What is the role of tramadol in treating a patient with moderate to severe Restless Legs Syndrome (RLS) who has not responded to first-line treatments?

Tramadol for Moderate to Severe RLS Refractory to First-Line Treatment

Tramadol is not recommended as a preferred opioid for treating moderate to severe RLS that has failed first-line therapy; instead, extended-release oxycodone, methadone, or buprenorphine should be used, as these have stronger evidence and are specifically mentioned in current guidelines. 1

Current Evidence-Based Treatment Algorithm

Before considering any opioid therapy, ensure the following have been addressed:

• Check iron status in all patients with clinically significant RLS—measure morning fasting ferritin and transferrin saturation after avoiding iron supplements for 24 hours. 2
• Supplement iron if ferritin ≤75 ng/mL or transferrin saturation <20% using IV ferric carboxymaltose (strong recommendation) or oral ferrous sulfate (conditional recommendation). 2, 1
• Verify adequate trial of alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin), which are first-line pharmacological therapy with strong recommendations and moderate certainty of evidence. 2, 1

Why Tramadol Is Not Preferred

While tramadol has shown efficacy in neuropathic pain conditions and is a weak opioid μ-receptor agonist that also inhibits serotonin and norepinephrine reuptake, it is not specifically mentioned in the 2025 American Academy of Sleep Medicine guidelines for RLS treatment. 3, 1

Critical safety concerns with tramadol include:

• Lowers seizure threshold, which is particularly problematic in patients with predisposing factors. 3
• Risk of serotonin syndrome when combined with SSRIs or SNRIs—a potentially fatal reaction that, while relatively uncommon, represents a serious drug interaction concern. 3
• Less robust evidence for RLS specifically compared to other opioids that have been studied in RLS populations. 1

Preferred Opioid Options for Refractory RLS

The American Academy of Sleep Medicine conditionally recommends the following opioids for moderate to severe RLS, particularly for refractory cases or dopamine agonist-related augmentation: 1

• Extended-release oxycodone (moderate certainty of evidence) 3, 1
• Methadone (most commonly used in national registry studies, with evidence of low abuse potential) 1
• Buprenorphine (preferred when opioid therapy is necessary due to reduced respiratory depression risk compared to other opioids) 1, 4

Long-term observational studies demonstrate:

• Relatively low risks of abuse or overdose in appropriately screened RLS patients 1
• Only small dose increases over 2-10 years of treatment 2

Critical Safety Considerations for Opioid Therapy

All opioids, including tramadol, carry important risks:

• Dose-dependent central sleep apnea and respiratory depression that increases with morphine equivalent dosing 1, 4
• Risk is compounded by concurrent use of sedative hypnotics, muscle relaxants, and alpha-2-delta ligands 1
• Screen for untreated obstructive sleep apnea before initiating opioid therapy, as this significantly increases respiratory depression risk 2, 1
• Appropriately screen patients for opioid misuse risk before initiating therapy 1, 4

Buprenorphine has a distinct advantage: It demonstrates reduced respiratory depression risk compared to other opioids, making it the safest opioid option when such therapy is necessary. 1, 4

Practical Clinical Approach

For a patient with moderate to severe RLS who has failed first-line alpha-2-delta ligands:

1. Confirm iron optimization (ferritin >75 ng/mL and transferrin saturation >20%) 2, 1
2. Verify adequate trial of gabapentin (up to 1800-2400 mg/day) or pregabalin (up to 300-600 mg/day) 2
3. If opioid therapy is necessary, choose extended-release oxycodone, methadone, or buprenorphine over tramadol 1
4. Start with low doses and titrate gradually while monitoring for respiratory depression 1, 4
5. Monitor regularly for efficacy, adverse effects, and signs of misuse 1

Common Pitfalls to Avoid

• Do not use tramadol simply because it is perceived as "safer" or "less potent"—the evidence specifically supports other opioids for refractory RLS. 1
• Do not initiate opioid therapy without first optimizing iron status and ensuring adequate trials of alpha-2-delta ligands. 2, 1
• Do not overlook untreated sleep apnea, which dramatically increases respiratory depression risk with any opioid. 1
• Do not combine tramadol with SSRIs or SNRIs without careful consideration of serotonin syndrome risk. 3