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.

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).

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).

• 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.

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).

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-diabetes – subclinical 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 80 and 86 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).

French maritime pink bark. French maritime pine bark has been studied in the context of a wide variety of conditions, including vascular and circulatory health (Belcaro 2018a; Belcaro 2018b). It is commonly known as Pycnogenol—the trade name of a particular standardized extract that has been validated in many studies. Pycnogenol has been shown to decrease oxidative stress, improve endothelial function, and inhibit inflammation (Enseleit 2012; Nattagh-Eshtivani 2022).

A 2022 clinical study found Pycnogenol was effective at alleviating symptoms of RLS and improved venoarteriolar response (ie, a reflex that reduces limb blood perfusion to prevent edema) and microcirculation (Belcaro 2022). In this study, 45 healthy adults with RLS were assigned to receive either standard management of RLS (regimen consisting of eight hours of sleep daily, 20 minutes of mild exercise four times weekly, and vitamin C plus B vitamins) or standard management plus 150 mg Pycnogenol daily for four weeks. Participants were also given advice on maintaining good posture; wearing adequate shoes; and limiting consumption of caffeine, salt, and spicy foods. Treatment with standard management led to a non-significant improvement in symptoms, while treatment with Pycnogenol led to significant improvement in all assessed symptoms including itching, crawling, creeping, and throbbing sensations, as well as sleep problems. Importantly, 19 of 21 participants in the Pycnogenol group reported perceiving clear benefits of supplementation, while standard management alone led to only minor perceived benefits. In addition, Pycnogenol treatment normalized resting skin flux, which had been slightly elevated at baseline, while standard management did not. Elevated resting skin flux is associated with dysregulated microcirculation, as in conditions such as diabetic microangiopathy. Pycnogenol also significantly improved venoarteriolar response after four weeks, whereas standard management alone did not. Finally, Pycnogenol significantly reduced plasma free radicals (oxidative stress), minimal edema score, and lessened the need for use of analgesics. Pycnogenol was well-tolerated with no observed side effects.

Additionally, a two-part clinical trial demonstrated that Pycnogenol reduced muscle cramping and pain. In the first part, 66 healthy participants who regularly experienced muscle cramps took 200 mg Pycnogenol daily for four weeks with an additional follow-up on the fifth week. The number of cramps decreased from the two weeks before supplementation compared with after supplementing in normal, venous, and athletic participants. The beneficial effects were still seen in the week after stopping supplementation. In the second part of the study, 47 participants with intermittent claudication or diabetic microangiopathy took 200 mg Pycnogenol or placebo daily for four weeks. No effect was seen with placebo, whereas those taking Pycnogenol experienced significantly fewer cramps and reduced muscle pain (Vinciguerra 2006).