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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.
Editor’s note: I had a problem immediately with this study. The dosage and duration of the study was just wrong. All LDN specialists will tell the majority of patients, whatever the condition, to start low and go slow. And all patients, with all conditions, experience the effects of LDN at different stages, and different doses, some taking longer than 12-weeks, some much sooner, some taking less than 1 mg and some up to 9 mg on split dosing.
In the above study 41 (84%) of 49 patients in the low-dose naltrexone group had an adverse event versus 43 (86%) of 50 in the placebo group. There should have been no surprise that 84% of the LDN group had side effects when started on 6 mg from the start regardless of their personal sensitivities and individuality.
It’s very rare that a prescriber, who knows anything about LDN, will start a patient on anything more than 1.5 mg – to be increased by either 0.5 mg or 1 mg over a period of weeks or even months, as and when the patient feels they can. If any side effects are experienced then the advice is to go back to the last dose they were comfortable on and increase with a smaller dose after a week or so. The problem with any side effects is usually solved with this method. There are rarely, if any, serious side effects with LDN if the dosage is properly managed in this way. The vast majority of side effects experienced are tolerable and transitory.
In March 2023 The Journal of Pain Research2 published a study of all available literature on the use of LDN for Fibromyalgia. This systematic review assessed and summarized the current body of evidence for the use of LDN in the management of FM and it concluded that overall, LDN therapy appears to be a safe and effective option in the treatment of fibromyalgia. The side effects that were experienced by some patients, over all studies, were transient insomnia, vivid dreams, headaches – all of which were minimised with a reduction in dose. Other reported side effects included diarrhea, mild and tolerable side effects which included fatigue, depression, nausea and abdominal pain (quite often the result of fillers used in the production of the LDN, not the naltrexone itself), and headache – all of which are generally managed with a slower titration period until the perfect dose for that individual is reached. They concluded, throughout all of the studies investigated, that 4.5 mg seemed to be the most appropriate dose for the management of fibromyalgia.
The duration of this study intervention ranged from 3 weeks to 14 months. This study stated that “The efficacy of LDN in treatment of FM has been demonstrated, though there is no consensus on a specific dose, frequency, or duration. Among the included studies, LDN doses varied from 0.1mg to 9mg daily, with 4.5mg once daily as the most common option.”
There is no consensus on a specific dose because each patient is an individual with different needs, lifestyles, body mass, chemical sensitivities - so many variables that there will not be, and cannot be, a one dose fits all scenario and this is also likely true of many, if not all, prescription drugs.
1. Karin Due Bruun, MD et al., “Naltrexone 6 mg Once Daily Versus Placebo in Women with Fibromyalgia: A Randomised, Double-Blind, Placebo-Controlled Trial,” The Lancet Rheumatology, (Dec 5th, 2023), https://doi.org/10.1016/S2665-9913(23)00278-3
2. Juan Yang et al., “The Safety and Efficacy of Low-Dose Naltrexone in Patients with Fibromyalgia: A Systematic Review”, The Journal of Pain Research, 16:1017-1023, (Mar 21st, 2023), https://doi.org/10.2147/JPR.S395457