Low-Dose Naltrexone Shows No Significant Effects in People With Fibromyalgia

Low-dose naltrexone (LDN) was not seen to modify pain in people with fibromyalgia in a randomized, placebo-controlled trial, although some differences in exploratory outcomes were observed.1

The FINAL trial (NCT0427877) evaluated the efficacy of 12 weeks of naltrexone 6 mg in 99 women with fibromyalgia. Investigators previously reported that LDN was not superior to placebo in reducing the average pain intensity, nor did it have an effect on pressure pain threshold, an assessment that may predominantly reflect peripheral mechanisms rather than central pain mechanisms.2 The trial also collected clinical measures of pressure pain tolerance, temporal summation of pain (TSP), conditioned pain modulation (CPM), and muscular endurance in the upper and lower extremities at baseline and after the 12-week treatment period. Measures of muscular fatigue were evaluated using the 30-s chair stand test and a shoulder abduction test. Analysis of these exploratory outcomes are reported in this new paper. Notably, the investigator stated that FINAL was the first LDN trial to include comprehensive measures of spinal and supraspinal pain capacity and functional capacity tests.1

“The widespread pain and muscular fatigue characteristics of fibromyalgia are believed to be mediated by central mechanisms. LDN has emerged as a new treatment option for fibromyalgia, possibly modulating central mechanisms via glial or opioid receptors,” lead investigator Karin Due Bruun, MD, PhD, Pain Research Group, Pain Center, Odense University Hospital, University of Southern Denmark, Odense, and The Parker Institute, Copenhagen University Hospital Bispebjerg and Frederiksberg, Copenhagen, Denmark, and colleagues wrote.1

The exploratory outcomes were assessed for 45 (92%) patients in the LDN group and 47 (94%) patients in the placebo group that completed the assessments at baseline and the 12-week follow-up, for a total of 92 patients.

Brunn and colleagues found that of the 5 examined outcomes, only change in CPM showed a significant between-group difference with greater enhancement following LDN treatment (2.0 kPa [95% CI, 0.4–3.7]) compared with placebo. Within-group changes in CPM showed an increase of 1.2 kPa (95% CI, 0.05–2.4 ) in the LDN group and a decrease of 0.8 kPa (95% CI, − 1.9 to 0.4) in the placebo group. Sensitivity analyses did not reveal any significant associations with CPM improvement and pain.

Overall, investigators stated that “on the basis of within-group differences and sensitivity analyses,” the differences were “a spurious finding.”

There were also significant group differences between responders and non-responders in pain tolerance in the right leg and the muscle endurance tests in the LDN treated group but not in the placebo group.

“The between-group difference was partly driven by a deterioration in CPM in the placebo group, and there was no association between change in CPM and pain response, which suggest that this finding is most likely spurious. Future studies investigating the effects of LDN on CPM with sufficient power are still warranted,” Brunn and colleagues concluded.1

REFERENCES

1. Bruun KD, Christensen R, Amris K, et al. Effect of Naltrexone on Spinal and Supraspinal Pain Mechanisms and Functional Capacity in Women with Fibromyalgia: Exploratory Outcomes from the Randomized Placebo-Controlled FINAL Trial. CNS Drugs. Published online April 11, 2025. doi:10.1007/s40263-025-01183-7

2. Due Bruun K, Christensen R, Amris K, Vaegter HB, Blichfeldt-Eckhardt MR, Bye-Moller L, Holsgaard-Larsen A, Toft P. Naltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial. Lancet Rheumatol. 2024;6(1):e31–9.