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

ABSTRACT 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.