A key to a 'faulty' lock: Why Aussie researchers are excited about naltrexone for CFS

What does long COVID have in common with chronic fatigue syndrome?

First, there is the constellation of overlapping symptoms, including post-exertional malaise, brain fog, fatigue, gastrointestinal issues, palpitations and dizziness.

Then, there is the absence of an overarching treatment or cure.

But immunologist Professor Sonya Marshall-Gradisnik — who has been studying myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) for more than a decade and helped define the clinical criteria for the condition — has found another shared feature that could unlock a new treatment.

There is no known cause of ME/CFS, but impaired functioning of natural killer (NK) cells has been shown to be a consistent feature of this condition, says Professor Marshall-Gradisnik.

And her team at Griffith University in Brisbane have slowly been answering why.

Across numerous studies, they found that the ion channel receptors TRPM3 and TRPM7 — molecular ‘locks and keys’ that control the movement of calcium in and out of NK cells — malfunction in those with ME/CFS.

And when they looked at patients with long COVID, they found a similar malfunction in TRPM3 receptors.

“I am not saying that viruses are the cause; I am saying that the origin is potentially because these particular receptors are not firing to bring calcium inside the cell,” Professor Marshall-Gradisnik tells AusDoc.

Having identified the “faulty” mechanism, her team have also tested ways to fix it — including the use of low-dose naltrexone.

“We used naltrexone in the laboratory and found it indirectly acts on the key and opens the lock,” she says.

“It improved the influx of calcium inside the cells and made the lock restored in function.”

“That gave us the impetus to test low-dose naltrexone in a clinical trial and, hopefully, depending on the results, be able to use it for an intervention for ME/CFS.”

While low-dose naltrexone is sometimes prescribed off-label for patients with ME/CFS, the recent breakthroughs — along with results from small trials on long COVID — have provided hope that a validated treatment is within reach.

Professor Marshall-Gradisnik says the lock-and-key mechanism, which is also found on muscle cells, could explain why patients prescribed graded exercise therapy have poor outcomes.

“[If] you have not got enough ability to bring calcium inside the cell, then you are going to have problems with muscle contraction, relaxation, and that could then cause pain, which is what ME/CFS patients report.”

She adds that pacing activity, or working within a patient’s ‘energy envelope’, is now the preferred self-management option.

Although this is reflected in guidance in the US, the UK and even the state of Victoria, where health authorities no longer advise graded exercise therapy because of a lack of clinical evidence to support it, the RACGP is yet to catch up.

The controversial and outdated treatment has been recommended for ME/CFS in the college’s Handbook of Non-Drug Interventions since 2015.

Professor Mark Morgan, chair of the RACGP Expert Committee — Quality Care, says the handbook entry contained the appropriate precautions for clinicians to consider.

“It is a very carefully written guide,” the Gold Coast GP academic tells AusDoc.

“There are many caveats and a lot of caution about how that should be applied, in whom and when.”

But Professor Morgan acknowledged the need to update this guidance with the emergence of new evidence.

He also stresses that diagnosing ME/CFS remains a lengthy and complicated process.

“Standard approaches to diseases are based on identifying a particular medicine or therapy that works for a single disease state, but I don’t think CFS or long COVID fits comfortably in that paradigm.”

When asked about the perception — and misconception — that ME/CFS was not a real condition, he says this was not a widely held view among GPs.

“A message we hear from consumers is they feel they have not always been listened to, and I don’t think that is because of the individual GP’s knowledge.

“I think it is more about the system we work in and some of the limitations of that system, but it is also the fact that these conversations take time.

“When we go on a journey with a patient and support them, are open about what works, what we know does not work and the uncertainties, that is where we are most likely to build a therapeutic relationship and make headway.”

He adds that the emergence of long COVID had led to greater awareness of ME/CFS because of the clinical overlap.

This was echoed by Professor Marshall-Gradisnik, who hopes her team’s work understanding ME/CFS could also fast-track research into long COVID.

“We are only in the infancy of long COVID, and we didn’t have a case definition until very recently,” she says.

“But that better informs how we can differentiate people who have long COVID and how we can investigate … potential therapeutic interventions.”

Professor Marshall-Gradisnik’s trials looking at low-dose naltrexone for treating ME/CFS and long COVID will be recruiting later this year. To find out more or to see if your patients are eligible, email ncned@griffith.edu.au