Medications and substances that can worsen restless legs syndrome (RLS) and/or periodic limb movements of sleep

Class	Examples	Risk
Antidepressants	Highest risk: Mirtazapine Doxepin	●●●
	Intermediate risk: Tricyclics (eg, amitriptyline, nortriptyline) SNRIs (eg, duloxetine, venlafaxine) SSRIs (eg, citalopram, escitalopram, fluoxetine, paroxetine, sertraline)	●●
	Lower risk: Nefazodone Trazodone	●
	Lowest/no risk: Bupropion	○
Antipsychotic drugs	First-generation agents (eg, haloperidol, thioridazine) Second-generation agents (eg, aripiprazole, clozapine, olanzapine, quetiapine, risperidone)	●●
Dopamine-blocking antiemetics	Chlorpromazine Metoclopramide Prochlorperazine	●●
Centrally acting antihistamines	Chlorpheniramine Diphenhydramine Hydroxyzine	●●
Antiseizure medications	Phenytoin Topiramate Zonisamide	● (Based on case reports)
Other substances	Alcohol (intoxication and withdrawal) Opioid withdrawal Sodium oxybate (in patients with narcolepsy)	●●

Risk:

1 dot (●): Low

2 dots (●●): Intermediate

3 dots (●●●): High

SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.

References:

Hoque R, Chesson AL. Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: Literature review, qualitative scoring, and comparative analysis. J Clin Sleep Med 2010; 6:79.
Hoxha O, Jairam T, Kendzerska T, et al. Association of periodic limb movements with medication classes: A retrospective cohort study. Neurology 2022; 98:e1585.
Kolla BP, Mansukhani MP, Bostwick JM. The influence of antidepressants on restless legs syndrome and periodic limb movements: A systematic review. Sleep Med Rev. 2018; 38:131.
Patatanian E, Claborn MK. Drug-induced restless legs syndrome. Ann Pharmacother 2018; 52:662.
Rottach KG, Schaner BM, Kirch MH, et al. Restless legs syndrome as side effect of second generation antidepressants. J Psychiatr Res 2008; 43:70.
Wei S, Song X, Chen R, et al. Exploring the top 50 drugs associated with restless legs syndrome based on the FDA data from 2004 to 2024. Nat Sci Sleep 2025; 17:929.

Graphic 88603 Version 7.0