Repurposing Drugs for Post–COVID-19 Fatigue Syndrome Methylphenidate, Duloxetine, and Brexpiprazole, 2022, Manu

https://journals.lww.com/americanth...ng_Drugs_for_Post_COVID_19_Fatigue.97973.aspx

pdf only

 

Whole article?

 

Methylphenidate, Duloxetine, and Brexpiprazole - these can otherwise be described as Ritalin, Cymbalta, and an atypical anti-psychotic - also described in Wikipedia as 'a dopamine D2 receptor partial agonist and has been described as a "serotonin–dopamine activity modulator" (SDAM)'.

It would appear that changing the thoughts and brains of sufferers is the prime purpose of these drugs. Ritalin can be addictive, Duloxetine/Dymbalta definitely is, and anti-psychotics are (I think).

Clearly there is no intention to worry about the physical health of sufferers. The possible side effects of these drugs are terrifying. Anyone with Long Covid should be afraid - very afraid.

 

I see a disaster.

 

Changing the brains of sufferers is exactly what you want to do if it turns out the underlying pathology in ME/CFS and long COVID lies in the brain. It has not been demonstrated, but there at least aspects of the disease that point to that such as ANS dysfunction, brain fog and some neuroinflammation findings.

I haven't read about any success stories from Ritalin or Cymbalta, but Brexpiprazole is a "successor" to Aripiprazole aka Abilify, which some even rather severe patients have reported improvement on in a low dose. Almost all of them developed tolerance and lost the benefits over time, but there is a potential for these type of drugs to treat more than just thoughts.

 

Blood clots in the lungs? Or the heart? Chest pain? The gut? Diarrhoea?

I'm sure there are many other symptoms of Long Covid than those above, and some of them may have a cause lying in the brain, I'm not denying that. But prioritising the brain rather than the lungs or the heart or the gut or the kidneys or whatever doesn't seem to be covering many of the possible angles. If someone has clots in the body causing pain or breathlessness then fixing those may fix depression. It depends on what is causing the depression.

I find it tiresome, this constant belief of doctors and researchers that they must give patients brain altering chemicals as the very first thing they do rather than fixing the things that cause pain as the first port of call.

 

Hmm.. not really. ANS dysfunction, ie dysautonomia, is found in many conditions which have been demonstrated to be caused by a physical pathological process outside of the brain.

“Examples of diseases in which secondary dysautonomia can occur include:

• Diabetes.
• Parkinson’s disease.
• Multiple sclerosis.
• Rheumatoid arthritis.
• Lupus.
• Sjogren's syndrome.
• Sarcoidosis.
• Crohn’s disease, ulcerative colitis.
• Celiac disease.
• Charcot-Marie-Tooth disease.
• Chiari malformation.
• Amyloidosis.
• Guillain-Barre syndrome.
• Ehlers-Danlos syndrome.
• Lambert-Eaton syndrome.
• Vitamin B and E deficiencies
• Human immunodeficiency virus (HIV).
• Lyme disease.

Some of the conditions caused by primary dysautonomia include:

• • Neurocardiogenic syncope (NCS):NCS is the most common form of dysautonomia. It can cause fainting spells that happen once or twice in your lifetime or multiple times every day. NCS is also called situational syncope or vasovagal syncope.
  • Postural orthostatic tachycardia syndrome (POTS): A disorder that causes problems with circulation (blood flow), POTS can cause your heart to beat too fast when you stand up. It can lead to fainting, chest pain and shortness of breath.
  • Familial dysautonomia (FD): People inherit this type of dysautonomia from their genetic relatives. It can cause decreased pain sensitivity, lack of eye tears and trouble regulating body temperature. FD is more likely to affect Jewish people (Ashkenazi Jewish heritage) of Eastern European heritage.
  • Multiple system atrophy (MSA): A life-threatening form of dysautonomia, multiple system atrophy develops in people over 40 years old. It can lead to heart rate issues, low blood pressure, erectile dysfunction and loss of bladder control.
  • Pure autonomic failure: People with this form of dysautonomia experience a fall in blood pressure upon standing and have symptoms including dizziness, fainting, visual problems, chest pain and tiredness. Symptoms are sometimes relieved by lying down or sitting.”

https://my.clevelandclinic.org/health/diseases/6004-dysautonomia

As for brain fog, there’s not enough research about that, but I’ve seen MS and sleep apnoea linked to brain fog, for example.

 

@JES is likely referring specifically to MECFS, and not generally to Long Covid. Several MECFS patients have responded well to Brexpiprazole (rexulti), similarly as many have responded to LDA (low dose Abilify)—same drug class. It’s pretty clear that MECFS is a neurological disorder, so I agree with @JES that it makes sense to look for treatments that affect the brain.

 

Both of these are neurological disorders, which means they do involve the brain.

 

Duloxetine is one of the pain relief options open to PwME. Mixed experiences but it does work for some ( MEA have a leaflet on it).


It's also used for bladder issues.
Gp has suggested it gor my daughter as the muscle tightness she has affects bladder and currently there is no way she could the testing procedure to fully assess this.

Under consideration.

 

I was referring specifically to Long Covid.

Duloxetine/Cymbalta has a reputation as one of the worst anti-depressants for prolonged SSRI discontinuation syndrome/post-acute withdrawal syndrome there is, as well as some very unpleasant adverse effects. As someone who has gone through this personally (although not with Duloxetine) I would never want to go through this ever again. The fact that doctors so casually prescribe such a drug still shocks me. And the fact that doctors no longer prescribe pain relief to many people in pain but prefer to prescribe drugs like Duloxetine also horrifies me. They've been doing this to women for decades (prescribing anti-depressants), but now they are doing it to everyone of any age, including children and both genders. I have a suspicion though that if the numbers were available such drugs would be prescribed far more often to young girls rather than young boys. I just can't get my head round it at all and I despair.

Edit : Another major problem with duloxetine is that people trying it for just a week or two can get severe withdrawal problems. It really doesn't take long to become a long-term problem. Some people never recover from discontinuation syndrome.

 

Google Scholar gives just a single retrospective study of off label prescribing i.e no controls - https://link.springer.com/article/10.1186/s12967-021-02721-9

ME/CFS may or may not be wholly or in part, in all patients or in some, a neurological condition but giving people medications merely on the basis that they 'affect' the brain seems a somewhat 19thC approach. The Stanford study did at least give a nod to having an hypothesis - "that ME/CFS involves inflammation of the brain" although it did not set out to test that hypothesis. Anyway the authors close with: "Overall, these results suggest that aripiprazole may effectively reduce symptoms of ME/CFS and warrants further investigation in a randomized clinical trial." which is a very long way from confirming that aripiprazole (at some dose or another !) is either suitable or helpful to ME/CFS patients.

 

thanks @Arnie Pye
I've been digging this morning and it dosn't look good - one of the side effects is a tightening of bladder muscles ( i suspect this is why it is used for bladder issues/ stress incontinence) - I can only supose that the GP is a bit confused as the issue is the opposite.

 

Yeah, the study was preliminary, small and low-quality, which isn't surprising since nobody from my knowledge did any groundwork or even attempted to look at Abilify and ME/CFS connection despite the drug existing for 20 years. I don't even have particularly high hopes for that one, but again it's something that could have easily been looked into and rejected if so deemed long ago.

It's the bigger issue I think. We can never get to a point of having phase three trials with the rate at which new drugs have been tested for ME/CFS. Rituximab, cyclophosphamide, CT38, rintatolimod... is there anything else that has reached even preliminary trials in the past decades? In order to hit the jackpot, I think they need to be testing hundreds if not more drugs and specifically by re-purposing ones that already exist.

With the long COVID research at least we have some drug trials underway now.

 

If she might be able to tolerate gabapentin, it can work like a dream for these issues. I had awful trouble, constantly needing the loo because of pressure on my bladder and always in pain from muscles that wouldn't relax. It really helped; like everything it has some unwanted effects, but at least I know it's there if I ever get into a really bad run with involuntary muscle tension again.

I've taken it twice, once for this (for about 10 months) and once for intractable menopausal drenching every few minutes (about three and a half years), and was able to taper off it slowly without having too hard a time. Even on a comparably low dose it makes me feel a bit weak and sluggish, so it's not something I'd want to stay on permanently—but luckily, a lot of symptoms do change over time.

 

Perhaps the involvement of e.g. dopamine, serotonin, --- something neurological --- would be indicated by a GWAS study? Yes, it seems to be inappropriate to give toxic drugs when there's no evidence that ME/CFS is a disease treated/targeted by those drugs.

I wonder if these drugs have been prescribed in people who have ME/CFS, e.g. if there was a culture of labelling ME/CFS as a psychiatric condition and these are commonly prescribed antipsychotic drugs, and if so is there any evidence that they worked?

 

Thank you @Kitty

 

Thankfully the suck it and see approach to pharmaceuticals is (mostly) not how science operates although open label prescribing remains an area open to abuse. Companies lacking the resources for full Phase 1- 3 trials, owning the rights to an orphan drug or some novel chemical of putative medical value, where the the main objective of the owners is to hype the share price with the hope of an eventual sale to one of Pharma majors are not unknown for overclaiming medicinal benefit when parasitically preying on patient desperation via pumping the drug out via compliant clinicians.

I don't know (or understand) enough about GWAS design to have a view on what might come out of the Decode ME study in respect of highlighting potential research avenues - however GWAS has certainly been used to aid research into repurposing/repositioning drugs. A couple of useful reads:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097480/

https://sci-hub.se/10.1038/nrd.2018.168

It's important to understand that repurposing/repositioning isn't some quick fix, yes it is faster and a lot cheaper than new discovery, but bringing a drug to full approval, and consequent availability via insurance, health provider etc still takes years and costs many millions - https://sci-hub.se/10.1177/1740774515625964 Phase 1 and 2 might be subject to short cut in some cases but to show the claimed benefit of a treatment you need a properly powered Phase 3 trial , to show that the drug has a beneficial effect beyond mere chance, and that for a particular patient group isn't more harmful than beneficial.

Re: the anti psychotic aspect, the doses are so low that comparison with schizophrenia treatment are probably not relevant even for the confirmed psychosomatic believers. I think the vulnerability of the patient group - willing to try anything - is the distinguishing feature.

 

Would rituximab be worth trialling for long covid

 

No, because most of Long Covid is likely yet to be diagnosed MECFS, and Ritux was not effective in treating MECFS. Cyclophosphamide is a possibility, but received negative reviews from some despite demonstrated effectiveness in a non-RCT study.