Low-dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, Double-Blind, Placebo-Cont...Crossover...Younger et al. 2013

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Thought we should have a thread for this trial as it is often cited as evidence of efficacy of LDN in fibromyalgia.

Randomized Controlled Trial
Arthritis Rheum. 2013 Feb;65(2):529-38. doi: 10.1002/art.37734.

Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels​

Jarred Younger, Noorulain Noor, Rebecca McCue, Sean Mackey

• PMID: 23359310
• DOI: 10.1002/art.37734

Abstract​

Objective: To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue.

Methods: Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain.

Results: When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported.

Conclusion: The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication.
Trial registration: ClinicalTrials.gov NCT00568555.
Copyright © 2013 by the American College of Rheumatology.

Link to abstract

 

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In their protocol, Due Bruun et al. 2021. said this of Younger et al.’s trial:

In the cross-over trial, the method is more robust with both randomization and double-blinding. However, the study also has some weaknesses. Although showing promising results, it is unclear if the study was sufficiently powered and the decision to exclude a washout period between the interventions increases the risk of bias.

What do our resident stats fiends think of whether the Younger et al. 2013 crossover study was sufficiently powered? n=28 analysed

 

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Due Bruun et al. went on to do a trial of 99 participants with fibromyalgia, comparing 6mg LDN to placebo. Here's what Due Bruun et al. 2024 found re pain:

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).

This study did not show that treatment with low-dose naltrexone was superior to placebo in relieving pain.

@Kalliope posted Younger's comments on Due Bruun et al.s study here:

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."

 

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Younger et al. checked blinding:

At each laboratory visit, participants were asked to guess whether they had been taking placebo or low-dose naltrexone for the previous 2 weeks. Each participant was allowed 8 guesses (2 during the placebo condition and 6 during the low-dose naltrexone condition). During the placebo condition, 52% of the guesses were accurate (with 48% wrongly guessing low-dose naltrexone). During the drug condition, 44% of the guesses were accurate (with 56% wrongly guessing placebo). Guess accuracy did not diverge significantly from chance ( 2 0.39, P 0.532).

This suggests that the 28 participants whose data were analysed were not experiencing significant side effects, on the whole. It will be interesting to see whether the same is true of pwME when the two current trials of LDN in ME/CFS are published.

Worth noting that participants were free to reduce from 4.5mg to 3.0mg if they wanted, and 3 taking LDN did so:

All participants were told that they had the option to reduce their daily dosage to 3.0 mg if they experienced side effects. Four individuals requested the 3.0-mg dosage. Three of those individuals were taking low-dose naltrexone at the time of the request;
1 reported having headaches, 1 reported heartburn, and 1 reported irritability. Another individual who requested a dosage reduction due to headaches was taking placebo. In all cases, the severity of side effects was reduced by the change in dosage.

And 3 of 31 dropped out:

Dropouts and missing data. One participant dropped out of the study during the first 3 days of taking capsules. This subject complained of dryness (eyes and mouth) and tinnitus. No usable data were obtained from this individual, and she was excluded from all analyses. She was taking low-dose naltrexone. One participant dropped out immediately after being switched from low-dose naltrexone to placebo because she perceived she had been switched to placebo and wanted to pursue taking low-dose naltrexone clinically. Because no placebo data had been collected, she was not included in the analyses. Problems with the handheld computer caused a loss of baseline data for 1 participant. She was excluded from the analyses.

 

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It is worth noting that they changes the outcome measures years after the trial was completed.

Many of the p-values are close to 0.05, and the is no mention on clinicaltrials.gov about pre-specified statistical analyses.

I also wonder if you have to do multiple testing corrections when you’ve got multiple outcomes like they do?

 

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It is worth noting that they changes the outcome measures years after the trial was completed.

Where can I read about that?

 

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Where can I read about that?

Here, go to the rightmost tab named Record History:

ClinicalTrials.gov

clinicaltrials.gov

 

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Here, go to the rightmost tab named Record History:

ClinicalTrials.gov

clinicaltrials.gov

Thanks. To be honest, I find it hard to follow what the changes were and discern whether they were problematic. Based on the Researcher View tab, it looks OK - the main change seemed to be that instead of having pain, fatigue and sleep as primary outcome measures, they changed sleep and fatigue to being secondary measures. I'm also unsure if some of these changes are just between the pilot study and the real one eg they reported mechanical pain sensitivity and heat pain sensitivity in the pilot only.

I don't think it's worth my energy looking into that further for such a tiny trial. If it were bigger, and positive, then yes, it would be worth it.

 

[Utsikt]

Thanks. To be honest, I find it hard to follow what the changes were and discern whether they were problematic. Based on the Researcher View tab, it looks OK - the main change seemed to be that instead of having pain, fatigue and sleep as primary outcome measures, they changed sleep and fatigue to being secondary measures. I'm also unsure if some of these changes are just between the pilot study and the real one eg they reported mechanical pain sensitivity and heat pain sensitivity in the pilot only.

I don't think it's worth my energy looking into that further for such a tiny trial. If it were bigger, and positive, then yes, it would be worth it.

Swapping primary and secondary outcomes is a big no-no without a very good reason, and they only specified how they would be measured after the fact. So essentially there was no pre-reigstration.

But yeah, it isn’t worth spending more time on. I mostly check because it might be useful to establish if certain researchers are able to do trials properly.