Alpha-2-Delta Calcium Channel Ligands to Treat RLS

Alpha-2-delta calcium channel ligands are a class of drugs used for chronic, persistent restless legs syndrome (RLS) when iron supplements do not work. These drugs may be an especially good choice in people who have RLS plus nerve pain, chronic pain, insomnia, anxiety, or impulse control disorders.1

The U.S. Food and Drug Administration (FDA) has approved 1 alpha-2-delta drug for moderate-to-severe restless legs syndrome. Others may be prescribed off-label.

Studies show that all of these drugs improve the ability to fall asleep and total sleep time in people with RLS and insomnia. These drugs do not seem to cause augmentation. Augmentation is when RLS symptoms get worse again after taking a drug for some time.2

How do alpha-2-delta drugs work?

These drugs work with the alpha-2-delta protein. This protein allows calcium to move into a nerve cell, and activates, deactivates, or stabilizes the electrical activity of the nerve.3

Formulations of alpha-2-delta drugs

Horizant® (gabapentin enacarbil)

Gabapentin enacarbil, sold under the brand name Horizant, is FDA-approved to treat moderate to severe RLS. In addition to improving RLS symptoms, it also reduces periodic limb movements during sleep, leading to fewer arousals per hour. The most common side effects are:1

  • Sleepiness/tiredness
  • Dizziness
  • Weight gain

About 1 out of 10 people stopped taking this drug due to side effects.

Lyrica® (pregabalin)

Pregabalin, sold under the brand name Lyrica, is an FDA-approved drug for people with nerve pain and seizures. It works by decreasing the number of pain signals sent out by nerves in the body. It may be prescribed off-label for RLS. About 3 out of 10 people who take pregabalin stop taking it due to side effects. The most common side effects are:1,4

  • Dizziness
  • Sleepiness/tiredness
  • Fatigue
  • Headache
  • Swelling in the arms, lower legs
  • Weight gain

Gralise® and Neurontin® (gabapentin)

Gabapentin has been shown to control RLS symptoms in a few small studies. Gabapentin is sold under the brand names Gralise and Neurontin.1

Doctors should begin with a small dose and gradually increase the amount given because it can cause sleepiness and problems walking. This is especially true in older people. Low doses of gabapentin have been effective in helping dialysis patients with RLS.1

Things to know about alpha-2-delta drugs

These drugs should not be taken by people with obesity, moderate to severe depression, gait instability, respiratory disease, or a history of substance use disorder.

In late 2019, the FDA issued a safety alert warning of serious breathing problems that can occur in some people using Neurontin, Gralise, Horizant, and Lyrica. These drugs should not be taken with opioids and other drugs that suppress the central nervous system because it can slow breathing too much. People with chronic lung disease and the elderly should be especially careful due to the risk of breathing problems.

All of these drugs may cause an increased risk of suicidal thoughts and behavior, so your doctor should monitor you for depression and suicidal behavior. Call your doctor immediately if you or a loved one shows signs of a serious reaction, including:5

  • Confusion, disorientation
  • Unusual dizziness or lightheadedness
  • Extreme sleepiness
  • Slow, shallow, or difficult breathing
  • Cannot wake them up
  • Bluish skin, especially on the lips, fingers, or toes

Side effects can vary depending on the specific treatment/drug you are taking. These are not all the possible side effects of alpha-2-delta drugs. Talk to your doctor about what to expect or if you experience any changes that concern you during treatment with alpha-2-delta drugs.

There are few studies looking at the long-term safety of taking these drugs. Most studies follow people for 12 weeks or less while they are taking one of these drugs. So, while RLS is a life-long disease, the safety of taking these drugs for decades is unknown.1

These drugs are also used as anticonvulsants and for Parkinson’s disease.1,3

Before beginning treatment for RLS, tell your doctor about all your health conditions and any other drugs, vitamins, or supplements you are taking. This includes over-the-counter drugs.”

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Written by: Jessica Johns Pool | Last reviewed: January 2022