Does nortriptyline (tricyclic antidepressant) cause Restless Legs Syndrome (RLS)?

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From the Guidelines

Nortriptyline can potentially cause or worsen restless leg syndrome (RLS) in some patients, as it affects neurotransmitters in the brain, particularly serotonin and norepinephrine, which can disrupt dopamine regulation - a key factor in RLS development. While not everyone taking nortriptyline will experience RLS, it's considered one of several medications that may trigger or exacerbate this condition. If you're taking nortriptyline (typically prescribed at doses ranging from 25-150 mg daily) and develop symptoms like uncomfortable sensations in your legs with an urge to move them, especially at rest or at night, discuss this with your healthcare provider. They may consider adjusting your dosage, changing the timing of your medication, or switching to an alternative medication that's less likely to affect RLS symptoms. Never stop taking nortriptyline abruptly as this can cause withdrawal symptoms; any changes should be made under medical supervision 1.

Key Considerations

  • Nortriptyline's impact on serotonin and norepinephrine can disrupt dopamine regulation, potentially leading to RLS symptoms.
  • Not all patients taking nortriptyline will experience RLS, but it is a possible side effect.
  • If RLS symptoms develop, healthcare providers may adjust the dosage, timing, or switch to an alternative medication.
  • Abruptly stopping nortriptyline can cause withdrawal symptoms, so any changes should be made under medical supervision.

Recommendations

  • Monitor for RLS symptoms when taking nortriptyline.
  • Discuss any symptoms with your healthcare provider to determine the best course of action.
  • Consider alternative medications or adjustments to your current treatment plan if RLS symptoms occur.

From the Research

Nortriptyline and Restless Legs Syndrome

  • The provided studies do not directly investigate the relationship between nortriptyline, a tricyclic antidepressant, and Restless Legs Syndrome (RLS) 2, 3, 4, 5, 6.
  • However, some studies suggest that antidepressants, in general, may induce or worsen RLS symptoms, although the evidence is limited and inconclusive 4.
  • Among the various antidepressants, mirtazapine may be associated with higher rates of RLS, while bupropion may reduce RLS symptoms 4.
  • Tricyclic antidepressants, such as amitriptyline, may increase periodic limb movements, but the clinical significance of this is unclear 4.
  • There is no direct evidence to suggest that nortriptyline specifically causes RLS, but it is possible that it may exacerbate symptoms in some individuals, as with other antidepressants 4.

Treatment of Restless Legs Syndrome

  • Dopaminergic agents, such as pramipexole and ropinirole, are commonly used to treat RLS, but may cause augmentation, a worsening of symptoms over time 2, 3, 5, 6.
  • Alpha-2-delta ligands, such as gabapentin and pregabalin, are also effective in treating RLS and may have a lower risk of augmentation 2, 5, 6.
  • Other treatments, such as opioids and clonazepam, may be used in some cases, but the evidence for their effectiveness is limited 5.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

The treatment of restless legs syndrome.

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2007

Research

Treatment of restless legs syndrome.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2014

Research

Comparison of pregabalin with pramipexole for restless legs syndrome.

The New England journal of medicine, 2014

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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