Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia, 2017, Parkitny and Younger

Hutan

Hutan

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489802/
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Abstract
Fibromyalgia (FM) is a complex, multi-symptom condition that predominantly affects women. The majority of those affected are unlikely to gain significant symptomatic control from the few treatments that are approved for FM. In this 10-week, single-blind, crossover trial we tested the immune effects of eight weeks of oral administration of low-dose naltrexone (LDN). We enrolled eight women with an average age of 46 years, symptom severity of 62 out of 100, and symptom duration of 14 years.

We found that LDN was associated with reduced plasma concentrations of interleukin (IL)-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, interferon (IFN)-α, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, and granulocyte-colony stimulating factor (G-CSF). We also found a 15% reduction of FM-associated pain and an 18% reduction in overall symptoms. The findings of this pilot trial suggest that LDN treatment in fibromyalgia is associated with a reduction of several key pro-inflammatory cytokines and symptoms. The potential role of LDN as an atypical anti-inflammatory medication should be explored further.
 
Only 8 participants
a 4.5 mg dose of LDN was administered orally every night.
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A crossover design, with BL (baseline period) and Drug (LDN treatment period).

Expressed plasma markers of inflammation were measured in blood samples that were collected twice weekly over the 10-week study period. Study visits were scheduled within a two-hour window to minimize potential bias associated with diurnal cycles of cytokine expression
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Symptom data were collected using SurveyToGo software (Dooblo, Kefar Sava, Israel) on a hand-held 7-inch Android tablet. Participants completed the survey prior to retiring to bed at night.
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That's good.

Here are the results for the cytokines:
Screen Shot 2023-01-13 at 12.23.33 pm.png


The y axis shows the the mean and 95% confidence intervals of within-person z-score standardized concentrations. There does seem to be something interesting happening there for a number of cytokines. Have a look at the chart for TNF-a top row, middle.

But here is the individual results for TNF-a, that is, the results for each woman:
Screen Shot 2023-01-13 at 12.30.41 pm.png

They are a whole lot less convincing I think. Levels go down in 3 women, go up in 2 women, and stay about the same in 3 women. Participant LDN09 had an ESR of 55 at baseline.

There were meaningful decreases in pain and overall symptoms reported. The standard errors are quite low.

Screen Shot 2023-01-13 at 12.37.26 pm.png

The authors acknowledge limitations:
The three main limitations of this study were the small sample size, the absence of a control group, and the short duration. First, while our longitudinal design gave us sufficient statistical power to detect effects in our cohort, it is not clear how generalizable these findings are to the wider FM population. In particular, we do not how well the findings of our LDN studies translate to men. Second, because we did not use a control group, we cannot conclusively conclude that LDN was solely responsible for the magnitude of the immune change observed in this study. Finally, the short length of the study also meant that we may not have observed the maximal effects of LDN, as previous reports suggest that clinically-beneficial responses develop over months [9]. All of these limitations can be addressed by the conduct of larger, placebo-controlled trials.
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At first glance, this study seems ok, although of course very small and fairly short.

Note that the y-axis of the TNF-a results varies for each participant. The magnitude of the change in the results for participant LDN09 (the one with the high ESR) might be driving the overall result. Can anyone spot other issues?

I can see why the authors would want to do a larger and longer study though. Did they in fact do such a study? Did any other researchers do such a study?
 
Looking at the individual data for TNF-a a bit closer, I see that there are a variable number of days of baseline results. That could create an opportunity for researchers to subconsciously be selective about how many days of baseline data are included and when the treatment starts.

Also, three of the participants don't have data for the 8th week, again raising questions about whether there was any bias related to the absence of that data. If someone wasn't feeling great, perhaps they would be less likely to bother with the blood draws? Edit to add - Thinking about how I would feel if I was in the study, if I had been feeling good and believed that the LDN had helped, and so was more active than usual, and then felt worse than usual, I might be hesitant to unfairly 'wreck the study' by reporting feeling worse, and so might avoid those final blood draws.

Doing a very rough determination of baseline averages and week 8 averages for each individual, I get the following as changes in the absolute levels of TNF-a:
0,-20, +13, -7,-5,0,+3,-47
That makes it even clearer that the average change for all participants is being largely driven by the result for Participant LDN09.
 
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Hutan said:
At first glance, this study seems ok, although of course very small and fairly short.

Note that the y-axis of the TNF-a results varies for each participant. The magnitude of the change in the results for participant LDN09 (the one with the high ESR) might be driving the overall result. Can anyone spot other issues?

I can see why the authors would want to do a larger and longer study though. Did they in fact do such a study? Did any other researchers do such a study?
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Hi @Hutan
Thanks very much for your analysis.

In his latest Health Rising interview, Jarred Younger said he has a number of studies where data needs to be analyzed, but there is a shortage of PhDs to do this work.

I don't know if he has replicated this particular study with a larger number of participants.
 
There was a two week baseline period, and 7 to 8 week treatment period. Participants were given the pills every two weeks and they were told that they might be given placebo pills at any time - although they were in fact not given placebo pills. Blood tests were done twice a week, and records of well-being and symptoms were made daily.

The control then is the baseline period, with changes over the treatment period being tracked.
 
Sure, I don't think this trial should have been described as a crossover trial in the published paper, it just has a (very short) baseline period.

Nevertheless, I don't think I'd say the authors have 'lost the plot'. The problem is that the trial is too small and too short, so that an outlier who may have had fibromyalgia but may have instead had some other reason for her pain and cytokine levels skewed the results. Maybe such small trials are better not done, because the results they produce aren't reliable. However, if that is all there is funds for, and if LDN had resulted in very obvious benefits to most of the participants in those ten weeks, making a larger trial easier to get funds for, then I think we would be saying that it was worth doing as a pilot.
 
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