What Medications Make Restless Legs Worse? Identifying Common Triggers

According to the Restless Legs Syndrome Foundation, many people with RLS experience worsening symptoms due to specific medications they are taking. Identifying what medications make restless legs worse is a crucial step in managing and alleviating this often-disruptive neurological disorder.

Quick Summary

Certain medication classes, including antidepressants, sedating antihistamines, and dopamine-blocking anti-nausea drugs, can induce or exacerbate restless legs syndrome symptoms. Long-term use of dopamine agonists can also cause augmentation, a worsening of the condition. Understanding these triggers is key to managing RLS.

Key Points

• Antidepressants often worsen RLS: Many SSRIs, SNRIs, and TCAs can exacerbate RLS symptoms due to their impact on the brain's dopamine and serotonin systems.

• Sedating antihistamines are a common trigger: Over-the-counter cold and allergy medications containing first-generation antihistamines like diphenhydramine often aggravate RLS.

• Dopamine-blocking drugs increase RLS risk: Anti-nausea medications (e.g., metoclopramide) and antipsychotics (e.g., olanzapine) that block dopamine receptors are strong RLS triggers.

• Long-term RLS medications can cause augmentation: Ironically, long-term use of dopamine agonists (ropinirole, pramipexole) can lead to a worsening of RLS symptoms over time.

• Always consult a doctor before changing medication: Never stop taking or alter a prescription drug on your own. Work with your doctor to find a safer alternative or dosage that won't exacerbate your RLS.

• Safer alternatives exist: Certain antidepressants (like bupropion) and non-sedating antihistamines are less likely to worsen RLS and can be explored as alternatives.

• Iron status matters: Low iron levels are linked to RLS. Your doctor may check your iron and ferritin levels, as addressing a deficiency can help manage symptoms.

For individuals with restless legs syndrome (RLS), finding relief can be a significant challenge, especially when standard treatments seem to fail or symptoms suddenly worsen. A lesser-known but common contributing factor is the use of certain medications. This phenomenon, known as drug-induced RLS, occurs when a prescription or over-the-counter drug exacerbates existing symptoms or even causes them in previously unaffected individuals. The key lies in identifying these potential triggers and working with a healthcare provider to find suitable alternatives or management strategies.

The Connection Between Medication and RLS

Research suggests that a dysregulation of dopamine in the brain is a key component of RLS pathophysiology. Many medications, particularly those affecting neurotransmitter systems, can interfere with dopamine pathways, leading to the onset or worsening of RLS symptoms. In essence, any drug that blocks dopamine receptors can trigger the symptoms, while others may alter the complex balance of neurotransmitters in a way that contributes to the problem.

Common Medication Culprits

Several classes of drugs are known to cause or aggravate RLS symptoms. Patients should discuss their entire medication list with their doctor, including over-the-counter drugs and supplements, to identify potential culprits.

Antidepressants

Antidepressants, particularly those that affect serotonin and norepinephrine levels, are a common cause of drug-induced RLS. While they are often necessary for managing depression or anxiety, they can disrupt the delicate balance of neurotransmitters in the brain and interfere with dopamine function.

• Selective Serotonin Reuptake Inhibitors (SSRIs): Common examples include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), and escitalopram (Lexapro). Studies indicate these can increase RLS risk.
• Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs): Venlafaxine (Effexor) and duloxetine (Cymbalta) have also been linked to RLS exacerbation.
• Tricyclic Antidepressants (TCAs): Older antidepressants like amitriptyline (Elavil) can also worsen RLS symptoms.
• Other Antidepressants: Mirtazapine (Remeron) has been consistently reported to have a high risk of worsening RLS.

Antihistamines and Cold Medications

First-generation (sedating) antihistamines, which are found in many over-the-counter cold and allergy products, can worsen RLS because they cross the blood-brain barrier and block histamine and dopamine receptors.

• Sedating Antihistamines: Examples include diphenhydramine (Benadryl, found in many OTC sleep aids like Tylenol PM and cold medications) and doxylamine.
• Safe Alternatives: Newer, non-sedating second-generation antihistamines such as loratadine (Claritin), fexofenadine (Allegra), and cetirizine (Zyrtec) do not cross the blood-brain barrier as readily and are less likely to aggravate RLS.

Anti-nausea Medications (Antiemetics)

Many anti-nausea drugs work by blocking dopamine receptors and can therefore trigger RLS or akathisia (a similar restless feeling). These should be used with caution in individuals prone to RLS.

• Examples: Metoclopramide (Reglan) and prochlorperazine (Compazine) are well-known dopamine-blocking antiemetics.

Antipsychotic Medications (Neuroleptics)

As potent dopamine antagonists, antipsychotics are particularly notorious for causing or exacerbating RLS. They are used to treat serious psychiatric conditions like schizophrenia and bipolar disorder.

• Examples: Olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and haloperidol (Haldol) are all associated with a higher risk of RLS.

Augmentation from RLS Treatments

Paradoxically, some medications used to treat RLS can worsen symptoms over time, a phenomenon known as augmentation. This happens with long-term use of dopamine agonists.

• Dopamine Agonists: Ropinirole (Requip), pramipexole (Mirapex), and rotigotine (Neupro) initially relieve symptoms but can lead to a compensatory downregulation of dopamine receptors. This requires ever-increasing doses and can cause symptoms to start earlier in the day and spread to other parts of the body.

Comparison of Medications and RLS Risk

This table provides a general overview of medication classes and their potential impact on RLS. Risk levels can vary depending on the specific drug, dosage, and individual patient. Consult your doctor before making any medication changes.

Medication Class	Examples	RLS Risk Level	Rationale
Antidepressants	Mirtazapine, SSRIs (Sertraline, Fluoxetine), SNRIs (Venlafaxine)	High to Moderate	Interferes with dopamine and serotonin balance.
Sedating Antihistamines	Diphenhydramine (Benadryl), Doxylamine	High	Blocks histamine and dopamine receptors in the brain.
Anti-nausea Drugs	Metoclopramide (Reglan), Prochlorperazine	High	Blocks dopamine receptors.
Antipsychotics	Olanzapine, Risperidone, Haloperidol	High	Strong dopamine antagonists.
Dopamine Agonists (Long-Term Use)	Ropinirole, Pramipexole	High (Augmentation Risk)	Can cause downregulation of the dopamine system, worsening symptoms.
Non-Sedating Antihistamines	Loratadine (Claritin), Fexofenadine (Allegra)	Low	Do not readily cross the blood-brain barrier.
Bupropion	Bupropion (Wellbutrin)	Low	Antidepressant that does not typically worsen RLS and may even help.
Opioid Analgesics	Methadone, Oxycodone	Low (Augmentation Not Typical)	Effective for severe RLS, but reserved for refractory cases due to dependence risk.

What to Do If Your Medication is Worsening RLS

If you suspect a medication is aggravating your RLS, do not stop taking it suddenly. Abruptly discontinuing antidepressants or antipsychotics can have serious health consequences. Instead, speak with your healthcare provider immediately. They can help you develop a safe and effective plan.

1. Review your medications: Provide your doctor with a complete list of all drugs you are taking, including over-the-counter options, to identify any potential triggers.
2. Explore alternatives: Your doctor may suggest switching to a different medication within the same class that is less likely to affect RLS. For example, opting for a non-sedating antihistamine or a safer antidepressant like bupropion.
3. Adjust the dosage: In some cases, adjusting the timing or dosage of the medication may help alleviate symptoms.
4. Manage with supportive care: While addressing the medication, your doctor may suggest other RLS management strategies. These could include improving sleep hygiene, moderate exercise, or using nerve-stimulating devices approved for RLS.

Conclusion

For many people with RLS, the struggle to find effective relief can be compounded by unknowingly taking medications that worsen their condition. By educating yourself on what medications make restless legs worse and partnering with your doctor, you can take a crucial step toward better symptom management. Identifying the right combination of therapies and avoiding pharmacological triggers is a vital component of long-term RLS care. Never make changes to your medication regimen without professional medical advice, as your provider can offer safe and effective alternatives to improve your quality of life. More information and support can be found at the Restless Legs Syndrome Foundation.

Frequently Asked Questions

Which antidepressants are least likely to make restless legs worse?

Antidepressants that are less likely to aggravate restless legs syndrome include bupropion, trazodone, and nefazodone. It is important to discuss switching or starting any new medication with a healthcare provider.

Can I use over-the-counter sleep aids if I have RLS?

You should generally avoid over-the-counter sleep aids if you have RLS, as many contain sedating antihistamines like diphenhydramine that are known to worsen symptoms. Using non-sedating antihistamines or consulting a doctor for RLS-friendly sleep solutions is a better approach.

What is augmentation, and how is it different from a worsening of RLS?

Augmentation is a specific condition where long-term use of dopamine-boosting RLS medications paradoxically makes symptoms worse. This can be distinguished from regular RLS progression because symptoms begin earlier in the day, become more intense, and may affect other parts of the body.

Why do some anti-nausea drugs worsen RLS?

Many anti-nausea drugs, such as metoclopramide and prochlorperazine, work by blocking dopamine receptors. Since low dopamine activity is linked to RLS, this action can trigger or exacerbate symptoms.

Are all antihistamines bad for RLS?

No, not all antihistamines are problematic. First-generation (sedating) antihistamines that cross the blood-brain barrier are the primary concern. Newer, second-generation (non-sedating) antihistamines like Allegra or Claritin do not cross into the brain as easily and are less likely to worsen RLS.

What should I do if my doctor prescribes an RLS-aggravating medication?

Inform your doctor about your RLS and the potential for a specific medication to worsen it. They can work with you to consider alternative medications or strategies to minimize the risk of side effects. Never stop a prescribed medication without medical guidance.

Can a medication trigger RLS in someone who has never had it before?

Yes, it is possible for medications to induce RLS symptoms in individuals who have no prior history of the condition. In such cases, symptoms typically appear shortly after starting the medication and resolve after it is discontinued.