes it means spending days there.

 

I disagree if I'm reading this correctly. I've experienced hypersomnia and insomnia, and yes, one might feel that can do more, but it won't lessen delayed PEM from going over your limit. That being said, the quality of sleep does help improve that wired/tired/hangover feeling.

 

I didn't have a good experience with modafinil at all. It did give me energy, but I also felt agitated. Also, my nose got stuffy to the point where it felt like it was closed for business. My doctor said a couple of his other patients reported extremely stuffy noses from it.

I agree that it's important to distinguish between fatigue and sleepiness. Once, when my insomnia was at its worst, I went a couple of years without feeling sleepy, but I was so tired that I wanted to die.

 

i have to sleep MANY hours, and have to take medicine to get to sleep and also back to sleep.

this is because i need restorative sleep to try to get back to baseline from pem, which occurs continually.

both sleeping again and resting with eyes covered for hours half-asleep as a slow awakening seem to help. the latter seems to not work as well and take longer.

most of 24h is resting or sleeping; without healing pem, disease has very high risk of progression.

for me wakefulness medicine seems like it would prevent the healing of pem. it is actually more complex because of circadian and there is more to figure out. but i don't think wakefulness would help.

when i was ambulatory, doctors gave me stimulants and they had the effect of allowing me to do more, at too high a cost of my body doing more than it knew i could, whether i knew it or not.

in contrast, sleep medicines help stop the tide of not getting restorative sleep. but they are not without risks.

if i did get enough medicine at night and got to bed at the right time, i have improved oi and fatigue and health the next day.

 

Modafinil didn't feel like a stimulant to me (well, it doesn't feel like caffeine and it didn't feel like taking d-amphetamine as a student long ago). It apparently acts via a completely different mechanism (orexinergic) to either the amphetamines and their analogues or to caffeine. The only reason I tried it was my brief foray into the world of private POTS specialists, a couple of whom like it a lot for their patients.

It's often described as a "wakefulness-promoting agent" in the literature and that is accurate in my experience. It has a longer elimination half-life - ~12-15 hours - than many other stimulants and the initial twice-a-day dosing severely disrupted my (already fractured & fragmented) sleep.

I found that I could easily tolerate a single 100mg morning dose, but not the same dose on successive days for a period of weeks. After 2-3 weeks of use, I ended up in an odd cycle where either I would blithely push through the subtle warnings that I usually get - or perhaps it suppressed them? - and the continued over-exertion would cause me to crash very badly indeed.

I still very occasionally use the modafinil I have left: one single, one-off 100mg morning dose on a day when I absolutely have to do something (usually, these days, for a medical appointment). It really does have an anti-fatiguing effect, but I know from experience not to over-exert myself, to just do the one planned thing & then spend the next day resting.