What is Restless Leg Syndrome (RLS)?

Restless leg syndrome (RLS), also known as Willis-Ekbom disease, is a neurological condition and sleep disorder characterized by an overwhelming urge to move the legs when at rest.

According to the National Institute of Neurological Disorders and Stroke, RLS affects 7-10% of the U.S. population. This condition more commonly affects Caucasians, women, and people assigned female at birth. People with RLS describe uncomfortable sensations in the leg muscles at rest as pulling, tugging, throbbing, burning, aching, itching, or crawling. Movement of the legs provides temporary relief from the discomfort.

In addition, RLS can cause leg jerks or twitching, which can make falling and staying asleep difficult. Severe RLS can lead to sleep deprivation, which can cause daytime sleepiness and mood changes.

Restless Leg Syndrome vs Periodic Limb Movement Disorder

Approximately 8 out of 10 people with periodic restless legs syndrome (RLS) experience periodic limb movement of sleep (PLMS), also known as periodic limb movement disorder (PLMD). PLMS consists of twitching or jerking movements that occur several times a minute and disrupt sleep, often lasting through the night. Many people with RLS also develop periodic limb movement disorder, but most people with PLMS do not develop RLS.

Causes of Restless Legs Syndrome

Scientists have not yet discovered the exact cause of RLS. However, we know that the basal ganglia, the part of the brain that controls movement, is involved. Research suggests that RLS develops when the basal ganglia does not produce enough of a natural brain chemical called dopamine. This lack of dopamine affects movement and can lead to restless leg symptoms. When RLS is unrelated to other medical conditions, it is called primary RLS.

Both genetic and environmental factors can induce restless legs syndrome. RLS can be inherited from one of your biological parents. Scientists have also found that low iron levels in the brain are linked to an increased risk of RLS. In addition to iron deficiency anemia, other medical conditions can cause RLS symptoms - this is called secondary RLS - for example:

Chronic kidney disease and kidney failure
Diabetes
Peripheral neuropathy
Attention deficit hyperactivity disorder (ADHD)
Substance use disorders
Pregnancy

Medication-Related Triggers: How Certain Medications Influence RLS Symptoms

Certain medications have been linked to RLS, including antidepressants, antihistamines, anti-nausea medicines, and antipsychotics or neuroleptics. These medications can cause RLS or worsen symptoms in RLS patients.

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Common Medications That Cause Restless Leg Syndrome

Antidepressants

Researchers have found that antidepressant medication use can cause or worsen RLS.

Among the various antidepressants, studies have shown the following about RLS:

Antidepressants associated with higher rates of RLS and periodic limb movements include mirtazapine and venlafaxine.
Antidepressants that may increase periodic limb movements but do not typically disrupt sleep include fluoxetine, sertraline, and amitriptyline.
Antidepressants that do not usually cause RLS symptoms include nefazodone, trazodone, and doxepin.

You might be at greater risk of RLS if you are taking several medications that can affect dopamine levels. You should speak with your doctor if you notice any signs or symptoms of this condition.

Keep in mind that not all antidepressants worsen RLS. For example, bupropion may be a suitable option for treating both depression and RLS, as it is designed to increase dopamine and norepinephrine levels in the brain.

Psychiatric Medications

Neuroleptic or antipsychotic medicines are used to treat psychiatric disorders such as schizophrenia and bipolar disorder. Patients taking neuroleptic drugs can develop akathisia as a side effect. Akathisia is a sensation of severe restlessness and an inability to remain still.

Studies have shown that some antipsychotic drugs have a higher risk of causing neuroleptic-induced akathisia - quetiapine, olanzapine, aripiprazole, and clozapine. In addition, there are case reports of akathisia associated with risperidone treatment.

There are also case reports of lithium-aggravated nocturnal myoclonus and restless legs syndrome. Lithium is a mood stabilizer that is prescribed for bipolar disorder.

Studies have also found a higher incidence of restless legs syndrome in patients receiving psychiatric inpatient treatment.

Find out which antipsychotic medications have the least amount of side effects.

Antihistamines

Allergy medications, such as diphenhydramine, can make RLS symptoms worse. Researchers have found that older sedating antihistamines are more likely to worsen symptoms than newer non-sedating antihistamines. There are case reports of restless legs syndrome induced by a combination of fexofenadine and pseudoephedrine.

Antiemetics

There are many case reports of patients with RLS that is worsened by antiemetics (anti-nausea medicines) such as trimethobenzamide, prochlorperazine, hydroxyzine, promethazine, metoclopramide, and meclizine.

Mechanism of Medication-Induced RLS

How Medications Affect Dopamine and RLS

Scientists do not fully understand why certain medications can cause RLS. Research suggests that the neurotransmitter dopamine plays a role. Low dopamine levels in the basal ganglia are believed to cause refractory restless legs syndrome. Experiments using opioid and dopamine antagonist drug challenges suggest that specific changes in dopaminergic pathways lead to the development of RLS.

What we know so far is:

Antipsychotic drugs may cause or worsen RLS symptoms by preventing dopaminergic neurotransmission and/or impacting iron metabolism in the body.
Antihistamines block the effects of a chemical called histamine, which is a neurotransmitter in the brain. First‐generation antihistamines, especially those that are centrally-acting (sedating), are more likely to induce restless legs syndrome than newer, non-sedating, second-generation antihistamines that do not cross the blood-brain barrier.
Restless legs syndrome induced by anti-nausea drugs may be due to their blockade of the dopamine system. People taking newer selective 5-HT3 receptor antagonists, such as ondansetron or granisetron, for nausea treatment are less likely to have restless legs syndrome diagnosed because these drugs do not bind to dopamine receptors.

Recognizing Medication Side Effects

If your symptoms begin shortly after starting a new medication, your RLS could be medication-induced. Also, if you previously had mild symptoms of RLS but developed severe symptoms after starting a new medicine, talk to your healthcare provider.

Importance of Consulting Healthcare Professionals

Your healthcare provider can establish a diagnosis of drug-induced restless legs syndrome based on:

Medical history (no RLS symptoms before starting the medicine).
Blood tests to rule out secondary causes such as iron deficiency, renal failure, peripheral neuropathy, or pregnancy.
Tests to rule out other movement disorders or neurological disorders.
Polysomnogram to rule out other sleep-related disorders such as obstructive sleep apnea.

Alternatives and Adjustments in Medication

Once other causes of RLS have been ruled out, patients presenting with drug-induced RLS may be offered the following treatment options:

A lower dose of the medicine causing RLS symptoms.
A switch to other medications from the same class. For example, a second-generation antihistamine, a newer antidepressant, or an anti-nausea drug instead of an older or first-generation drug.
In severe cases, treatment with the drug-causing RLS may need to be stopped.
Patients who are severely affected by drug-induced RLS may need to take medications for RLS. Examples of drugs to treat RLS include:
- Dopamine agonists such as ropinirole, pramipexole (Mirapex), and rotigotine.
- Benzodiazepines such as clonazepam.
- Over-the-counter non-opioid analgesics.
- Opioid analgesics such as oxycodone.
- Sedative-hypnotics (sleep meds) such as Ambien.
- Anticonvulsants such as gabapentin enacarbil (Horizant) and pregabalin (Lyrica).
- Parkinson’s disease medications such as levodopa are sometimes used for restless legs syndrome.

Managing Medication-Induced RLS

The following lifestyle changes may help in managing mild symptoms of medication-induced RLS:

Take warm baths and get massages to relax your leg muscles.
Alternate hot and cold packs to reduce abnormal leg sensations.
Use a foot wrap or vibrating pad to relieve restless legs.
Practice good sleep hygiene to reduce fatigue and sleep deprivation. To this end, you should:
- Get at least 7 hours of sleep each night.
- Go to bed and get up at the same time every day.
- Sleep in a cool, dark, quiet bedroom.
- Switch off electronics 1-2 hours before bedtime.
Engage in regular moderate exercise to ease symptoms of RLS. However, experts advise avoiding strenuous exercise in the second half of the day, which can worsen RLS symptoms.
Avoid alcohol, caffeine, and nicotine, which are known triggers for RLS.

Frequently Asked Questions About RLS and Medications

What Medications Trigger RLS?

Medications known to trigger RLS include antidepressants, antihistamines, antipsychotics, and antiemetics.

Can Vitamins or Supplements Help with RLS?

Iron supplementation may help to relieve RLS. In addition, magnesium, vitamin B6, vitamin B12, and vitamin D supplements may reduce the severity of RLS symptoms in some people and improve sleep quality.

Read more about how vitamins can help with RLS.

What Is The Best Thing To Stop Restless Leg Syndrome?

There is nothing that can stop restless legs syndrome completely or cure the condition. However, lifestyle changes and RLS medications can help you stay comfortable and get better sleep. If you have severe symptoms, your healthcare provider may prescribe specific RLS drugs to treat the condition.

What Is The Biggest Cause of RLS?

The exact cause of RLS is not known. However, genetics is believed to play a role, and RLS runs in some families. Low iron levels in the brain are also known to cause RLS.

Can Caffeine Help Restless Leg Syndrome?

No, caffeine does not help with restless legs syndrome. In fact, caffeine can make RLS symptoms worse. If you have RLS, avoid caffeinated beverages such as tea, coffee, sodas, and chocolate.

What Vitamin Stops Restless Leg Syndrome?

Iron supplementation may stop restless legs syndrome. Other vitamins and dietary supplements that may help with RLS symptoms include B vitamins, vitamin D, and magnesium.

What Is Mistaken For Restless Leg Syndrome?

Some of the conditions that can be mistaken for restless legs syndrome include:

Periodic limb movement disorder
Peripheral neuropathy
Nocturnal leg cramps
Arthritis
Akathisia
Intermittent claudication
Myalgia (muscle aches and pains)
Vascular disease (blood vessel problems)
Growing pains in children

What Drink Helps Restless Legs?

There isn’t a specific drink that helps with restless legs. However, it’s important to stay well hydrated for overall health. People with RLS often have low iron levels. If your doctor prescribes an iron supplement, try taking it with a glass of orange juice, which is a good source of vitamin C (vitamin C helps with iron absorption).

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