Protocol Trial registration: Low-dose Naltrexone for Post-COVID Fatigue Syndrome, 2022, Luis Nacul, British Columbia Women's Hospital & Health Centre

[Andy]

Clinical trial registration.

There is a growing number of individuals who do not recover to previous levels of health and function following an acute infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but rather develop what has been referred to as 'Long-COVID'. Long-COVID is believed to be multi-causal, with a significant proportion of Long-COVID cases developing a clinical picture indistinguishable from myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) or post-viral fatigue syndrome (PVFS), which we will refer to as post-COVID-19 fatigue syndrome (PCFS). It is characterized by persistent disabling fatigue and other symptoms, such as nonrestorative sleep and post-exertional malaise. Diagnosis is clinical and based on symptom reports owing to the absence of diagnostic biomarkers. Viral and other infections are 25 times more likely to trigger ME/CFS than any other factors. This highlights the possibility of COVID-19 survivors having post-viral symptoms which progress to PCFS, either as the only sequelae or combined with other dysfunctions. Other Long-COVID symptom profiles in addition to PCFS include: a) post-intensive care syndrome; b) organ damage; and c) other debilitating symptoms related to mental health and other conditions.

There is no evidence-based treatment for PVFS, however, low-dose naltrexone (LDN), i.e. in doses up to 4.5 mg/day, has been used with some success in cases not related to COVID-19, due to its potential anti-inflammatory, analgesic properties and other mechanisms, targeting potential key mechanisms involved in the development of PVFS and the persistence of symptoms long-term.

Previous literature has demonstrated the safety and effectiveness of LDN in other chronic conditions, such as fibromyalgia (FM). The use of LDN as an off label treatment for fibromyalgia and myalgic encephalomyelitis has been used extensively within the BC Women's Hospital + Health Center's Complex Chronic Diseases Program (CCDP) to treat symptoms of pain and fatigue in these clinical populations. The experience of doctors in the CCDP in administering LDN as a medication for these related diseases follows international clinical experience with LDN and the recommended usage from clinical trials in fibromyalgia.

Naltrexone is an opiate antagonist approved by Health Canada for treatment for alcohol and opiate use disorders. It is used off label at low doses for conditions such as ME/CFS, fibromyalgia and Crohn's disease, with good safety profile and some evidence of benefit.

The impact the COVID-19 pandemic makes finding evidence for an effective and safe treatment for PCFS urgent. With currently no curative treatment for ME/CFS or PCFS, a larger number of people are predicted to be impacted by the long-term morbidity and disability associated with these conditions, with high costs to healthcare and social services.

The Double Blind Randomized Trial of Low-Dose Naltrexone for Post-COVID Fatigue Syndrome (PCFS) is a randomized parallel group double-blinded placebo-controlled trial of daily oral capsules of LDN or placebo for individuals 19-69 years old of both sexes for the treatment of PCFS. 160 participants will be treated with either LDN or placebo for 16 weeks.

https://clinicaltrials.gov/ct2/show/NCT05430152

 

[Trish]

Does anyone know whether they are also doing a trial for LDN in pwME? It would seem obvious to include both patient groups, especially as they are already prescribing LDN off label for ME/CFS.

 

[hinterland]

randomized parallel group double-blinded placebo-controlled trial of daily oral capsules of LDN or placebo

Personally, when I tried LDN, I found the syrupy liquid mixture, that’s measured out with an oral syringe, more effective than the capsules. It was supplied by Dickson Chemist, Glasgow. I don’t know why, but that was my experience. With the capsules, from a different pharmacy, that I tried before, I only got a hint they were working. I think the liquid mixture may be absorbed better, and faster, and this could have implications for efficacy. LDN is very dose-sensitive, and, this is just speculation, but what if the pharmacokinetics matters? I don’t think anyone knows exactly how LDN works, but one theory is that the temporary blocking of opioid receptors is integral to it, so fast and full absorption of the LDN could matter, to get the best block and unblock effect.

 

[Wyva]

Post copied from the Long Covid in the media thread

Long article about treating long covid with LDN in Rolling Stone: Can an Addiction Drug Treat Long Covid?

Digging into the research, Korbutov learned that while naltrexone only has approval from the U.S. Food and Drug Administration (FDA) for treating people recovering from addiction to heroin, morphine, oxycodone, and alcohol, some doctors prescribe it off-label in much smaller doses for chronic conditions like fibromyalgia, multiple sclerosis, and Crohn’s disease.

“Once I looked into the science, I was kind of shocked that it wasn’t more mainstream medication,” Korbutov tells Rolling Stone. “It’s one of those things you have to discover yourself.”

This is, in part, because unlike new-to-the-market blockbuster drugs, pharmaceutical companies don’t stand to profit much from one that’s been around for decades, and, as a result, aren’t spending money promoting it. LDN also has yet to go fully mainstream because the medical establishment has long ignored and dismissed the chronic and invisible conditions it has been used to treat — myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in particular.

(...)

For now, Luis Nacul, MD, PhD, an associate professor at the University of British Columbia’s Faculty of Medicine and the principal investigator of a clinical trial investigating the use of LDN as a potential treatment for post-Covid fatigue, discourages LDN’s off-label use.

“Until this research is completed, we do not recommend the use of LDN for people with Long Covid-19 because it is essential to create the evidence before recommending its use,” Nacul told Rolling Stone in an email. ​

 

[John Mac]

Merged thread

Future trial on naltrexone

Abstract
Introduction
A significant proportion of individuals suffering from post COVID-19 condition (PCC, also known as long COVID) can present with persistent, disabling fatigue similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-viral fatigue syndromes.
There remains no clear pharmacological therapy for patients with this subtype of PCC, which can be referred to as post-COVID fatigue syndrome (PCFS).
A low dose of the opioid antagonist naltrexone (ie, low-dose naltrexone (LDN)) has emerged as an off-label treatment for treating fatigue and other symptoms in PCC.
However, only small, non-controlled studies have assessed LDN in PCC, so randomised trials are urgently required.

Methods and analysis
A prospective, randomised, double-blind, parallel arm, placebo-controlled phase II trial will be performed to assess the efficacy of LDN for improving fatigue in PCFS.
The trial will be decentralised and open to eligible individuals throughout the Canadian province of British Columbia (BC). Participants will be recruited through the province-wide Post-COVID-19 Interdisciplinary Clinical Care Network (PC-ICCN) and research volunteer platform (REACH BC).
Eligible participants will be 19–69 years old, have had a confirmed or physician-suspected SARS-CoV-2 infection at least 3 months prior and meet clinical criteria for PCFS adapted from the Institute of Medicine ME/CFS criteria.
Individuals who are taking opioid medications, have a history of ME/CFS prior to COVID-19 or history of significant liver disease will be excluded.
Participants will be randomised to an LDN intervention arm (n=80) or placebo arm (n=80). Participants in each arm will be prescribed identical capsules starting at 1 mg daily and follow a prespecified schedule for up-titration to 4.5 mg daily or the maximum tolerated dose.
The trial will be conducted over 16 weeks, with assessments at baseline, 6, 12 and 16 weeks. The primary outcome will be fatigue severity at 16 weeks evaluated by the Fatigue Severity Scale.
Secondary outcomes will include pain Visual Analogue Scale score, overall symptom severity as measured by the Patient Phenotyping Questionnaire Short Form, 7-day step count and health-related quality of life measured by the EuroQol 5-Dimension questionnaire.

Ethics and dissemination
The trial has been authorised by Health Canada and approved by The University of British Columbia/Children’s and Women’s Health Centre of British Columbia Research Ethics Board. On completion, findings will be disseminated to patients, caregivers and clinicians through engagement activities within existing PCC and ME/CFS networks. Results will be published in academic journals and presented at conferences.

https://bmjopen.bmj.com/content/14/5/e085272

 

[Lou B Lou]

Is 16 weeks long enough?

 

[Mij]

I took LDN for less than 2 weeks and knew it wasn't for me. The agitation and insomnia was awful. But it has helped some with pain syndromes.

 

[Eleanor]

Is 16 weeks long enough?

That was my thought too. Especially as it takes several weeks just to work up to the full dose.

 

[Creekside]

It didn't reduce my fatigue-like symptom, but it did block my ME pain completely. The first dose had full effect in less than 24 hrs.

I hope they don't ignore any effects other than on reported fatigue. Identifying the various possible effects of LDN on PWME would be useful. Are there subgroups that need to start low and take 16 weeks to start to show an effect? What percentage show full effects in a day or two? What negative side-effects do some people show. I think those are more important than how many people are likely to notice a reduction in fatigue, since that's likely to be a small fraction.

 

[Ash]

I was on LDN and it took 2-4 months to get the full positive effects, on cognitive capacity and pain reduction, can’t remember if physical fatigue was affected or not for me.

I had headaches and altered consciousness at the beginning, but the latter I found quite enjoyable and the former was horrible but not overwhelming, can’t remember how many weeks it was till everything settled down, but a few I think, maybe a month plus. I was also hyped up I remember for a while.

I had to come off it for some reason that I can’t remember and when I went back on it I was impatient to get to the good effects stage and upped my dose a bit too fast, the normal rate for people without ME, I just couldn’t get past the migraines or the nightmares and insomnia which would of probably worn off after a 6 weeks or a couple of months it was just too painful because even when I went back to super slow, I’d obviously sensitised myself and the headaches were still brutal so I quit.

I was always told 3-4 months to start seeing an improvement overall to your health, you’re gonna know you’re taking something from day one because it alters your mental state and bodily sensations, but to know if its doing anything beneficial and lasting that’s gonna take a lot longer. Although I was told to pack it in at four months if I didn’t get solid improvements, so I guess there’s your 16 weeks but from experience I’d say absolutely not long enough because of how much extra time it’s likely to take a person with ME to get to the therapeutic dosage without damaging themselves.


Edit: added a bit of detail on my first experience side effects.