What is the maximum recommended dose of low-dose naltrexone (LDN) for treating fibromyalgia?

Maximum Dose of Low-Dose Naltrexone for Fibromyalgia

The maximum recommended dose of low-dose naltrexone (LDN) for fibromyalgia is 4.5 mg taken at bedtime, with gradual titration starting at 1.5 mg and increasing by 1.5 mg every two weeks. 1

Dosing Protocol

The evidence-based approach to LDN dosing in fibromyalgia follows this specific algorithm:

• Starting dose: 1.5 mg at bedtime 1
• Titration schedule: Increase by 1.5 mg every 2 weeks 1
• Target/maximum dose: 4.5 mg at bedtime 1

This dosing recommendation comes from guideline-level evidence published in Ophthalmology (2017), which specifically addresses LDN use in chronic neuropathic pain conditions including fibromyalgia. 1

Evidence Supporting the 4.5 mg Maximum

The 4.5 mg dose is supported by the highest quality clinical trial data. A randomized controlled trial of 31 fibromyalgia patients demonstrated that LDN 4.5 mg resulted in significant pain reduction and improved life satisfaction compared to placebo. 1

More recent dose-response research (2020) calculated that the effective dose in 50% of patients (ED50) was 3.88 mg and in 95% of patients (ED95) was 5.40 mg, confirming that 4.5 mg is an appropriate target dose for most patients. 2

Important Caveat: Recent Contradictory Evidence

A 2024 high-quality randomized controlled trial in The Lancet Rheumatology tested a higher dose (6 mg) and found no superiority over placebo for pain reduction (between-group difference -0.34 points, p=0.27). 3 This trial enrolled 99 women with fibromyalgia and represents the most recent and rigorous evidence available. However, this study did suggest potential benefit for memory problems associated with fibromyalgia. 3

Clinical Recommendation Despite Mixed Evidence

Given the conflicting evidence, the conservative approach is to not exceed 4.5 mg daily, as:

• The guideline-level recommendation explicitly states 4.5 mg as the maximum 1
• The 2024 trial showing no benefit used 6 mg, suggesting higher doses may not provide additional efficacy 3
• Earlier pilot studies (2009) using 4.5 mg showed >30% symptom reduction over placebo 4
• The dose-response study (2020) supports 4.5 mg as a reasonable target 2

Side Effect Profile

Common side effects at the 4.5 mg dose include:

• Headache 1
• Tachycardia 1
• Vivid dreams 1
• Insomnia (rare and transient) 4

These side effects are generally described as minor and transient. 4 Discontinuation rates due to adverse events remain low (8% in the 6 mg trial). 3

Practical Considerations

Do not use LDN in patients currently taking opioid medications, as naltrexone is an opioid antagonist and will precipitate withdrawal. 4 The mechanism of action involves transient opioid receptor blockade leading to rebound endorphin function, as well as inhibition of microglial activity and reduction of pro-inflammatory cytokines. 1, 4

Baseline inflammatory markers may predict response: patients with higher erythrocyte sedimentation rates showed greater symptom reduction in pilot studies, with ESR predicting over 80% of variance in drug response. 4