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Fatigue

Amantadine is the go-to drug for fatigue in multiple sclerosis.

It seems a bit odd that we haven’t heard much about amantadine (Gocovri, Symadine, and Symmetrel) in chronic fatigue syndrome (ME/CFS) or long COVID. They are, after all, the two big fatiguing diseases on the planet, and amantadine is the go-to drug for fatigue in another highly fatiguing disease – multiple sclerosis (MS).

Fatigue is often the most limiting symptom found in MS. Given the generous funding that MS receives, it’s perhaps not surprising that the fatigue in MS has received many more treatment trials than the fatigue in “chronic fatigue syndrome” has. A recent systematic survey of clinical trials focused on fatigue in MS came up with a rather incredible 91 reviews and systematic reviews, 78 randomized controlled trials, no meta-analyses, and 107 clinical trials.

That review found that “all trials that compared amantadine (200 mg) with placebo showed a significant effect of amantadine on fatigue”. While the review pointed out the small nature and short duration of many of the trials, it also noted that amantadine is the only treatment currently recommended by the National Institute for Health and Care Excellence (NICE) for fatigue in MS.

The Long-COVID Amantadine Study

The 66-person, randomized, open-label, pre-vaccination, Iranian long-COVID trial, “A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigue“, was not placebo-controlled; i.e. everyone knew if they were getting the drug or not. The Fatigue Severity Scale (FSS) and Visual Analogue Fatigue Scale (VAFS) were used to assess the drug’s effectiveness. One hundred mg of amantadine was given once in the morning and once at night for two weeks.

The high p values (p<.001) indicated that the results were not due to chance; i.e. they were real. The VAFS score in those taking Amantadine decreased from 7.90 to 3.37 and in the control group from 7.34 to 5.97. The FSS (Fatigue Severity Scale) in those taking Amantadine decreased from 53.1 to 28.4, and in the control group from 50.38 to 42.59.

Put in plainer language, in those given the Amantadine, their VAFS score decreased from having “a high degree of fatigue that interferes with daily living” to “a low to moderate degree of fatigue” that does not affect daily living.

Placebo effect

The results were promising. A placebo effect could have added to them, however.

Those not given the drug, however, also reported less fatigue. Their VAFS score dropped from having “a high degree of fatigue that interferes with daily living” to “a moderate level of fatigue, which may affect your daily functioning and quality of life to some extent.”

Similarly, those taking the drug dropped from being “easily fatigued” and possibly being disabled by fatigue to having “a low degree of fatigue” on the Fatigue Severity Scale. Those not taking the drug were still categorized as being “easily fatigued”.

The authors reported that the side effects were transient and tolerable for patients, except for one who stopped taking the drug due to severe nausea and abdominal pain. They stated that the drug is usually well tolerated, and characterized it as having a “mild side-effect profile’. Amantadine is well-known for its ability to produce hallucinations but those appear to be mostly a problem at higher doses. Care should be taken when it is used with additional CNS stimulants or anticholinergic drugs.

The trial suggested then that over a short period of time, Amantadine may be able to substantially help with fatigue in some people with long COVID. The big fly in the ointment with this study was the lack of a placebo control group meant that a placebo effect – people anticipating that they might get better and therefore improving – could have contributed to the results.

We know that Amantadine can help with fatigue in MS and this study suggests it can help with fatigue in long COVID – so what is this drug?

THE GIST

  • It seems a bit odd that we haven’t heard much about Amantadine (Gocovri, Symadine, and Symmetrel) in chronic fatigue syndrome (ME/CFS) or long COVID.  Amantadine is the go-to drug for fatigue in another highly fatiguing disease – multiple sclerosis (MS).
  • With hundreds of clinical trials, fatigue has been well-studied in MS. A recent review reported that all Amantadine trials found that it significantly reduced fatigue.
  • A 66-person, randomized, open-label, 2-week long-COVID trial found that Amantadine significantly helped with fatigue. One symptom assessment found that those given the Amantadine went from “a high degree of fatigue that interferes with daily living” to “a low to moderate degree of fatigue that does not affect daily living.
  • Another symptom assessment found that people given fatigue went from being “easily fatigued” and possibly being disabled by fatigue to having “a low degree of fatigue”. People not given the drug improved their fatigue as well but not nearly to the same degree.
  • Note, though, that the trial was not placebo-controlled, indicating that the placebo effect could be responsible for some of the positive effects.
  • The authors reported the drug is usually well tolerated, and characterized it as having a “mild side-effect profile’. Few side effects were reported in the trial. Care should be taken when it is used with additional CNS stimulants or anticholinergic drugs.
  • The drug appeared to be effective and safe in the long-COVID trial but half the participants dropped out in an 8-week 1997 ME/CFS trial. Perhaps the drug is better used for short periods. The Clinician’s Coalition for ME/CFS reports the drug can be helpful for mild to moderate fatigue.
  • Amantadine tones down the excitatory neurons in the brain that may cause neuroinflammation, and increases dopamine and norepinephrine levels.
  • A recent review asserted that both Amantadine and a similar drug, memantine, “improve vigilance, lack of attention and concentration, (and) fatigue syndromes… in patients with chronic neurodegenerative processes”. Highlighting Amantadine’s help with fatigue or chronic exhaustion and memantine’s effect on cognition, they proposed that both be tried in long COVID.
  • Applying the Arseneau test of whether or not to try something: The evidence is not solid, but the fact that the drug might possibly help with fatigue, its low cost, and probably low risk suggests a short-term trial might be worth a try (???).

 

 

Amantadine

Amantadine has been around for a long time. Developed as an antiviral in the 1950s, it’s now used in central nervous system diseases. (It came to be used in Parkinson’s Disease after a person with Parkinson’s felt better after using it for the flu).

It’s believed to inhibit the overactivated excitatory NMDA glutamate receptors that may be causing neuroinflammation and burning out neurons in these diseases. It also increases the release of the feel-good neurotransmitter dopamine as well as norepinephrine in the brain. Like memantine – which may be helpful in fibromyalgia – amantadine also appears to have anticholinergic effects.

Amantadine also appears to be helpful in traumatic brain injury which can mimic the symptoms found in long COVID and ME/CFS.

Amantadine and ME/CFS

Amantadine Memantine

Amantadine is closely related to memantine. Both were recently recommended to be trialed to reduce fatigue and improve cognition in long COVID.

Once again, we see long COVID triggering treatment trials that could’ve, would’ve, and should’ve have been done in ME/CFS. A small early trial in ME/CFS, though, may have turned the field off to the drug.  A 30-person, 8-week 1997 trial found that half the patients dropped out and no discernible effects on fatigue or other symptoms were found.

Pointing to their quite positive findings from the long COVID trial and the lack of significant side effects, the authors suggested that 8 weeks may have been too much. In any case, amantadine is used from time to time in ME/CFS and the Clinician’s Coalition for ME/CFS states that amantadine “may help mild to moderate fatigue. May interact with psychiatric medications but does not warn about side effects in its usage section.

Another glutamate inhibitor – memantine – presents a possibility. A review of memantine’s effects on neuropathic pain stated that memantine has the “safest side-effect profile” and that the “excellent benefit/risk ratio” the drug presents made it a good target for larger studies. A recent placebo-controlled fibromyalgia study found that memantine moderately reduced pain levels. Another study indicated it was able to increase cerebral metabolism.

A recent review asserted that both amantadine and memantine “improve vigilance, lack of attention and concentration, (and) fatigue syndromes… in patients with chronic neurodegenerative processes”. Highlighting Amantadine’s help with fatigue or chronic exhaustion, and memantine’s effect on cognition, they proposed that both be tried in long COVID.

Applying The Arseneau “Should I Try a Treatment or Not” Test

The Arseneau test assesses the factors below to help decide whether or not to try a treatment. Note that different people will get different results. For instance, people with more resources may feel more comfortable trying more expensive and unproven treatments. Likewise, people who’ve had bad reactions to treatments in the past may be less likely to try things that don’t have a strong evidence base. In other words, the final results are person-dependent.

  • The credibility of the source – a journal publication, plus many studies in MS – the credibility of the source is good.
  • Quality of the evidence – lacking. A small study and good results but no blinding means a placebo effect could be present. Plus, we have an old negative ME/CFS study. Countering that, the drug is on the list of the Clinician Coalition’s drugs for possible fatigue reduction in ME/CFS and has been well-studied in MS.
  • The benefit, the cost, and the risk–benefit analysis – the benefit is probably moderate, and the cost is low (@$25/month). The risk is a bit iffy as a longer-term trial of the drug had a high dropout in ME/CFS but the drug has been tolerated well in MS and was in this long COVID trial.

 

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