“A river cuts through rock, not because of its power, but because of its persistence.”
– James N. Watkins

Restless Legs Syndrome

(also known as Willis-Ekbom Disease)

Restless legs syndrome is a neurological sleep disorder that make one have an overwhelming urge to move their legs, often making it difficult to get comfortable enough to fall asleep. Symptoms may improve by getting up and walking around although they may return again when returning to bed. The symptoms are usually worse at night but sometimes occur during the day as well. 


See also:


Insomnia – CAM Treatment Options


Gabapentin (Neurontin) & Lyrica



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Restless Legs Syndrome (RLS)


Symptoms of RLS

The primary symptom of Restless Legs Syndrome (RLS) is a sensation of discomfort in the legs that people often find difficult to describe. The feeling is different than leg cramps or numbness from circulation problems. Patients have used the following words to describe this sensation:

  1. Itchy
  2. Crawling
  3. Burning
  4. Creepy
  5. Throbbing


These feelings are usually coupled with the urge to move the legs. The desire usually worsens when lying down down or resting. Symptoms may improve with movement of the legs or walking around, but invariably are associated with an strong desire to move one’s legs, distinguishing RLS from conditions such as neuropathy or vascular insufficiency. One may have trouble sitting still for long periods of time and long car rides or airplane travel may be difficult. The disruption of sleep often leads to sleep deprivation which in turn leads to daytime fatigue.



RLS affects about 5-15% of the general population and becomes more prevalent with age, but it can occur in children. In patients with severe RLS, 33-40% had their first symptom before the age of 20 years old. RLS usually progresses slowly to daily symptoms and severe disruption of sleep after age 50 years. Women are affected more commonly than men, in a ratio of almost 2:1.


Criteria for the Diagnosis of RLS:

1. An urge to move the legs that is usually accompanied by or occurs in response to uncomfortable and unpleasant sensations in the legs, characterized by all of the following:

(1) the urge to move the legs begins or worsens during periods of rest or inactivity;

(2) the urge is partially or totally relieved by movement; and

(3) the urge to move legs is worse in the evening or at night than during the day or occurs only in the evening or at night

2. Symptoms occur at least 3 times per week and have persisted for at least 3 months

3. Symptoms cause significant distress or impairment in social, occupational, educational, academic, behavioral or other areas of functioning.

4. The symptoms cannot be attributed to another mental disorder or medical condition (e.g., leg edema, arthritis, leg cramps) or behavioral condition (e.g. positional discomfort, habitual foot tapping)
 and cannot be explained by the effects of a drug of abuse or medication.

Additional Features of RLS


Periodic Leg Movement Disorder (PLMD)

Most (85-90%) of patients with RLS have periodic movements of their extremities during sleep, usually involving the legs (periodic leg movement disorder (PLMD), characterized by involuntary, forceful dorsiflexion of the foot lasting 0.5-5 seconds and occurring every 20-40 seconds throughout sleep. However, the presence of PLMD symptoms do not define RLS nor does lack of PLMD symptoms exclude RLS.


RLS and PLMD share a common pathophysiology, pharmacology, genetics, and epidemiology, and they may also share a similar risk for cardiovas-cular disease. PLMD symptomsare associated with the use of many antidepressant medications, including tricyclic antidepressants (amitriptyline/Elavil), fluoxetine (Prozac), and venlafaxine (Effexor) but not buproprion (Wellbutrin). Similarly, antidepressant medications can worsen the severity of RLS symptoms, further supporting the argument for a shared pharmacology and  pathophysiology of RLS and PLMS.



Other findings commonly associated with RLS include:

  1. Sleep disturbances
 and sleep fragmentation consisting of recurrent arousal from sleep
  2. Daytime fatigue likely related to sleep deprivation
Involuntary, repetitive, periodic, jerking limb movements: Either during sleep or while awake and at rest
  4. Depression related to sleep deprivation and interference with quality of life

Causes of RLS


Primary RLS

RLS may occur on its own (primary) or as a consequence of another disorder (secondary). In most cases, RLS is a primary, central nervous system (CNS) disorder of uncertain cause (idiopathic). Such idiopathic RLS is inheritable in 25-75% of cases. Inheritable RLS tends to start at an earlier age (<45 y/o) and progresses in severity more slowly.


Secondary RLS

Secondary RLS occurs as a result of certain conditions, particularly iron deficiency and hereditary neuropathies but not in patients with acquired neuropathies, such as diabetic neuropathy.


Other causes of RLS include the following:

  1. Folate
  2. Magnesium deficiency
  3. Amyloidosis

  4. Diabetes mellitus

  5. Lumbosacral radiculopathy (sciatica)
  6. Lyme disease
  7. Rheumatoid arthritis

  8. Sjögren syndrome

  9. Vitamin B-12 deficiency
  10. Pregnancy (affecting up to 25-40% of pregnancies, usually resolving within a few weeks after delivery. However, women who developed RLS during pregnancy have a 4-fold increased risk of developing chronic RLS.
  11. End-stage kidney disease
  12. Opioid withdrawal


RLS Associated with Opioid Withdrawal

Symptoms of RLS are not uncommon in those who abruptly discontinue chronic opioid pain management or opioid abuse triggering the opioid withdrawal syndrome. While usually transient, there are reports of protracted courses of RLS symptoms triggered by acute withdrawal but persisting for weeks and months and sometimes relatively resistant to conventional treatment. The association between opioid withdrawal and RLS symptoms is related to the disruption of dopamine homeostasis in various parts of the brain, particularly areas associated with reward and impulsivity.


Because in almost all cases, the symptoms of RLS associated with opioid withdrawal are temporary, they do not meet criteria for RLS, a chronic, often progressive condition. The treatment of opioid withdrawal-related RLS does not necessarily differ from treatment of other etiologies of RLS. However, unless contraindicated, the use of opioids especially buprenorphine (Suboxone, Zubolv, Bunavail) is very effective.


Pathology of RLS

The mechanisms of RLS are unclear but currently, the most widely accepted mechanism involves a genetic component, along with abnormalities in the brain dopamine pathways and impaired iron metabolism.



When centrally acting dopamine receptor antagonists are administered to patients with the syndrome, symptoms are reactivated. Results studies of brain scans have suggested a deficiency of dopamine D2 receptors (see Reward Deficiency Syndrome).



Iron homeostasis abnormalities have been implicated through cerebrospinal fluid (CSF) iron profile measures. A strong relationship is present between iron deficiency and RLS.



Research has also shown an increased severity of RLS with decreasing availability of serotonin transporter in the brainstem, which supports the theory that increasing serotonin transmission in the brain may exacerbate RLS. This is also consistent with the fact that antidepressant medications which increase serotonin activity are known to worsen RLS.



While definitive research remains forthcoming, there is evidence to suggest the possibility of an inflammtory basis for RLS. Based on the conclusion that 75% of cases of secondary RLS are associated with inflammation, it has been suggested that RLS may be mediated through inflammatory or immunological mechanisms. There also appears to be an increased incidence of RLS in patients with Irritable Bowel Syndrome (IBS), Celiac Disease and Crohn’s Disease. Studies indicate that there is increased prevalence of small intestinal bacterial overgrowth (SIBO) in patients with IBS and RLS. The inflammatory theory is strengthened by the belief that inflammation is also associated with iron deficiency which is a known contributor to RLS.



Treatment of RLS

Treatment of RLS is directed at restoring effective sleep. Basic sleep hygiene measures are recommended to all patients (see Sleep). Those who are sensitive to caffeine, alcohol, or nicotine should avoid these substances.


Medications thought to contribute to RLS that should be avoided include:

  1. Antidepressants (SSRIs, SNRIs and TCAs) – See Antidepressants
  2. Antihistamines such as Benadryl (diphenhydramine)
  3. Beta blockers: Propranolol
  4. Others: Dilantin, Lithium, Reglan (metaclopramide)


Prescription medications used to treat RLS include:

  1. Iron salt:  when RLS is associated with iron deficiency
  2. Gabapentin (neurontin), Lyrica (pregabalin) see Gabapentinoids
  3. Tegretol  carbamazepine)
  4. Baclofen
  5. Alpha 2 -adrenergic agonists: Clonidine
  6. Dopaminergic agents: D3-receptor agonists (Requip/ropiranole), Mirapex/pramipexole and Neupro/rotigotine) are more effective than D2-receptor agonists (Parlodel/bromocriptine)
  7. Opioids (see Opioids)
  8. Benzodiazepines: As a last resort
 (see Benzodiazepines)


CAM Treatment: Natural and Herbal Preparations for RLS

SynaptaGenX, a natural “medical food,” has been demonstated in many studies to be an effective dopamine agonist and therefore is likely to benefit RLS.


Yokukan-san is an herbal treatment that has been used in traditional Chinese and Japanese medicine for more than 400 years and has been reported to be effective in RLS. Yokukansan is composed of  seven herbs; Angelica acutiloba, Atractylodes lancea, Bupleurum falcatum, Poria cocos, Glycyrrhiza uralensis, Cnidium officinale and Uncaria rhynchophylla. Traditionally, yokukansan is used to treat insomnia and irritability as well as sleep tremors and neurological disorders including dementia and Alzheimer’s disease.
See references below for more information.

OTC Remedies for RLS

D,L Phenylalanine
D,L Phenylalanine, an amino acid precursor building block for the body’s manufacturing of dopamine has an anecdotal reputation for aiding in the suppression of RLS symptoms in opioid withdrawal-related RLS.. Definitive research is lacking on it as a stand-alone treatment.
While melatonin has not been shown to help for nonspecific insomnia, there are people who report melatonin to be beneficial for RLS symptoms associated with opioid withdrawal-related RLS.
Imodium (Loperamide)
Imodium is an OTC preparation commonly taken for diarrhea. It is a very mild opioid that does not cross the blood brain barrier. Anecdotal reports find it to be beneficial for RLS symptoms associated with opioid withdrawal-related RLS.
A 2009 study concluded that that the use of 800 mg of valerian for 8 weeks improves symptoms and decreases daytime sleepines of RLS.
Warm Baths with Epsom Salts (Magnesium Sulfate)
Transient relief of RLS symptoms is obtained with warm water soaks with the addition of epsom salts. Epsom salts consist of magnesium sulfate which is readily absorbed through the skin and along with heat, are very effective in reducing muscle tightness and often the leg discomfort.
Stretching Exercises and Yoga
Stretching may help reduce symptoms temporarily, but some people find that deep stretching like yoga provide hours of symptoms relief.
See yoga



Sleep – Overviews

See Sleep

Restless Leg Syndrome (RLS) – Overviews

  1. Restless Legs Syndrome:Periodic Limb Movement Disorder: National Sleep Disorders Research Plan, 2003
  2. Treatment for Restless Legs Syndrome – 2012
  3. A mixed treatment comparison of gabapentin enacarbil, pramipexole, ropinirole and rotigotine in moderate-to-severe restless legs syndrome. 2014 – PubMed – NCBI
  4. Restless Legs Syndrome – Would You Like That with Movements or Without? – 2015
  5. Further thoughts on ‘‘The Restless Legs Syndrome – Would You Like that with Movements or Without?’’ – 2015
  6. Profile of altered brain iron acquisition in restless legs syndrome – 2011
  7. Restless legs syndrome – diagnostic criteria, special considerations, and epidemiology – 2013
  8. Diagnosis of Restless Leg Syndrome (Willis-Ekbom Disease). – PubMed – NCBI


RLS – Inflammatory Bowel Disease

  2. Small Intestinal Bacterial Overgrowth in Irritable Bowel Syndrome – Systematic Review and Meta-analysis – 2009


RLS – Opioid Dependency and Withdrawal

  1. Restless Legs Syndrome in Opioid Dependent Patients – 2014


RLS – Pregnancy

  1. Restless leg syndrome in pregnancy. – PubMed – NCBI


RLS – Renal Disease

  1. Effect of Renal Transplantation in Restless Legs Syndrome


RLS – Treatment

  1.  Treatment for Restless Legs Syndrome – 2012
  2. The Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder in Adults —An Update for 2012 – Practice Parameters with an Evidence-Based Systematic Review and Meta-Analyses – 2012


RLS  Treatment – Dopamine Agonists (Pramipexole)

  1. Preferential D2 or preferential D3 dopamine agonists in restless legs syndrome. – PubMed – NCBI
  2. Dopamine agonists for restless legs syndrome. – PubMed – NCBI
  3. Efficacy of Pramipexole for the Treatment of Primary Restless Leg Syndrome: A Systematic Review and Meta-analysis of Randomized Clinical Trials. – PubMed – NCBI
  4. Rotigotine Transdermal Patch: MedlinePlus Drug Information
  5. Safety Information > Neupro (Rotigotine) Transdermal System
  6. Rotigotine transdermal system – a short review – 2006


RLS – CAM Natural and Herbal Preparations for RLS

RLS SynaptaGenX

  1. Dopaminergic Neurogenetics of Sleep Disorders in Reward Deficiency Syndrome (RDS) – 2014
  2. Decision-Making, Reward-Seeking Behaviors and Dopamine Agonist Therapy in Restless Legs Syndrome – 2013


RLS Valerian

  1. Does valerian improve sleepiness and symptom severity in people with restless legs syndrome? – PubMed – NCBI


RLS Yokukan-san

  1. Yokukan-san – a review of the evidence for use of this Kampo herbal formula in dementia and psychiatric conditions
  2. Traditional Chinese medicine herbal preparations in restless legs syndrome (RLS) treatment: a review and probable first description of RLS in 1529. – PubMed – NCBI

Periodic Limb Movement Disorder

  1. Periodic Limb Movement Disorder
  2. Periodic Limb Movement Disorder Causes and Treatments on MedicineNet.com
  3. Restless Legs Syndrome:Periodic Limb Movement Disorder: National Sleep Disorders Research Plan, 2003


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