Restless Leg Syndrome

Restless Leg Syndrome

1 Overview

Summary and Quick Facts

  • Restless leg syndrome (RLS) is characterized by uncomfortable feelings in the legs. People with RLS often feel compelled to move their legs in attempt to get more comfortable, leading to insomnia and stress.
  • In this protocol, you will learn how nerve problems can cause the unpleasant sensations of RLS. You’ll discover how elevated blood sugar and vascular problems can trigger RLS symptoms, and what medications may help temporarily relieve symptoms.
  • Combining medical treatments with healthy dietary and lifestyle changes may help promote comfortable legs.
  • Supplements including magnesium and the flavonoid diosmin may help support healthy blood flow and nerve function in the legs.

What is Restless Leg Syndrome?

Restless leg syndrome (RLS) is a neurological disorder characterized by unpleasant or painful throbbing, pulling, or creeping sensations in the legs. RLS patients often feel irresistibly compelled to constantly move their legs, and these relentless symptoms can cause insomnia, emotional distress, and a significantly diminished quality of life.

RLS can be classified as primary or secondary; the exact cause of primary RLS is not known, although altered dopamine signaling is thought to play a part, while secondary RLS is connected to an underlying medical condition such as diabetes, chronic venous disorders, and iron deficiency.

Several natural interventions such as diosmin and folate may help relieve the symptoms or underlying causes of RLS.

What are the Causes and Risk Factors for Restless Leg Syndrome?

  • Family history
  • Kidney disease
  • Diabetes/impaired glucose tolerance
  • Chronic venous disorders
  • Iron deficiency (or regularly donating blood)
  • Pregnancy
  • Sedentary lifestyle
  • Obesity

What are Conventional Medical Treatments for Restless Leg Syndrome?

Note: Generally, RLS is not treated pharmacologically unless it is chronic, persistent, and unresponsive to nonpharmacologic treatments such as correcting iron deficiency and lifestyle changes. Also, treating primary RLS should not be considered until possible secondary causes are addressed.

  • Dopamine agonists such as ropinirole, pramipexole, and rotigotine (Neupro)
  • Levodopa, a dopamine precursor (usually for intermittent treatment)
  • Benzodiazepines
  • Gabapentin
  • Low-dose opioids (typically a last resort)

What Lifestyle Changes Can Be Beneficial for Restless Leg Syndrome?

  • Avoid stimulants such as nicotine and excessive caffeine
  • Exercise regularly, but not right before bed
  • Massage and acupuncture, in conjunction with medications or alone, may offer relief to some people with RLS

What Natural Interventions May Be Beneficial for Restless Leg Syndrome?

  • Iron. Iron deficiency or altered brain iron metabolism have been linked to RLS; supplementation is often recommended for RLS patients who have been tested and shown to be deficient. Iron supplementation has been shown to significantly improve symptoms in iron-deficient RLS patients.
  • Folate. Low levels of folate may play a role in RLS, especially in pregnant women. Pregnant women with lower folate levels were more likely to develop RLS than women who took vitamins during pregnancy.
  • Magnesium. Low magnesium levels can cause excitability of neurons; magnesium supplements are often used to prevent abnormal activity in the nervous system. A case study indicated magnesium may improve symptoms and sleep problems associated with RLS.
  • Diosmin. Diosmin is a natural flavone derivative often used for supporting venous function. Since venous disorders have been linked with RLS, diosmin is a promising possible treatment.
  • Green coffee extract. Diabetes and pre-diabetes are known risk factors for RLS. Green coffee extract may help maintain healthy glucose levels.
  • Valerian root. Valerian, an herbal sedative, is often used as a sleep aid. In a clinical trial, supplementation with valerian resulted in improvements in RLS symptoms and less daytime sleepiness.
  • Other natural interventions that may help relieve RLS symptoms include D-ribose and vitamins C and E.

2 Introduction

Restless legs syndrome (RLS) is a neurological disorder associated with impaired sleep and characterized by throbbing, pulling, creeping, or other unpleasant sensations in the legs. Patients with RLS often complain of an almost irresistible urge to move their legs. The relentless and tormenting course of RLS symptoms often significantly diminishes quality of life for many of those affected and leads to significant emotional distress (NINDS 2011).

Sleepless nights and mental anguish contribute to a considerable physical and psychological burden for those afflicted with RLS (restless legs syndrome). Unfortunately, drugs used to treat psychological effects associated with RLS, such as tricyclic antidepressants (TCAs) and selective serotonin uptake inhibitors (SSRIs), may trigger or worsen RLS symptoms (Pullen 2011; Lee 2008; Winkelmann 2005; Hornyak 2010).

Pharmaceutical treatment strategies, such as dopaminergic medications, can offer relief for those with RLS. However, a pitfall of dopaminergic drugs used at high doses is that quite often they may exacerbate RLS symptoms via a phenomenon known as augmentation or rebound. Fortunately, the 2012 approval of sustained release, transdermal rotigotine may overcome this roadblock (Bell 2012; Elshoff 2012; Boroojerdi 2010; Godau 2011).

Many people do not realize that RLS can be classified as primary or secondary. Primary RLS has no known cause, whereas secondary RLS is related to another medical ailment. For example, secondary RLS is often associated with high blood sugar related nerve damage or chronic vascular disease like deep vein thrombosis and arterial claudication (Gemignani 2007; McDonagh 2007).

In this protocol, you will learn about possible causes of RLS and discover that treatment strategies vary based on the origins of the condition. You will also learn about convenient blood tests that might help uncover unexpected secondary causes of RLS symptoms.

3 Causes of RLS

Primary RLS The exact cause of primary RLS is unknown. However, there does appear to be a genetic component as approximately 40 to 50 percent of patients with primary RLS have a family history of the disorder and certain genetic variations are associated with the condition (Ferri 2012; Bradley 2008; Miletic 2011).

Although many think of primary RLS as a disease of the peripheral nervous system, studies suggest that the central nervous system may also be involved. Because RLS is akin to some other movement disorders the neurotransmitter dopamine, which helps facilitate uniform, controlled movements, has been theorized to be a possible causative factor. Indeed, altered dopamine signaling within the brain has been observed in several RLS studies, but results have been insufficient to draw firm conclusions (Clemens 2006; Cervenka 2006; Ruottinen 2000; Turjanski 1999; Eisensehr 2001). Additionally, alterations in dopamine signaling in the spinal cord have been observed, which lends further support to the hypothesis that dopamine is involved in RLS (Paulus 2006; Clemens 2006).

Secondary RLS Over twenty medical conditions are connected to secondary RLS (Miletic 2011).

Secondary RLS is a common complication of end-stage kidney disease. Estimates indicate that up to 60% of patients on dialysis have RLS (Walker 1995; Thorp 2001; Kavanagh 2004). People with diabetes or impaired glucose tolerance are more likely to have RLS, and RLS is a prominent part of diabetic peripheral neuropathy (Bosco 2009; O’Hare 1994; Lopes 2005; Merlino 2007). RLS may also be associated with Parkinson’s disease, another disorder associated with dopaminergic dysfunction in the nervous system. However, the link has not yet been clearly established (Guerreiro 2010; Gjerstad 2011). People with RLS also have an increased risk of developing high blood pressure, possibly due to overactivity of certain parts of the nervous system (Walters 2009; Batool-Anwar 2011).

Chronic venous disorders are a major contributor to secondary RLS (McDonagh 2007). In a 2007 study, researchers found that 36% of patients suffering from chronic venous disease also had RLS. In comparison, the control group only had a 19% occurrence of RLS. However, when the control participants who showed positive for RLS were studied more closely, it was noted that 91% of them had mild indications of venous problems (McDonagh 2007). In another study, participants with RLS who received medical treatment for chronic venous disease reported a 36% increase in quality of sleep and a 67% decrease in severity of symptoms (Tison 2005).

Role of Iron in RLS

One of the more commonly accepted hypotheses about the origins of RLS is that iron metabolism within the central nervous system plays a role (Miletic 2011; Connor 2008). As many as 25% of RLS patients have an iron deficiency (Rangarajan 2007), and iron supplementation was shown to relieve RLS symptoms in iron-deficient subjects (O’Keeffe 1994). Another study found that regular blood donors were more likely to develop RLS, particularly if they had reduced serum iron levels. Intravenous iron relieved RLS symptoms in this population (Birgegard 2010). Levels of ferritin (an iron storage protein) in the cerebro-spinal fluid (CSF) may also be reduced in patients with RLS (Earley 2000). Iron levels in the substantia nigra (a brain region in which dopamine is produced) may be particularly important as a study using MRI imaging found reduced iron concentrations in the substantia nigra of RLS patients (Allen 2001; Connor 2011). Other studies have further confirmed iron insufficiency in the substantia nigra as important for RLS. Also, people suffering from RLS often have abnormal levels of other proteins involved in iron handling (e.g., ferroportin and transferrin) (Connor 2003 and 2004).

4 Conventional Pharmacologic Treatment

The main pharmacologic agents used to treat primary RLS are dopamine agonists, levodopa (L-DOPA), benzodiazepines, gabapentin, and opioids. However, treatment of primary RLS should not be considered until possible causes of secondary RLS are ruled out, especially venous disorders (Miletic 2011).

  • Dopamine Agonists. Dopamine agonists are drugs that directly activate dopamine receptors in the nervous system. They are currently considered the first-line therapy for severe RLS and are typically less associated with augmentation or rebound than high doses of L-DOPA (see below). Several different dopamine agonists are used to treat RLS, including:
    • Ropinirole. The efficacy of ropinirole has been demonstrated in two large randomized, double-blind, placebo-controlled trials. In both studies, standardized assessment showed that 1) symptoms were significantly less, and 2) both quality and quantity of sleep were significantly improved in the ropinirole-treated groups compared with controls (Walters 2004; Garcia-Borreguero 2004).
    • Pramipexole. Pramipexole is highly effective in the reduction of periodic limb movements as well as improving subjective severity of RLS and sleep quality (Benbir 2006; Inoue 2010). Compared to ropinirole, pramipexole is equally effective but with significantly lower incidence of nausea, vomiting and dizziness (Quilici 2008).
    • Rotigotine - on April 3, 2012 the FDA approved topical delivery of rotigotine for the treatment of RLS (Bell 2012). Branded Neupro®, the topical delivery system represents a paradigm shift in the delivery of a dopamine agonist in the treatment of RLS. By delivering the drug in a sustained manner, Neupro® may lessen side effects common with orally administered dopamine agonists, which bombard dopamine receptors with a single, quickly absorbed dose (Farlow 2011; Elshoff 2012; Boroojerdi 2010).
  • Levodopa (L-DOPA). L-DOPA serves as a precursor for dopamine in the human body. L-DOPA crosses the protective blood-brain barrier, whereas dopamine itself cannot. Once L-DOPA has entered the central nervous system, it is converted into dopamine with the aid of pyridoxal 5'-phosphate (the active form of vitamin B6) (Allen 2009). In studies, L-DOPA reduced the number of periodic limb movements during sleep and improved sleep quality compared to placebo (Benes 1999; Trenkwalder 2007; Scholz 2011). L-DOPA can provide relief within 20 minutes; however, it does not provide sustained relief for those with persistent symptoms. Levodopa/carbidopa is generally reserved for patients with infrequent symptoms, because of problems with augmentation and rebound (Bayard 2008). Therefore, L-DOPA is recommended for intermittent treatment (less than three times a week) of bedtime symptoms or as prophylaxis during infrequent sedentary activities such as long plane trips, car rides, or theater events (Gamaldo 2006). L-DOPA has a relatively benign side effect profile, though there is some concern that it can cause symptoms to occur earlier in the day and more quickly at rest, and spread to the upper limbs (Garcia-Borreguero 2007).

A pitfall of dopaminergic drugs is that, paradoxically, they may cause or exacerbate RLS symptoms – a phenomenon known as augmentation. As many as 20% to 60% of patients treated with L-DOPA or dopamine agonists develop augmentation; so “it is important for physicians to carefully screen patients for changes in RLS symptoms for as long as they are on dopamine agents, with particular attention paid to those patients who present with the most severe RLS symptoms prior to treatment initiation” (Allen 2011; Hogl 2010).

  • Benzodiazepines. Benzodiazepines (e.g., clonazepam and lorazepam) enhance the effect of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), giving them sedative, sleep-inducing, anti-anxiety, anticonvulsant, and amnesic qualities (Rudolph 1999). These drugs are often useful for treating insomnia associated with RLS (Yee 2009). A small placebo-controlled study measured the acute effects of 1 mg clonazepam on sleep and awakening quality in 10 RLS and 16 periodic limb movement disorder (PLMD) patients. Insomnia associated with both RLS and PLMD was improved by clonazepam (Saletu 2001). Benzodiazepines are sometimes combined with dopamine agonists in patients with refractory RLS (Bayard 2008). These drugs can adversely impact cognitive ability and coordination and may rarely exacerbate anxiety and irritability.
  • Gabapentin. Gabapentin is a medication often used to treat epilepsy and peripheral neuropathy; and some studies have also found that it may be useful in treating painful variants of RLS (Yee 2009; Kushida 2009; Happe 2001; Garcia-Borreguero 2002). Gabapentin may be effective in individuals with RLS-associated neuropathic pain that has not responded to dopaminergic drugs (Bayard 2008). The U.S. FDA approved Horizant® (gabapentin enacarbil) for the treatment of moderate-to-severe RLS in April 2011.
  • Low-dose opioids have been used successfully in some cases of RLS (Kaplan 1993; Walters 1993). However, the mechanism by which they provide relief is not clear and the role of the endogenous opioids system in RLS is complex (von Spiczak 2005). Opioids are typically reserved as a last-resort treatment for refractory RLS.

5 Lifestyle Considerations and Non-Pharmacological Treatments

Stimulant Avoidance. Certain chemicals (e.g., nicotine and caffeine) stimulate both the central and peripheral nervous system, and can affect the body long after being ingested. As a result, many experts recommend that patients with RLS eliminate nicotine and avoid excess caffeine consumption throughout the day (Pigeon 2009; Bayard 2008). There is some controversy, however, regarding nicotine: there is a case report of nicotine actually helping alleviate symptoms in a patient (Oksenberg 2009), and another case report of exacerbation of RLS symptoms following smoking cessation (Juergens 2008). However, the evidence for nicotine as treatment for RLS is otherwise undocumented. In addition, excessive caffeine intake and nicotine use can also contribute to insomnia, which may exacerbate already existing RLS and increase daytime drowsiness.

Exercise. Increased physical activity may be one way for RLS patients to reduce their symptoms. Risk factors for RLS can include a lack of regular physical activity (Phillips 2000), higher BMI, and obesity (Ohayon 2002). A randomized controlled trial found that aerobic exercise and lower-body resistance training 3 days per week significantly reduced symptoms of RLS (Aukerman 2006). Regular physical activity improved sleep patterns and reduced periodic limb movements (PLM), and thus may be a useful non-pharmacological treatment for PLM (Esteves 2009). However, it is important to not engage in physical activity shortly before going to bed, as this can exacerbate RLS symptoms (Ohayon 2002).

Massage and Acupuncture. Both massage and acupuncture may produce some benefit for people with RLS (Stanislao 2009; Rajaram 2005; Russel 2006). A comprehensive review found that more research is needed to determine the benefit of acupuncture in RLS, as only two studies were deemed suitable for inclusion in the analysis (Cui 2008). However, one study did find that combining dermal needle therapy with medications and massage was more effective than medications and massage alone (Zhou 2002). Similarly, massage of the affected regions of the leg may provide counter stimuli that can alleviate RLS symptoms (Gamaldo 2006). Other massage techniques (e.g., myofascial release, trigger point therapy, deep tissue massage), and enhanced external counter pulsation may also relieve RLS symptoms (Rajaram 2005; Russel 2006).

6 Targeted Nutritional Interventions

Iron. Due to the presumed link between iron deficiency or altered iron metabolism in the brain and RLS (Conner 2008), one of the more common alternative treatments for RLS is iron supplementation (Trotti 2009).

Various routes for iron supplementation have been studied as a treatment for RLS. Oral iron supplementation has been found to significantly ameliorate RLS in patients with low-normal levels of iron in their blood (Wang 2009). However, it is unclear if oral iron supplements are as effective for patients with no signs of iron deficiency (Davis 2000). Oral iron supplementation is also beneficial for treating RLS in the elderly, particularly those with low iron levels (O’Keeffe 1994). Intravenous iron supplementation in the form of iron dextran has also been found to significantly reduce RLS symptoms (Sloand 2004; Earley 2004). Although intravenous iron may be more effective than oral iron supplementation, it can cause severe complications including anaphylaxis (Silverstein 2004). It is important to note that only those with a blood test-verified iron deficiency should take supplemental iron. Ingestion of excess iron has been linked to cancer, atherosclerosis and other degenerative diseases.

Folate. Folate deficiencies may also play a role in the development of RLS. Pregnancy often precipitates signs of RLS (Manconi 2004) and folate levels are of paramount importance during pregnancy for healthy fetal development. Researchers have also found that pregnant women with low folate levels are more likely to develop RLS (Lee 2004), whereas women who take vitamins during pregnancy are less likely to develop RLS (Tunc 2007). Low levels of folate may also play a role in non-pregnant RLS patients (Patrick 2007). Older studies have found that folic acid supplementation can help treat certain paresthesias and other disorders of the peripheral nervous system as well (Botez 1976 and 1977).

Magnesium. Low levels of magnesium can cause neurons to become more easily excited, thus affecting a person’s mental status. As a result, magnesium supplements are often used to stabilize neuronal membranes and prevent abnormal activity in the nervous system (Trenkwalder 2008). Magnesium supplementation has been studied as a treatment for RLS. One case study found that magnesium supplements were able to relieve symptoms of RLS and improve sleep (Hornyak 1998). A novel form of magnesium – magnesium-l-threonate – may be even more effective for RLS because it is better able to gain access to the central nervous system (Slutsky 2010). However, the impact of magnesium-L-threonate on RLS has yet to be clinically validated.

Diosmin. The link between chronic venous disease and secondary RLS is well established (see above) (McDonagh 2007). Although it can be difficult to treat chronic venous issues, one therapy that has gained support is diosmin.

Diosmin is a natural venotonic that supports venous function, thereby preventing or reversing some of the changes of chronic venous disease (Carpentier 1998; Maksimovic 2008). Although the effectiveness of diosmin for treating RLS has not been tested, it remains a promising possible treatment.

Green Coffee Extract. Diabetes is a well-known risk factor for secondary RLS. However, less appreciated is that pre-diabetessubclinical elevations in blood sugar – may also cause RLS while remaining under the diagnostic radar of most physicians (Gemignani 2007; Bosco 2009).

A study examining subjects with impaired glucose metabolism unearthed a significantly increased risk of RLS in this population. RLS affected 41% of those with pre-diabetes, while only 18% of those with healthy glucose tolerance experienced the condition (Bosco 2009).

Maintaining healthy glucose metabolism, even for those not diagnosed with diabetes, may be helpful in RLS. Even slightly elevated blood sugar can damage delicate nerve cells and contribute to unpleasant sensations called paresthesias (Yagihashi 2007). Life Extension suggests that all aging individuals should strive to maintain blood glucose levels between 70 and 85 mg/dL for optimal health. Green coffee extract, with minimal caffeine content, represents a powerful tool for those aiming to maintain healthy blood sugar levels. It may also help control glucose elevations, which have been associated with RLS. However, this theory has yet to be tested in clinical trials.

Valerian root. Often used as an herbal sedative, valerian root has shown promise at reducing symptom severity of RLS. In an 8-week clinical trial, supplementation with 800 mg of valerian root daily resulted in improvements in daytime sleepiness and RLS symptoms (Cuellar 2009). Additional data also support the effectiveness of valerian root in treating insomnia in postmenopausal women (Taavoni 2011).

Experimental Alternative Therapies

Other less established interventions are also being explored for the treatment of RLS, including:

  • D-ribose. D-ribose is a naturally occurring carbohydrate that is essential for the body. It may decrease the symptoms of RLS when taken daily (Shecterle 2008).
  • Vitamins C and E. In a clinical trial among dialysis patients with RLS, supplementation with vitamins C and E significantly improved RLS symptoms (Sagheb 2012).
  • Near-infrared light. Another RLS treatment that has shown promise is exposing the legs to near-infrared light for several sessions over a period of a week. This treatment may affect leg blood vessels in a way that relieves RLS symptoms (Mitchell 2011; Mitchell 2010).

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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