The INNOVA RCT compared LDN 4.5 mg/day to placebo as add-on therapy in 96 women with fibromyalgia (FMS) over 12 months, with the primary outcome being change in NRS pain intensity at 3 months (ITT population); secondary outcomes included functional impairment (FIQR), mood, cognition, disability, and global impression of change at 3, 6, and 12 months.
LDN did not outperform placebo at any time point: the adjusted between-group difference in NRS pain at 3 months was 0.49 points in favor of placebo (p=0.236, d=0.19), and differences remained non-significant at 6 and 12 months; responder rates were low and similar across all thresholds (e.g., ≥30% pain reduction: LDN 10.6% vs. placebo 18.4%), with no serious treatment-related adverse events in either arm.
- Sample was smaller than planned (n=96 vs. 100) due to logistical constraints, slightly reducing statistical power, though CIs were centered near zero suggesting no meaningful effect. - Single fixed dose (4.5 mg) precluded dose-response evaluation, and no objective pain measures were included. - All-female, single-centre Spanish sample limits generalizability to men and other settings.
LDN 4.5 mg/day does not reduce pain or improve function meaningfully compared to placebo in women with FMS over 12 months—current evidence does not support its routine use for this indication. Clinicians should focus on multimodal, evidence-based strategies rather than off-label LDN for FMS.
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