By Brandon Peters, MD

Although many people with restless legs syndrome (RLS) may never be able to identify a cause to their disorder, often it results from other secondary causes. This thus results in two categories of the condition, the former being primary RLS (of unknown cause) and the latter deemed secondary RLS. There are many conditions that may independently lead to symptoms of RLS and these are described here.

1. Iron Deficiency

The relationship between iron deficiency and RLS symptoms has been extensively studied. In several research studies, low iron levels have been found in the blood and spinal fluid of individuals suffering from RLS. The lower the iron levels, the worse the symptoms. Magnetic resonance imaging (MRI) has shown that the iron content in an area of the brain called the substantia nigra is lower in those with RLS compared to normal individuals, which may contribute to the disorder. In addition, pathological studies have confirmed this change within the brain.

It is therefore recommended that you have your serum ferritin level (a marker of iron stores) checked if you have symptoms of RLS. If the ferritin level is low, generally at a value <75, a trial of oral iron replacement should be undertaken. Even if the levels are normal, some individuals respond to iron replacement.

2. End-stage Kidney Disease

RLS is very common among individuals suffering from end-stage kidney disease, especially those who are dependent upon dialysis. The incidence has been reported to range from 6 to 60 percent. It is unclear what may be contributing to RLS in this group. Anemia, iron deficiency, or even low parathyroid hormone levels may have a role based on various studies. In some cases, treating anemia with erythropoietin therapy or iron replacement has been effective.

3. Diabetes

In people with Type 2 or adult-onset diabetes, RLS may develop. If diabetes is left uncontrolled, nerve damage can result. This is thought to occur because of high levels of glucose within the blood. This can lead to damage of small blood vessels that supply the nerves called vaso nervorum. When these become clogged, the nerve itself will become damaged. Often this leads to a peripheral neuropathy, which consists of pain and a pins-and-needles sensation in the feet. This may progress up the legs and even involve the hands. Associated with these sensory changes, some people will also have symptoms of RLS. Therefore, it is thought that diabetes may be an independent risk factor for developing RLS. In people who have undergone pancreas and kidney transplants, their symptoms of RLS have improved.

4. Multiple Sclerosis

There is a growing body of evidence that multiple sclerosis seems to be associated with an increased risk of having RLS. Some of the studies are conflicting, however. In one of the larger studies that included 1500 subjects, the prevalence of RLS was 19 percent in people with MS compared to only 4 percent of those people without it.

5. Parkinson’s Disease

It is thought that RLS and Parkinson’s disease may be caused by a similar problem, namely disruptions in the neurotransmitter called dopamine. This is not fully understood, however. Regardless, RLS may be present in individuals who have Parkinson’s disease, with a prevalence ranging from 0 to 20.8 percent, based on the study. Parkinson’s disease often involves a sense of restlessness (called akathisia) that may also occur in RLS, which may make it difficult to discriminate between the disorders. When both conditions are present, RLS usually occurs after Parkinson’s disease has become apparent.

6. Pregnancy

Not all conditions that may lead to RLS are disorders. In fact, the state of being pregnant seems to increase not only the incidence but also the degree of RLS symptoms. In a study of 626 pregnant women, only 10 percent had symptoms of RLS prior to becoming pregnant but this increased to 27 percent during pregnancy. It seemed to worsen in the third trimester. The good news is that the symptoms rapidly improved after delivery. It is not clear what causes the increased frequency of RLS during pregnancy. It may be due to iron or folate deficiency or even because of hormonal changes associated with being pregnant.

7. Rheumatic Disease

There are many conditions such as rheumatoid arthritis, Sjogren’s syndrome, and fibromyalgia that may have an association with symptoms of RLS. This relationship is unclear. In one study, 25 percent of individuals with rheumatoid arthritis had RLS symptoms compared to only 4 percent of osteoarthritis. In another study, 42 of 135 patients with fibromyalgia had RLS. The exact reason for this association is not fully understood.

8. Varicose Veins

In some instances, poor blood flow in the legs has been associated with RLS. In particular, weak veins that distend and become uncomfortable have been blamed. These so-called varicose veins are often engorged and blue in color and may be a sign of venous insufficiency. In a study of 1397 patients, 312 people complained of symptoms of RLS.

Treatment of varicose veins has proven to be effective in alleviating some of the symptoms of RLS. Sclerotherapy led to initial improvement in 98 percent of people, with relief maintained at two years in 72 percent. Medication treatment, including hyrdoxyethylrutoside, has also been shown to be modestly effective.

9. Other Conditions

Beyond the conditions described above, there are many other disorders that seem to be associated with RLS symptoms. These include:

Obesity
Obstructive sleep apnea
Hypothyroidism
High blood pressure
Heart disease
Peripheral neuropathies
Vitamin deficiencies
Excessive caffeine intake
Low blood sugar
Lumbosacral radiculopathy
Spinal stenosis
Use of mianserin (an antidepressant medication)

Sources:

Earley, CJ et al. “Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome.” Neurology 2000; 54:1698.

Allen, RP et al. “MRI measurement of brain iron in patients with restless legs syndrome.” Neurology 2001; 56:263.

Connor, JR et al. “Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome.” Neurology 2003; 61:304.

Kavanagh, D et al. “Restless legs syndrome in patients on dialysis.” Am J Kidney Dis 2004; 43:763.

Merlino, G et al. “Association of restless legs syndrome and quality of sleep in type 2 diabetes: a case-control study.” Sleep 2007; 30:866.

Manconi, M et al. “Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study.” Sleep 2008; 31:944.

Lee, JE et al. “Factors contributing to the development of restless legs syndrome in patients with Parkinson disease.” Mov Disord 2009; 24:579.

Manconi, M et al. “Restless legs syndrome and pregnancy.” Neurology 2004; 63:1065.

American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd Edition Text Revision. 2024.

Walters, A. “Restless legs syndrome and periodic limb movements of sleep.” Continuum. Neurol 2007;13(3):115-138.

Restless legs syndrome (RLS) is a neurological disorder that affects hundreds of millions of people worldwide, characterized by an overwhelming urge to move the legs, often accompanied by uncomfortable sensations like crawling, tingling, or itching. These symptoms tend to worsen during periods of rest or inactivity, particularly at night, and can severely disrupt sleep. The condition can lead to significant distress, anxiety, and fatigue. While there is no definitive cure for RLS, several treatments can help manage its symptoms, one of which is gabapentin.

Gabapentin, or Neurontin, is a medication primarily used to treat conditions such as epilepsy, neuropathic pain, and anxiety disorders. However, its effectiveness in managing RLS symptoms has made it an increasingly popular treatment option. This article will explore how gabapentin works, its potential benefits and side effects, and how it compares to other treatment options for this condition.

Understanding Restless Legs Syndrome

Before delving into gabapentin’s role in treating RLS, it is essential to understand the condition itself. RLS is a chronic disorder that causes an uncontrollable and often irresistible urge to move the legs. The symptoms are usually accompanied by uncomfortable sensations that can be described as crawling, tingling, or itching. These sensations tend to occur when the person is at rest, particularly when lying in bed or sitting for long periods. Movement often provides temporary relief from these sensations, which is why individuals with RLS may experience difficulty falling asleep or staying asleep, leading to chronic fatigue and irritability.

The exact cause of RLS is not fully understood, but several factors are thought to contribute to its development, including genetic predisposition, iron deficiency, and abnormalities in dopamine function. Dopamine is a neurotransmitter involved in controlling movement and is believed to play a role in the development of RLS symptoms. Additionally, other factors such as pregnancy, certain medications, and underlying medical conditions like kidney failure, diabetes, and sleep apnea can exacerbate RLS symptoms.

How Gabapentin Works

Gabapentin is an anticonvulsant medication that was originally developed to treat epilepsy by stabilizing electrical activity in the brain. Over time, it was found to be effective in treating neuropathic pain, which occurs when nerves become damaged or malfunction, causing persistent pain. Gabapentin works by affecting the central nervous system and modulating the activity of neurotransmitters that play a role in nerve signaling.

The mechanism by which gabapentin treats RLS symptoms is not entirely clear. However, it is believed to affect the neurotransmitter systems involved in movement and sensation, particularly by increasing the levels of gamma-aminobutyric acid (GABA). GABA is an inhibitory neurotransmitter that helps calm nerve activity. In patients with RLS, gabapentin may help modulate the abnormal nerve signaling that causes the uncomfortable sensations and urge to move the legs.

Gabapentin is often preferred for the treatment of RLS due to its ability to relieve both the sensory and motor symptoms associated with the condition. It is thought to reduce the intensity and frequency of the discomforting sensations and to improve sleep quality, thereby helping individuals manage the daily challenges posed by RLS.

Gabapentin for RLS: Benefits and Effectiveness

Research has demonstrated that gabapentin can be an effective treatment for RLS, especially in cases where other medications, such as dopaminergic drugs like ropinirole (Requip) and pramipexole (Mirapex), have not provided sufficient relief or have led to unwanted side effects. It can be used occasionally on an as-needed basis for additional relief.

Gabapentin can significantly reduce the severity of RLS symptoms. One of the main benefits of gabapentin is its ability to alleviate the uncomfortable sensations that drive the urge to move the legs. By modulating nerve activity, gabapentin can help reduce the crawling or tingling feelings, making it easier for patients to rest and fall asleep.

Since RLS symptoms tend to worsen during periods of inactivity, particularly at night, many people with RLS struggle with insomnia. Gabapentin has been shown to improve sleep quality by reducing the frequency and intensity of RLS-related disruptions. By helping to manage symptoms, it can enable individuals to experience deeper, more restorative sleep.

In addition to addressing the sensory symptoms of RLS, gabapentin can also help reduce the pain associated with the condition. Some individuals with RLS experience a burning or aching sensation in the legs, and gabapentin’s pain-relieving properties can help provide relief from these discomforts.

Because RLS can have a significant impact on day-to-day life, including social interactions, work performance, and overall well-being, managing its symptoms is crucial for improving quality of life. By reducing the need to move constantly and improving sleep, gabapentin can help patients feel more comfortable and less fatigued, leading to enhanced daily functioning and better mental health.

Side Effects of Gabapentin

While gabapentin is generally well-tolerated, like all medications, it does come with the potential for side effects. Some individuals may experience mild side effects, including drowsiness, dizziness, peripheral edema (swelling in the extremities), and gastrointestinal issues such as nausea or indigestion. It may contribute to weight gain.

Gabapentin can cause sedation or drowsiness, which may be beneficial for individuals with RLS who have trouble sleeping. However, it can also be problematic if it impairs daytime functioning. Some individuals report feeling lightheaded or dizzy, especially when standing up quickly, which can increase the risk of falls, particularly in older adults. Swelling in the hands and feet can occur in some individuals taking gabapentin. Nausea, vomiting, and indigestion are potential side effects, although they are typically mild and temporary.

More serious side effects, such as allergic reactions or mood changes, are rare but can occur. As with any medication, it is important to work closely with a healthcare provider to monitor for potential side effects and adjust the dosage if necessary.

Gabapentin vs. Other RLS Treatments

Gabapentin is one of several options available for managing RLS symptoms, and its effectiveness may vary depending on the individual. Other common treatments for RLS include pregabalin (Lyrica), dopaminergic medications, iron supplements, opioids, and benzodiazepines.

Dopaminergic medications were previously considered first-line treatment for RLS, but over time they worsen the condition. Medications such as pramipexole and ropinirole increase dopamine activity in the brain and can alleviate the symptoms of RLS. However, long-term use of dopaminergic drugs can lead to tolerance, where higher doses are needed to maintain efficacy, and augmentation, where symptoms worsen with use. This is one of the reasons why gabapentin may be considered a good alternative or adjunct therapy.

Since low iron levels are associated with RLS, iron supplementation may help improve symptoms in some individuals, especially if they have iron deficiency with a serum ferritin level <75. This treatment is often used in combination with other therapies.

In severe cases of RLS that do not respond to other treatments, opioids or benzodiazepines may be prescribed. However, these medications are typically considered a last resort due to their potential for dependence and side effects.

In addition to medications, lifestyle changes such as regular exercise, maintaining a consistent sleep schedule, avoiding caffeine and alcohol, and practicing relaxation techniques can help reduce RLS symptoms.

Conclusion

Gabapentin offers a promising treatment option for individuals suffering from restless legs syndrome, particularly for those who have not found sufficient relief with other medications. Its ability to modulate nerve signaling, alleviate discomfort, improve sleep quality, and reduce pain makes it a valuable tool in the management of RLS symptoms. While side effects are possible, they are generally mild and can be managed with proper medical supervision. Gabapentin’s effectiveness in treating RLS, coupled with its relatively favorable safety profile, makes it an important part of the therapeutic arsenal for this challenging condition. As with any treatment, it is important to consult with a healthcare provider to determine the best approach for each individual’s unique needs.

This article was created using OpenAI’s ChatGPT on February 23, 2025 and it was personally reviewed and edited by Brandon Peters, M.D. to ensure its accuracy. This use of augmented intelligence in this way allows the creation of health information that can be trusted.

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