What to do when robust evidence; i.e. evidence-based medicine – medicine that has been thoroughly assessed by scientific studies – just isn’t present? That’s the dilemma that both ME/CFS/FM and long-COVID doctors and patients have faced for decades, yet this is the first time that I remember anyone explicitly addressing it. (Thanks to Karen for letting me know about it :))
If anyone knows how to tackle this knotty issue, though, it would probably be Dr. Ric Arseneau, an ME/CFS/FM specialist who once taught medical residents how to interpret and use evidence-based medicine.
Dr. Arseneau ((MD FRCPC MA(Ed) MBA FACP CGP) has an unusual history. He started off as a veterinarian, became an MD, received an MA and a PhD in Adult and Higher Education, garnered numerous teaching awards, then got an MBA in Business Administration, and about ten years ago trained in Group Psychodynamic Psychotherapy.
In 2021, he was the Physician Lead on the Provincial ECHO Education Program for Long COVID and was the Director of Program Planning for Complex Chronic Diseases Clinic at the BC Women’s Hospital from 2013 to 2019.
Before we get to the treatment section, check out a British Columbia long COVID update from Dr. Arseneau.
A British Columbia Long-COVID Clinic Update
Lamenting the closing of the province’s Post-COVID Recovery Clinics, Dr. Arseneau reported that “very few” B.C. physicians he knows of are taking on the long-COVID patients despite the fact that:
“in the majority of (long COVID) patients that… (he sees), it’s lifelong. About three-quarters of the patients that (he sees) are unable to work.”
“This is real. We need to have an organized approach to taking care of these patients. The haphazard (approach), wherever you happen to fall, is just not going to cut it. The idea of closing these long COVID clinics — it’s like I tell my patients, we may be over COVID but COVID is not over us.”
For its part, citing a reduction in monthly long-COVID referrals, from a high of about 755 in 2021 to 80 per month, British Columbia reported that it consolidated its five post-COVID clinics into a virtual, online service.
Arseneau reported, though, that the complex, chronic diseases clinic at the B.C. Women’s Hospital has a 3,000-person waitlist.
How to Decide What Medications/Treatments to Try When Large Evidence-Based Medicine Studies or Protocols Aren’t Available
Dr. Arseneau posted this video on his ME TV YouTube channel.
Note that I added some tidbits to the talk – many of which are in parentheses – which may not conform to Dr. Arseneau’s thoughts.
Neither ME/CFS nor fibromyalgia have much in the way of evidence-based medicine – at least not in the way it’s usually thought. These diseases don’t have the 10,000-person randomized, placebo-controlled trials to go on that cardiologists, say, do. We’re really happy when we get a 100-person trial!
Dr. Arseneau noted that if he could only make treatment prescriptions based on meta-analyses of large clinical trials that provided practice guidelines, he literally would have nothing to offer his patients.
That said, evidence-based medicine has evolved and now incorporates what the patient is willing – and can – pay, what type of risk the patient is willing to take on, what kinds of treatments they prefer, who they trust, etc. Plus, deciding what treatments to try has taken on extra meaning in the era of Dr. Google, blogs, Twitter accounts, etc.
Four Factors to Keep Aware of
- Beware of vested interests – cigarettes were once touted as cures for asthma
- The credibility of the source – is it a blog (and if it is, is it a good blog?), a tweet, a patient report, doctor’s report, etc.
- Quality of the evidence – is it a rigorous study with large numbers of participants, or something else?
- The benefit, the cost, and the risk – Arseneau’s key question – what is the potential benefit of the treatment compared to its cost and possible risk. In general, the higher the cost or risk – the better quality of evidence is required.
Stay Away From the Top of the Funnel of Knowledge
The funnel of knowledge is wide at the top; i.e. there are lots of things that look good in preclinical studies, the majority of which will probably never pan out. These include lab and animal studies that may take decades if ever, to come to fruition – yet media outlets or anecdotal reports treat them as if they are real possibilities.
Beware the “monetization of early research findings” by supplement companies. It’s not uncommon at all to see supplement companies jump on the bandwagon based on a small study on rats which is unlikely to pan out.
Moving down the Funnel of Knowledge, we get the more primitive clinical studies. Going from less to more trustworthy, we have:
- Anecdotal – non-statistical subjective assessments
- Retrospective trials – historical assessment of efficacy and safety using doctor records; no placebo controls, no randomization – prone to bias and confounding
- Observational – no placebo controls – mainly used in an exploratory context
- Phase I – small trials to assess safety, treatment response to various doses, no placebo-controls, randomization
- Phase II (several hundred patients) and phase III (double-blinded and randomized trials that can contain thousands of patients) – are required for FDA approval of a drug…and need to be validated
- Meta-Analysis of Past Studies – indicates that the treatment really is… ready for prime time.
(The only meta-analysis of treatments for ME/CFS that I can remember have been for cognitive behavioral therapy and graded exercise therapy – two treatments the UK and the Netherlands governments poured enormous amounts of money into. Neither fared particularly well.)
The Most Important Thing
The most important thing is pacing and energy conservation, but we tend to go for the goodies, the quick fixes which he called the icing, and the colorful sprinkles on the cake – many of which are quite expensive.
When you have a “well-developed” practice of energy conservation and pacing – and your symptoms are stable – that’s when you go for the goodies – which is what this video is about.
(Arseneau’s focus on pacing and energy conservation brings to mind Dr. Martin Lerner’s admonition to his long-term herpesvirus antiviral treatment patients – that it would not work unless the patient practiced pacing.)
Two examples of going for the colorful sprinkles on the cake are stem cell therapy – one clinic offers it for $50,000 (with nary a single human or animal study) to recommend it and blood washing ($60,000).
He had one patient who spent a quarter of a million dollars traveling around the world and learned the hard way about unproven claims.
Source credibility – he likes Health Rising and the COVID Weekly newsletter, as well as Canada’s Drugsearch.ca which shows which drugs are covered by which plans and what the cost is.
The Three Main Questions
The three main questions in his algorithm regarding possible treatments are:
- How good is the source?
- What’s the cost?
- What’s the risk?
The higher the cost and/or the higher the risk – the better quality evidence is needed to move forward.
Next, Dr. Arseneau used this formula to assess a wide variety of potential past and present treatments. A big part of the formula depends on the patient. Is cost a factor? Are they comfortable with the risk involved? Is it the kind of treatment they want to try?
Rituximab – An Unfortunate NO
The Rituximab trials are a case in point how a seemingly good thing can go bad when it’s fully and rigorously tested. The Rituximab saga started off well with a placebo-controlled, double-blinded trial that was successful, but note how small it was – just 28 patients. Still, the results were good with 64% of patients achieving good results – some of whom had REALLY good results.
That was enough to convince some people to pay several thousand dollars to try out this powerful drug. (While most people probably weren’t harmed, Rituximab made Whitney Dafoe much worse – which brings up another factor doctors surely assess: if a bad reaction occurs, how well will the patient be able to tolerate it? One pilot, in vitro (lab) study suggested that Rituximab may impede natural killer cell functioning.)
Three years later, though, the large follow-up trial failed. Despite the early reports of patients recovering, more patients getting the placebo did better than those on the drug.
(While it seemed clear from earlier studies that some patients did recover on the drug (or was it the placebo effect?), the second trial also made it clear that that progress didn’t apply to the ME/CFS population as a whole; i.e. the risk-benefit ratio was out of whack – it’s simply not worth spending thousands of dollars on a powerful drug that the study indicated probably will not work.
(One last note on the Ritxumab saga. Dr. Scheibenbogen believes that cost-cutting measures which included a reduction of the maintenance dose in the Phase III trial could have affected its results.)
Low Dose Naltrexone (LDN) – A Clear YES
Low-dose naltrexone (LDN) presents a different kind of possibility. LDN is a relatively inexpensive drug that usually produces minimal side effects (if dosed up slowly). The drug increases levels of the feel-good chemicals called endorphins that are likely lacking in these diseases, and can reduce neuroinflammation as well. (Dr. Arseneau joked it puts the glee back in glial cells :))
The quality of the evidence is not great – a couple of small, randomized, fibromyalgia studies (none in ME/CFS) – show about a 20% improvement in symptoms.
If about 70% of ME/CFS patients have fibromyalgia, and pain and fatigue are common in both diseases, though, and there’s evidence that LDN is helpful with chronic pain – you can infer that LDN is worth a try in ME/CFS.
If it was expensive or posed a real risk, Dr. Arseneau would give it a pass based on the evidence – but the fact that it’s relatively affordable, safe and there is something of an evidence base for it makes it a no-brainer for a knowledgeable, ME/CFS/FM expert. (Another reason to question the RECOVER Initiative passing on trying it out in long COVID).
Dr. Arseneau noted that a large, randomized, placebo-controlled LDN FM trial and a long-COVID trial are underway – and an ME/CFS clinical trial – one he will surely be glad to see is about to be announced.) The 99-person Danish LDN FM trial has finished up and a 120-person FM Spanish trial and a small FM+migraine trial is underway in Philadelphia.
That long-COVID trial, by the way, is a nice-sized trial (n=160) that’s taking place at BC Women’s Hospital. According to clinicaltrials.com, it hasn’t started recruiting yet. Contact Travis Boulter, 236-990-9519; LDNtrial@phsa.ca for more information.
The cost is the fly in the ointment for some LDN – which is usually compounded. It’s not expensive so far as drugs go but is not covered by insurance and with 2/3rds of his patients not working and the majority of his patients on disability, the cost can be a problem.
A new study, though, which indicated that naltrexone is stable in liquid makes it possible, though, to put a 50 mg tablet into 50 ml liquid and use a 1 or 5 mg syringe to titrate it (starting at 0.5 – 1 – 1.5, etc. all the way up potentially to 4.5 mg). Theoretically, you get to very low doses – like .1 mg or even lower using this approach. Three naltrexone tablets cost $30 making it affordable for many but the real punch line comes in the fact that while low-dose naltrexone is not covered by insurance – naltrexone is.
Use the handouts on his website “Naltrexone – How to Make it Yourself” and “Naltrexone” to bring to your doctor and get the prescription. With its low risk and zero cost when using the titration option, it was easy for Dr. Arseneau to recommend LDN.
Abilify (aripiprazole) – safe, cheap and possibly effective – a definite YES
In low doses Abilify (< 2mg) increases dopamine levels (another feel-good chemical) in the brain. A retrospective study – not very high-quality evidence – found that about 75% of patients responded.
The study results were almost too good to be true: about a 50% reduction in fatigue and brain fog and 20% of patients reported that their post-exertional malaise had disappeared. With no healthy controls, the quality of the evidence was not great, but the drug’s mechanism of action – reducing neuroinflammation in the brainstem – made sense.
Abilify clearly fits in the LDN category. While the evidence base is not great, the drug makes sense, is cheap and the risk of side-effects is low. It’s a clear YES in Dr. Arseneau’s book.
Oxaloacetate – Safe and Possibly Effective But Very Expensive – a Clear NO for Most (but Not All) Patients
Oxaloacetate is another intriguing candidate. It’s mechanism of action – it generates NAD+, helps with glucose metabolism, amino and fatty acid synthesis, and energy production – makes sense and the risk of side effects is low. Since it’s a supplement, it’s readily available. Like LDN and Abilify, it has something of an evidence base but not a strong one.
The 76-person, 6-week study found that more was better (1,000 mg 2x/day was better than 500 mg 2x/day) with the higher dose resulting in a 60% reduction in fatigue (with the proviso that the fatigue reduction did not show up in all the fatigue scores). Overall, 80% of the patients showed improvements, with some patients showing really dramatic improvements. (Indeed, Dr. Kaufman began the trial because he was surprised at the improvements some of his patients reported.) The study was not, however, randomized.
Nevertheless, so far so good – it’s a safe treatment, has a good mechanism of action and while the quality of the evidence is not great, it does have an evidence base. The minimum cost (500 milligrams 2x a day) is about $500/month and the more effective dose (1000 mg 2x/day) at $1,000/month is double that.
In this case, the evidence base is not robust enough for Dr. Arseneau to recommend oxaloacetate given its high cost. Of course, for people for whom a couple of thousand dollars a month is a drop in the bucket – it’s another story. He has some patients who have told him it works but doesn’t have enough of those patients, though, to be able to get a handle on how effective oxaloacetate is.
A long-COVID oxaloacetate study is underway…
Repetitive transcranial magnetic stimulation (rTMS) – a qualified YES
rTMS is in an entirely different animal. Instead of existing on the fringes of medicine like LDN and oxalacetate, rTMS is FDA-approved for depression, obsessive-compulsive disorder, migraine and smoking cessation, has obviously been well studied, is being used in fibromyalgia, and is being assessed in many diseases including ME/CFS, cognitive issues, neuropathic pain, Alzheimer’s, Parkinson’s Disease, stroke, ADHD.
What’s not to like? While the quality of the evidence base (case report series, open-label trial) in ME/CFS is not great, the evidence suggests it can work in FM and the mechanism – boosting the prefrontal cortex (a known problem in ME/CFS) and taming the limbic system and the fight/flight response – makes sense.
In this case, if a patient can find someone to pay for it, or if an insurer will, Dr. Arseneau usually recommends giving it a try.
An intriguing Solve M.E.-funded UCLA ME/CFS study is underway that’s targeting two areas of the brain in an attempt to tame the amygdala (the screaming almond of terror!) and the limbic system and calm down the fight/flight response and reduce pain.
Of his patients who’ve tried it, some have improved and some have not.
Amygdala Retraining Program – YES
Ashok Gupta’s Amygdala and Insular Retraining program (AIR) is the first to give neuroplasticity a test in ME/CFS/FM and long COVID. A randomized trial in fibromyalgia which used relaxation therapy as a control found that the AIR program produced significantly greater reductions in functional impairment, anxiety, and depression and a higher improvement in mindfulness and self-compassion. No changes in cytokines were found, but significant decreases in a pain factor called BDNF were found.
A US long-COVID study that used a control group that participated in an online program that involved dietary management, stress reduction, etc. also achieved good results. The study found a significant decrease in fatigue after 3 months and double the increase in fatigue compared to the control group in the AIR group. The authors proposed that the program had helped calm overactive and hypervigilant nervous and immune systems.
If a patient is open to neuroplasticity, trying Gupta’s AIR program given its low costs was a clear YES for Dr. Arseneau.
CT38 – Promising Mechanism – Not Ready for Prime Time – NO
Cortene’s CT38 drug presents yet another intriguing scenario. Arseneau called the hypothesis behind the drug – a quick reset of the limbic system and the HPA axis “interesting”, and noted that it fits the current thinking about an always-on stress response in ME/CFS/FM. The drug attempts to turn off a receptor called CRF2 – and return the system to its normal state (homeostasis). He linked the drug’s action to the amygdala (that screaming almond of terror).
The mechanism was good, but the very small trial – which primarily assessed safety – had moderate results. Since the drug would be very expensive to get, CT38 is not ready for prime time without further study. (Cortene is trying to raise the money for a larger study).
Metformin – Gold Standard Studies Abound – YES (if you get a COVID infection)
Next, a new entry to the ME/CFS/FM field – a commonly used drug with a long history behind it – metformin. The huge, long, multi-site, randomized, blinded, placebo-controlled COVID study clicked all the boxes – the first to do so in Arseneau’s review. While the study was a preprint- and had not been peer-reviewed – it looked to be a strong study – indeed, Dr. Arseneau called it a “gold standard” study.
It found metformin produced a 42% reduction in the risk of coming down with long COVID over time. The drug is cheap, is “relatively well tolerated” (diarrhea can be a problem), and is relatively “low risk” if you’re trying it for two weeks. Plus, it’s cheap.
Arseneau noted that while he’s traveling, he brings it, Paxlovid and COVID tests so he can take it if he gets ill. Trying metformin for ME/CFS is fine given its cost and risk profile, but he’s not had patients respond to it.
The same study found that Ivermectin – (a hot internet item at one time that so many were sure – absolutely sure – was helpful)- failed miserably.
Guanfacine – YES (if you can afford it).
A very small study (n=12) of guanfacine (1-2 mcg) plus NAC (600 mg) found that 2/3rds improved. One-third stopped it because of dizziness – adding salt may help with that). The drug’s typical use – ADHD – was promising given how much ADHD is found in ME/CFS/FM.
Plus unlike other ADHD drugs, it’s not a stimulant and can calm the “screaming almond of terror” – the amygdala – and thus the fight/flight response. Stimulant drugs like Vyvanse, Ritalin, and methylphenidate, can be helpful in ME/CFS/FM but can increase anxiety and dysautonomia and provide a false sense of energy which can send patients crashing.
The vast majority of his patients who stay on Guanfacine have reported a reduction in their fight/flight response and some found an improvement in their heart rate variability – a physiological measure of the fight/flight response.
The drug is not cheap in Canada (@$100-$165/month) (but is much cheaper in the US). He starts patients at 400 mcg/3xs a day or 600 mcg/2xs a day. After two months, double the dose to see if it helps.
Micronized PEA (palmitoylethanomide) – A clear YES
Micronized PEA shows how wide the world of treatment options is as PEA is in a category all to itself. A “food product”, it’s been well assessed in Europe and indeed has been studied enough for a meta-analysis to have been done which concluded that it can be effective in treating chronic pain (but has rarely, until recently, been mentioned much in the U.S. and Canada.) Dr. Arseneau noted that 5 years ago it had to be imported from the Netherlands at about $200/month but can now be purchased for about $30-60/month.
PEA has been so well-studied that Dr. Arseneau called the evidence base “the best we ever get for these conditions at virtually no risk”. It’s a clear yes for those who can afford it.
- It’s a great question – given limited resources of energy, money, and time how to choose which treatments to try? Dr. Ric Arseneau, who was the Director of Program Planning for Complex Chronic Diseases Clinic at the BC Women’s Hospital, has some ideas.
- Noting that diseases like ME/CFS and FM don’t get the 10,000-person randomized, placebo-controlled trials that major diseases rely on for answers Arseneau asserted there are ways to filter the wheat from the chaff.
- He suggested assessing 4 factors. First, beware of vested interests – companies willing to sell anything to make a buck. Ask if the information is from a credible source (he likes Health Rising and the Long COVID watch), what kind of evidence backs up the claim (full-fledged, large, randomized, and placebo-controlled, trial?), and finally, the benefit, the cost, and the risk.
- The three main factors are: “How good is the source?”, “What’s the .ost?” and “What’s the risk?”
- Whether or not someone decides to try something depends on their tolerance for risk, their financial situation, and the kinds of treatments they feel comfortable with.
- Dr. Arseneau then worked his analysis on a dozen well-known ME/CFS treatments including Abilify, LDN, rTMS, Guanfacine, and Metformin. Check out what he said on those in the blog.
DAO – A Mast Cell Stabilizer
A small 2019 open-label study found that 0.3 mg of DAO taken before meals 3xs a day in patients with histamine intolerance “improved all symptoms” and when the supplementation stopped – the symptoms came back. The evidence base was not great, (small open-label study, no placebo control/randomization) but with the risk (side-effects) being virtually zero, it all comes down to cost – which at $65-$90 Canadian is not low.
Dr. Arseneau then presented a most interesting slide – a common medication list he might give to a patient.
Q & A
What about hyperbaric oxygen treatment (HBOT)? It’s definitely useful – the problem is the cost. He’s interested in nicotine patches. There is a risk of addiction and nicotine is a stimulant that could make things worse but he is going to look more into it. He’s never seen any evidence that nutritional IV’s are helpful.
- Great Resource! Dr. Arseneau has handouts that describe benefits, side effects, dosing, etc. for over 40 treatments on his website. You can either download them to your computer or to Dropbox.
- Check out Dr. Arseneau’s past video’s and signup for his ME TV YouTube channel here.
I hope that Dr. Arseneau does another session like this and covers things like stellate ganglion block, blood clotting medications, vagus nerve stimulation, nicotine patch, Rapamycin, craniocervical instability surgery (apparently not available in Canada).
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