Trial Report Naltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trialBruun 2023

Summary
Background
Low-dose naltrexone is used to treat fibromyalgia despite minimal evidence for its efficacy. This trial aimed to investigate whether 12-week treatment with 6 mg low-dose naltrexone was superior to placebo for reducing pain in women with fibromyalgia.
Methods
We did a single-centre, randomised, double-blind, placebo-controlled trial in Denmark. We enrolled women aged 18–64 years who were diagnosed with fibromyalgia. Participants were randomly assigned 1:1 to receive low-dose naltrexone (6 mg) or an identical-appearing placebo, using a computerised algorithm with no stratifications applied. Participants, investigators, outcome assessors, and statistical analysts were all masked to treatment allocation. The primary outcome was change in pain intensity on an 11-point numeric rating scale from baseline to week 12, in the intention-to-treat population. Safety was assessed in participants in the intention-to-treat population who received at least one dose of their allocated intervention. This trial was registered with ClincalTrials.gov (NCT04270877) and EudraCT (2019-000702-30).
Findings
We screened 158 participants for eligibility from Jan 6, 2021, to Dec 27, 2022, and 99 patients were randomly assigned to low-dose naltrexone (n=49) or placebo (n=50). The mean age was 50·6 years (SD 8·8), one (1%) of 99 participants was Arctic Asian and 98 (99%) were White. No participants were lost to follow-up. The mean change in pain intensity was –1·3 points (95% CI –1·7 to –0·8) in the low-dose naltrexone group and –0·9 (–1·4 to –0·5) in the placebo group, corresponding to a between-group difference of –0·34 (–0·95 to 0·27; p=0·27, Cohen's d 0·23). Discontinuations due to adverse events were four (8%) of 49 in the low-dose naltrexone group and three (6%) of 50 in the placebo group. 41 (84%) of 49 patients in the low-dose naltrexone group had an adverse event versus 43 (86%) of 50 in the placebo group. One serious adverse event occurred in the placebo group and no deaths occurred.
Interpretation
This study did not show that treatment with low-dose naltrexone was superior to placebo in relieving pain. Our results indicate that low-dose naltrexone might improve memory problems associated with fibromyalgia, and we suggest that future trials investigate this further.
Funding
The Danish Rheumatism Association, Odense University Hospital, Danielsen's Foundation, and the Oak Foundation.

https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(23)00278-3/fulltext

 

https://www.medpagetoday.com/rheumatology/fibromyalgia/107722


Opioid Antagonist Flops as Fibromyalgia Therapy
— But maybe all is not lost

 

Yeah, but "patient report of memory problems" was better with LDN. Not objective enough.

 

Good to see this confirmation that low dose naltrexone doesn’t do anything.

 

Medscape Low-Dose Naltrexone Researchers Disputes Fibromyalgia Study Negativity by Miriam Tucker

quote:

Younger, director of the Neuroinflammation, Pain and Fatigue Laboratory at the University of Alabama, Birmingham, was speaking on December 13, 2023, at a National Institutes of Health meeting about myalgic encephalomyelitis/chronic fatigue syndrome about the potential use of low-dose naltrexone for that patient population. He had checked the literature in preparation for his talk and saw the new study, which had just been published December 5, 2023.

During his talk, Younger said, "It looks like the study was very well done, and all the decisions made sense to me, so I don't doubt the quality of their data or the statistics."

But as for the commentary, he said, "I strongly disagree, and I believe the physicians at this conference strongly disagree with that as well. I know plenty of physicians who would say that is not good advice because this drug is so helpful for so many people."

Indeed, Anthony L. Komaroff, MD, who heard Younger's talk but hadn't seen the new study, told Medscape Medical News that he is a "fan" of low-dose naltrexone based on his own experience with one patient who had a "clearly beneficial response" and that of other clinicians he's spoken with about it. "My colleagues say it doesn't work for everyone because the disease is so heterogeneous…but it definitely works for some patients."

 

It looks as if it doesn't work usefully.
Younger and Komaroff's comments are'nt very helpful. If the difference I this small it is very unlikely that routine clinical use would allow a physician to tell that the drug was effective - for anyone.

The idea that it might work through some effect on microglia seems very doubtful.

 

Replace the names Younger & Komaroff, with BPS fanclub names, & LDN with GET/CBT & we have heard it all before. Whats the difference.

Physicians need to stop telling people that because a few of their patients improved *after* taking/doing whatever, that it means that whatever it is 'works for some people', despite evidence to the contrary. They are no better than the BPS fans who are so certain from their experience that CBT/GET "work for some patients" and must therefore still be prescribed and the NICE GL are wrong etc etc etc.

Just like the 'I took vitamin C/did yoga/Buddist meditation/ate more apples/turned around 3 times and shouted Beetlejuice, and i got better after that, so it must be that which made me better' people all over social media.
Post hoc propter hoc fallacy. Association does not equal causation.

Why is it that I, a lowly patient with no scientific background except involvement in S4, knows this, and an eminent physician does not! so frustrating.

 

Agree. I often listen to Professor Racaniello's and Dr. Griffin's Weekly Clinical Update Podcast, and Dr. Griffin often says that the four most dangerous words is a doctor saying: "In my clinical experience..."

 

Since membership of S4 my heart sinks whenever my own GP says that, & yet my carer & everyone around me says 'oh well they know'.
They dont.

 

Komaroff's comments read like a parody. Personal clinical experience with ONE patient vs. n=100 double-blind placebo controlled trial.

 

Cohen's d of 0.23 is a small effect size, easily caused by functional unblinding because LDN causes obvious/known side effects. It's almost certain to fall below MCID perceptible by the patient or the clinician.

 

The trial is useless if they did not titrate doses. 6mg is too much

 

The difference between the LDN fans and the GET defenders is that GET cannot possibly work in anyone with ME. This illness is defined by post-exertional malaise. If your chronic fatigue is relieved by exertion, it’s not ME.

LDN, on the other hand, could logically work for some very small subset of patients. But it does now seem very likely a that it doesn’t work for any clinically useful proportion of patients.

I would like to see a similarly well-designed LDN trial in ME to settle this beyond dispute. I tried LDN and found it ineffective for me with debilitating side effects, but I fear unless this drug is tested a little further, others will still be tempted by doctors’ “clinical experience” to waste energy, money and time on it.