Efficacy of Low‐Dose Naltrexone in Women With Fibromyalgia Syndrome: A 12‐Month Randomised, Double‐Blind, Placebo‐Controlled Single‐Centre Clinical Trial ( INNOVA Study)

BACKGROUND: Low-dose naltrexone (LDN) has been used off-label for fibromyalgia syndrome (FMS) for over a decade, supported by small crossover trials. The INNOVA study evaluated the safety and efficacy of LDN 4.5 mg versus placebo on pain intensity over 12 months in women with FMS. METHODS: In total, 98 women with FMS were randomised to LDN 4.5 mg/day (n = 48) or placebo (n = 50). The primary outcome was change in pain intensity (NRS 0-10) from baseline to 3 months in the intention-to-treat population. Secondary outcomes included functional impairment (FIQR), anxiety-depressive symptoms (DASS-21), cognitive impairment (MISCI), disability (WHODAS 2.0), pathological worry (GAD-7) and impression of change (PGIC/PSIC), assessed at baseline and at 3, 6 and 12 months. Perceived treatment allocation and safety were also assessed. RESULTS: At 3 months, mean change in pain intensity was -0.33 points with LDN and -0.64 with placebo, with an adjusted between-group difference of 0.49 (p = 0.236, d = 0.19). Secondary outcomes showed minor and inconsistent changes, with low and similar responder rates (p = 0.219-0.954). Exploratory analyses suggested some improvement among participants who believed they had received LDN, although effects were inconsistent. Adverse events, predominantly mild and transient, were reported by 33 (68.8%) participants in LDN and 36 (72%) in placebo, and no treatment-related serious events occurred. CONCLUSIONS: LDN was well tolerated but did not demonstrate a clinically meaningful benefit over placebo for pain-related outcomes, underscoring the need for more effective pharmacological treatments. SIGNIFICANCE STATEMENT: This RCT provides the first long-term evidence on the efficacy and safety of LDN in FMS. LDN (4.5 mg), administered as an add-on treatment, has a favourable safety profile, but the findings indicate that it does not produce clinically meaningful improvements in FMS symptoms compared to placebo at short- or long-term follow-up. These findings contribute to the growing body of evidence questioning its clinical utility.