Protocol Low-dose naltrexone for post-COVID fatigue syndrome: a study protocol for a double-blind, randomised trial in British Columbia, Nacul et al, 2024

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

 

Is 16 weeks long enough?

 

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.

 

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

 

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.

 

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.