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LONDON — Low-dose naltrexone (LDN) failed to outperform placebo in reducing pain or improving secondary outcomes in women with fibromyalgia, according to data presented at the European Alliance of Associations for Rheumatology (EULAR) 2026 Annual Meeting. However, patients who believed they were part of the intervention group reported improvements in some of their symptoms.

The findings from the 12-month, randomized, double-blind, placebo-controlled trial challenge prior data from smaller pilot studies that had initially suggested LDN might be an effective, well-tolerated therapy for the chronic primary pain syndrome. “Results have been controversial,” said Juan Luciano, PhD, a health psychologist and associate professor at the Autonomous University of Barcelona, Bellaterra, Spain, who presented the study results at the meeting.

“Regretfully, [the results from this trial] were quite disappointing. It's an unsuccessful trial because you can see [LDN] does not give a meaningful reduction in pain or distress,” he said.

Jasminka Milas-Ahic, MD, PhD, head of rheumatology and clinical immunology at University Hospital Osijek, Croatia, who chaired the session and was not involved in the study, told Medscape Medical News that despite the lack of differentiation between the two arms, the study provides valuable clarity for clinicians. “This study was really very well designed, but unfortunately it didn't show any difference,” she said. "However, it’s important that we publish it. We don't need to quit [on LDN]; we just need to rethink the approach.”

No Clinical Edge Over Placebo

In the single-center study, 96 women with fibromyalgia were randomly assigned to receive 4.5 mg of LDN daily (n = 47) or placebo (n = 49). The participants had a mean age in their 50s, an average disease duration of approximately 8 years, and high baseline rates of psychiatric comorbidities such as depression.

The primary endpoint was the change in average pain intensity over the previous 7 days, measured on an 11-point numeric rating scale at 3 months. Secondary endpoints included functional impairment, anxiety, depression, perceived stress, cognitive dysfunction, disability, and Patient Global Impression of Change evaluated at 6 and 12 months.

At the 3-month mark, both study arms showed only minor decreases in pain intensity. The mean pain intensity score decreased by 0.33 points in the LDN group and by 0.64 points in the placebo group.

Secondary outcomes showed minor, inconsistent changes over the 12-month follow-up period, with low and comparable responder rates between the two arms.

Luciano said these findings align with another recent trial conducted in Denmark using a 6-mg dose, which similarly demonstrated no superiority of LDN over placebo. “Our results suggest that [LDN] is not recommendable in clinical practice,” he said.

Expectancy Effects

The investigators evaluated whether participants’ beliefs regarding their treatment allocation influenced their clinical outcomes. At the end of the trial, participants were asked to guess whether they had received the active drug or placebo.

While most participants were unable to accurately guess their assigned group, those who believed they were taking LDN reported a reduction in symptom impairment at 3 months and 12 months, regardless of whether they were actually taking the drug or placebo.

“This was very interesting,” Milas-Ahic said. “It might mean that we might need to better stratify patients that takes into account the complexity of the psychological component in patients with fibromyalgia, then we might recognize the group of patients who might benefit [from LDN].” She said that giving all patients the exact same therapeutic regimen may obscure benefits hidden within specific subgroups.

Luciano agreed that clinical anecdotes often point to subsets of patients, including those with comorbid conditions such as chronic fatigue syndrome, who report significant symptom reduction.

Addressing Sleep and Multidisciplinary Care 

Because fibromyalgia lacks a simple physical or inflammatory driver, managing it remains one of the steepest challenges in rheumatology.

Patients with fibromyalgia “are among the most difficult to treat in clinical practice,” Milas-Ahic explained, saying that the condition is rooted heavily in complex neurologic and psychological pain processing. “I usually refer patients to a psychiatrist or a clinical psychologist. A multidisciplinary approach is essential; this condition cannot be treated by rheumatology alone.”

She suggested that therapies targeting specific pathogenic mechanisms, rather than generalized pain, might hold the key — particularly those addressing sleep quality.

“The main problem is sleep disturbances because that is a core part of the pathophysiology,” Milas-Ahic said. “If you can improve the quality of sleep in those patients, it seems to directly and positively affect their pain.”

The trial was sponsored by the Fundació Sant Joan de Déu. Luciano and Milas-Ahic have reported no relevant financial relationships. 

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, New Scientist, The Guardian, MIT Technology Review, and others.