Does trazodone exacerbate Restless Leg Syndrome (RLS)?

Trazodone's Effect on Restless Legs Syndrome

Trazodone can exacerbate restless legs syndrome (RLS) and should be avoided in patients with this condition. While not specifically mentioned in the American Academy of Sleep Medicine (AASM) guidelines, case evidence demonstrates that trazodone can trigger or worsen RLS symptoms.

Evidence for Trazodone's Effect on RLS

• A case report documented a 39-year-old female patient who developed RLS symptoms (burning, tingling, and restlessness in legs with an urge to move) after the first night of trazodone (100mg/day) treatment for insomnia 1
• The patient's RLS symptoms disappeared one day after discontinuing trazodone, establishing a clear temporal relationship between the medication and symptoms 1
• Trazodone's complex agonistic/antagonistic effects on the serotonergic system may contribute to its potential to induce RLS 1

Medications Known to Exacerbate RLS

• The AASM guidelines specifically note that serotonergic medications can exacerbate RLS and should be addressed as potential triggering factors 2
• Multiple antidepressants have been documented to induce or worsen RLS symptoms, including:
  • SSRIs: escitalopram, fluoxetine, sertraline, citalopram, and paroxetine 3, 4
  • Other antidepressants: mirtazapine and mianserin 4, 5

Management Recommendations for RLS

• The AASM recommends addressing potential exacerbating factors, including serotonergic medications, as part of RLS management 2
• First-line pharmacological treatment for RLS should be alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) rather than dopaminergic agents 2
• Iron supplementation should be considered if serum ferritin ≤75 ng/mL or transferrin saturation <20% 2

Alternative Medications for Patients with RLS

• For patients with RLS requiring treatment for insomnia or depression, consider:
  • Bupropion, which may actually reduce RLS symptoms in the short term 4
  • Sedating antidepressants such as nefazodone and doxepin, which do not appear to aggravate periodic limb movements 4

Clinical Implications

• When a patient with RLS develops worsening symptoms, medication review should include assessment of trazodone and other serotonergic agents 2
• If trazodone is suspected of exacerbating RLS, discontinuation should lead to symptom improvement within days 1
• For patients with both insomnia and RLS, alternative non-serotonergic sleep medications should be considered 2, 4

The evidence clearly indicates that trazodone should be used with caution in patients with RLS, and alternative medications should be selected when treating comorbid conditions in these patients.