by Alan R. Gaby, M.D.

Restless legs syndrome (RLS) is a common condition characterized by dysesthesia (such as a painful burning, prickling, or aching feeling) in the legs and an irresistible urge to move the legs. The prevalence of this condition has varied in different studies, from 4% to 29% of adults in Western countries. Symptoms often occur at night and interfere with sleep. Dopamine agonists are the most commonly prescribed drugs for RLS. Three dopamine agonists have been approved by the US Food and Drug Administration (FDA) to treat RLS: ropinirole, pramipexole, and rotigotine.

Dose-related side effects of dopamine agonists include daytime sleepiness, nausea, impulse control disorders (such as pathological gambling), and other psychiatric conditions. In addition, long-term use of dopamine agonists for RLS can lead to a situation known as augmentation, in which the duration of action of the drugs becomes shorter and the symptoms become worse and/or spread to the upper extremities. It has been estimated that augmentation occurs in 20-30% of patients treated with a dopamine agonist for RLS. Physicians often respond to the occurrence of augmentation by increasing the dosage of the medication. This dosage increase typically produces short-term improvement in RLS symptoms, but eventually causes a return of augmentation (sometimes more severe than before). A vicious cycle of progressively worsening symptoms and progressively higher medication dosages can result in patients taking dopamine agonists at far higher dosages than are approved by the FDA for RLS.

A study was recently conducted to determine to what extent RLS patients in the US are receiving potentially excessive dosages of dopamine agonists.[1] The study examined data from a US prescriptions database from October 2017 through September 2018. This database included about 65% of all retail and mail-order prescriptions in the US. Of 670,404 patients diagnosed with RLS without Parkinson’s disease, 58.8% were prescribed a dopamine agonist. The dosage of these drugs was categorized as “low/middle” if it was within or slightly above the FDA-approved dosage range; “high” if it was 101%-149% of the maximum approved dosage; and “very high” if it was 150% or more of the maximum approved dose. Overall, 19.1% of RLS patients were receiving a dosage above the maximum FDA-approved level, and 10.4% of the patients were receiving a “very high” dosage. The frequency of high/very high-dose prescribing increased with increasing age of the patients and was highest for those aged 70-79 years. Extrapolating the findings from this study to the entire US population, approximately 115,000 people with RLS are receiving dopamine agonists in dosages above FDA guidelines. The author of this report concluded that progressively increasing the dosage of dopamine agonists in the face of progressively worsening symptoms is widespread but inappropriate, “akin to putting out a fire with gasoline.”

Nutritional therapy for RLS

A number of nutritional treatments have been reported to be effective for patients with RLS. Most of these treatments are not well known to the conventional medical community, although many doctors are aware of the importance of identifying and treating iron deficiency.

Dietary factors

In one study, of 131 patients with reactive hypoglycemia, 59 (45%) had RLS. The symptoms usually improved on a diet designed to improve blood glucose control.[2] Such a diet typically includes avoidance of refined sugar, other refined carbohydrates, caffeine, and alcohol; consuming abundant amounts of protein and complex carbohydrates; and eating small, frequent meals.

Iron

In several studies, iron deficiency was found in around 25% of RLS patients.[3] [4] [5] [6] Among patients who were iron-deficient, iron supplementation frequently reduced or eliminated the symptoms of RLS.[7] [8]

Magnesium

One of the manifestations of magnesium deficiency is neuromuscular and central nervous system irritability, which could contribute to the development of RLS. Suboptimal magnesium intake and low or suboptimal magnesium status are common in Western societies.[9] Certain factors that tend to deplete magnesium, such as pregnancy, stress, alcohol consumption, and caffeine intake, are also associated with an increased risk of RLS. In an uncontrolled trial, 6 patients suffering from insomnia related to mild-to-moderate RLS received 300 mg of magnesium (as magnesium oxide) each evening for 4 to 6 weeks. Five of the 6 patients reported a decrease of RLS symptoms and/or an improvement in insomnia.[10] In my experience, magnesium supplementation is frequently beneficial for people with RLS.

Vitamins E

Nine patients with a history of RLS for 1.5 to 30 years were treated with vitamin E at a dose of 300-1,600 IU per day. Seven patients experienced prompt and almost complete relief and the other 2 patients reported improvements of 75% and 50%, respectively. Symptoms tended to recur if vitamin E was discontinued, or if the dose was reduced below an adequate maintenance level.[11] Two patients responded to a dose of 300 IU per day, and in 1 case the improvement was maintained with 200 IU per day.[12] The mechanism of action of vitamin E is not known.

Folic acid

In a small proportion of patients with RLS, the condition appears to be caused by a genetically determined folic acid dependency. One investigator described 45 patients from 5 families with folic acid-responsive RLS. The amount of folic acid required to control the symptoms ranged from 5 mg to 30 mg per day.[13] I have a seen a few patients with familial RLS who required high doses of folic acid to relieve their symptoms. One patient was symptom-free on 10 mg to 25 mg per day, but experienced a partial return of symptoms when the dose was reduced to 5 mg per day. For comparison, a typical diet provides approximately 0.3 mg per day of folic acid. High-dose folic acid therapy should be considered for patients with RLS who have a strong family history of the disorder.

Conclusion

As is often the case with many health conditions, mainstream medicine tends to overlook safe and effective nutritional therapies and to overprescribe potentially dangerous medications, sometimes in excessive dosages. If doctors would pay closer attention to these nutritional treatments, the need for dopamine agonist therapy could probably be greatly decreased.

[1] Winkelman JW/. High national rates of high-dose dopamine agonist prescribing for restless legs syndrome. Sleep. 2022;45:zsab212.

[2] Roberts HJ. Spontaneous leg cramps and “restless legs” due to diabetogenic hyperinsulinism: observations on 131 patients. J Am Geriatr Soc. 1965;13:602-638.

[3] Ekbom KA. Restless legs syndrome. Neurology. 1960;10:868-873.

[4] Ulfberg J, Nystrom B. Restless legs syndrome in blood donors. Sleep Med. 2004;5:115-118.

[5] Matthews WB. Iron deficiency and restless legs. Br Med J. 1976;1:898.

[6] O’Keeffe ST, et al. Iron status and restless legs syndrome in the elderly. Age Ageing. 1994;23:200-203.

[7] Tilma J, et al. Early childhood-onset restless legs syndrome: symptoms and effect of oral iron treatment. Acta Paediatr. 2013;102:e221-e226.

[8] Wang J, et al. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study. Sleep Med. 2009;10:973-975.

[9] Gaby AR. Magnesium. In Gaby AR. Nutritional Medicine, Second Edition. Concord, NH, 2017. doctorgaby.com, chapter 27.

[10] Hornyak M, et al. Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: an open pilot study. Sleep. 1998;21:501-505.

[11] Ayres S Jr, Mihan R. “Restless legs” syndrome: response to vitamin E. J Appl Nutr. 1973;25(3-4):8-15.

[12] Ayres S Jr, Mihan R. Leg cramps (Systremma) and “restless legs” syndrome. Calif Med. 1969;111:87-91.

[13] Botez MI. Folate deficiency and neurological disorders in adults. Med Hypotheses. 1976;2:135-140.