Drug-Induced Restless Legs Syndrome

Restless legs syndrome (RLS) is a neurological movement and sensory disorder. It is diagnosed solely based on the following largely subjective criteria: (1) an urge to move the legs; (2) the urge occurs or is aggravated during periods of rest or inactivity, such as lying down or sitting; (3) the urge is relieved partially or totally by movement; (4) the symptoms are worse or occur only in the evening or night; and (5) the symptoms are not connected to another medical or behavioral condition.[1] The movement urge associated with this syndrome usually is accompanied by unpleasant sensory symptoms, such as burning, electric-shock-like or tingling sensations in the lower limbs that sometimes extend to the arms.[2]

RLS is the most common movement disorder, affecting 5 to 10 percent of the population, most commonly women older than 35.[3] The negative impact of the syndrome varies among patients based on the severity of the symptoms.[4] For at least half of the cases, symptoms are mild or infrequent.[5] Patients with minor symptoms report simple annoyance. But those with severe symptoms may experience disruption in their quality of life, social activities, sleep and work. Only a small portion of people affected by the syndrome will seek treatment for their symptoms,[6] possibly because they have never heard of this disorder.

The syndrome can be idiopathic (has no identifiable cause; also called primary) or secondary to certain medical conditions, including iron deficiency anemia, chronic kidney disease or pregnancy.[7] A family history of RLS is common among those affected.

Unbeknownst to many patients, some of their prescription and over-the-counter drugs also can cause or worsen the syndrome. Learn about these drugs to protect yourself and your loved ones from this troublesome adverse effect.

Drugs that trigger RLS

The most common drugs that have been implicated in causing or exacerbating RLS are certain antidepressants, antiepileptics (drugs for treating seizures), antihistamines (often present in sleep or allergy pills), antipsychotics, dopamine-antagonist antiemetics (drugs for preventing or treating nausea and vomiting) and mood stabilizers (see examples in Table, below). Notably, the risk of developing this adverse effect increases in patients who are taking more than one of these drugs.

Examples of Drugs That Can Cause Restless Legs Syndrome[8],[9],[10],[11]

*Designated as Limited Use
**Designated as Do Not Use
***Topiramate also is approved for the prevention of migraine headaches.

Treatment

If appropriate, after a discussion with your doctor, discontinuing the causative drug(s) should be the first approach to treating drug-induced RLS.[12] In such cases, the syndrome typically resolves shortly after the causative drug is discontinued.[13] Alternatively, lowering the dosage of the causative drug(s) may minimize the symptoms.

However, there are cases in which the causative drug cannot be discontinued, such as when no alternative treatment is available or when the drug's benefits outweigh its movement-related adverse effects. In such cases, nonpharmacological approaches are recommended. These include avoiding caffeine, alcohol and nicotine; good sleep hygiene; regular exercise; and massage therapy.[14]

Drugs that are approved by the Food and Drug Administration (FDA) for treatment of moderate-to-severe primary RLS include extended-release gabapentin enacarbil (HORIZANT) and certain dopamine agonists (pramipexole [MIRAPEX], ropinirole [REQUIP] and rotigotine transdermal system ([NEUPRO]).[15] However, these medications are not approved by the FDA for treatment of drug-induced RLS, and they also come with their own set of significant adverse effects.

One of those adverse effects is augmentation:the potential for the drug to change the pattern of the symptoms of RLS, make patients physically dependent on the medications or require them to take higher doses over time. Dopamine agonists also can cause low blood pressure when standing up, nausea, hallucinations (or even psychosis) and impulsive behavior (including pathological gambling, hypersexuality and compulsive shopping). Pramipexole may lead to a slightly increased risk of congestive heart failure. Extended-release gabapentin enacarbil can cause suicidal thoughts.

What You Can Do

If you develop RLS symptoms, make a list of your current medications and consult your doctor to find out whether your symptoms may be caused by any of these medications. If your doctor suspects that one of your current medications is causing your symptoms, he or she may advise that you stop taking this medication, which oftentimes reverses the symptoms. If your doctor recommends continuing the causative drug(s), opt for the aforementioned nonpharmacological steps to minimize your symptoms and avoid using gabapentin enacarbil, pramipexole, ropinirole or rotigotine transdermal system.

References

[1] Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria--history, rationale, description, and significance. Sleep Med. 2014;15(8):860-873.

[2] Drug-related restless legs syndrome. Prescrire Int. 2018;27(194):158.

[3] Rizek P, Kumar N. Restless legs syndrome. CMAJ. 2017;189(6):E245.

[4] Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Comparative Effectiveness Review No. 86. Agency for Healthcare Research and Quality. Rockville, MD; 2012.

[5] Ohayon MM, O'Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. 2012;16(4):283-295.

[6] Harris MK, Shneyder N, Borazanci A, et al. Movement disorders. Med Clin North Am. 2009;93(2):371-388.

[7] Ekbom K, Ulfberg J. Restless legs syndrome. J Intern Med. 2009;266(5):419-431.

[8] Patatanian E, Claborn MK. Drug-induced restless legs syndrome. Ann Pharmacother. 2018;52(7):662-672.

[9] Hoque R, Chesson AJ. 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(1):79-83.

[10] Drug-induced restless legs syndrome. Prescrire Int. 2010;108(19):164-165.

[11] Hensley JG. Leg cramps and restless legs syndrome during pregnancy. J Midwifery Womens Heal. 2009;54(3):211-218.

[12] Patatanian E, Claborn MK. Drug-induced restless legs syndrome. Ann Pharmacother. 2018;52(7):662-672.

[13] Drug-induced restless legs syndrome. Prescrire Int. 2010;108(19):164-165.

[14] Patatanian E, Claborn MK. Drug-induced restless legs syndrome. Ann Pharmacother. 2018;52(7):662-672.

[15] Restless legs syndrome: overdiagnosed and overtreated. Worst Pills, Best Pills News. December 2014. /newsletters/view/934. Accessed January 2, 2019.