Free Shipping on orders over $99

Restless Leg Syndrome: A full review

Sleep Disorders, Age related illnesses, General | August 19, 2014 | Author: The Super Pharmacist


Restless Leg Syndrome: A full review

Restless legs syndrome (RLS) is a major cause of insomnia and can lead to significant physical and emotional disability. It is a common, distressing neurologic movement disorder of the limbs characterised by discomfort of, and urge to move the legs, occuring primarily during rest or inactivity. Symptoms are typically present or worsen in the evening and releived by movement.

Although RLS becomes more prevalent with age, it has a variable age of onset and can occur in children. In children, it is often misinterpreted as attention deficit hyperactivity disorder (ADHD), growing pains or other sleep disorders.

Causes of Restless legs syndrome

RLS can be either primary (idiopathic or having no known cause) or arise from secondary causes. The mechanisms underlying primary RLS remain unknown but a strong genetic component is suspected (family history). 

Causes of Restless legs syndromeSecondary RLS can develop as a result of certain conditions or factors, such as iron deficiency, peripheral neuropathy and pregnancy. 

RLS also occurs in as many as 25-50% of patients who have end-stage renal disease; these patients find their symptoms to be particularly irritating during hemodialysis.


The following medications have been known to cause or exacerbate the symptoms of RLS:

  • Antidopaminergic medications (eg, neuroleptics)
  • Diphenhydramine
  • Tricyclic antidepressants (TCAs)
  • Selective serotonin reuptake inhibitors (SSRIs)
  • Serotonin-norepinepherine reuptake inhibitors (SNRIs)
  • Alcohol
  • Caffeine
  • Lithium
  • Beta blockers


Conditions associated with iron-deficiency such as in pregnancy, renal failure, and anaemia, may develop RLS and can occur even without significant anaemia but with deficient iron stores (defined by a serum ferritin concentration of <50 µg/L). 


RLS symptoms are alleviated by dopamine agonists (drugs that activate dopamine receptors), suggesting dopamine is considered central to the pathogenesis of RLS. Considerable evidence suggests that RLS is related to a dysfunction in the brain’s basal ganglia circuits that use the neurotransmitter, dopamine, which is needed to produce smooth, purposeful muscle activity and movement. Disruption of these pathways frequently results in involuntary movements. People with Parkinson’s disease, a disorder of the basal ganglia’s dopamine pathways, can often have symptoms of RLS. It is interesting to note that iron is a cofactor in dopamine synthesis.

Periodic limb movement of sleep (PLMS)

More than 80% of people with RLS also experience a more common condition known as periodic limb movement of sleep (PLMS).

PLMS is characterised by involuntary leg twitching or jerking movements during sleep that typically occur every 15 to 40 seconds, sometimes throughout the night. The symptoms cause repeated awakening and severely disrupted sleep.

This neurological movement disorder is also known as "Nocturnal Myoclonus," meaning a sudden shock-like involuntary movement. Although many people with RLS also develop PLMS, most people with PLMS do not experience RLS.

People who have PLMS and do not have RLS or another cause for the PLMS may be diagnosed with periodic limb movement disorder (PLMD). PLMD may be a variant of RLS and thus respond to similar treatments.

Treating Restless leg syndrome

Primary versus secondary RLS?

Before beginning treatment of RLS, it is important to determine whether the disorder is idiopathic (primary) or secondary.

Treating Restless leg syndromeResolving a causative condition such as iron deficiency, uremia, or even neuropathy may cure RLS.

Kidney transplant has been shown to resolve RLS, but dialysis generally is not very helpful.  Pregnancy-onset RLS usually resolves soon after delivery.

However, in many cases it may not be possible to fully resolve the underlying disorder and in such cases, it may be necessary to introduce RLS-specific therapies as well.

Medication-induced RLS?

It is important to determine whether there any medications that may be provoking RLS symptoms. Offending medications (eg, selective serotonin reuptake inhibitors [SSRIs], diphenhydramine, and dopamine antagonists) should be discussed with a medical practitioner to find an alternative. 

Non-pharmacologic management

Certain lifestyle modifications may alleviate RLS. Sleep deprivation worsens RLS, so one of the goals is to optimise sleep.

  • Incorporation of good sleep habits or sleep hygiene 
  • Avoiding caffeine, alcohol, or smoking
  • Exercise or a hot bath before bedtime
  • Falling asleep quickly will often hide RLS symptoms before sleep blocks awareness of sensation. In this regard, sedative-hypnotics may have a role in RLS.

Non-pharmacologic management and sleep hygiene measures are the treatments of choice in children. A regular sleep/wake schedule and the elimination of stimulating activity and dietary stimulants before bedtime are important measures.

Pharmacologic management

In accord with a recent algorithm, it is easiest to divide RLS patients into three categories:

  • those with intermittent symptoms
  • those with daily symptoms
  • those who have failed prior first-line therapies

This algorithm for the management of RLS was developed by members of the Medical Advisory Board of the Restless Legs Syndrome Foundation and is based on scientific evidence and expert opinion.

​Intermittent Restless leg syndromeDaily RLS 

Dopamine agonists are the drugs of choice in most patients with daily RLS. Alternatives to the dopamine agonists for daily RLS include low-potency opioids which have the advantage of a long half-life and pose no risk of augmentation and gabapentin which is most useful when pain is prominent. 

Refractory Restless leg syndrome

Refractory restless legs syndrome is defined as daily RLS treated with a dopamine agonist with one or more of the following outcomes:

  • Inadequate initial response despite adequate doses
  • Response that has become inadequate with time, despite increasing doses
  • Intolerable adverse effects
  • Augmentation that is not controllable with additional earlier doses of the drug

Intermittent Restless leg syndrome

Intermittent RLS is defined as RLS that is troublesome enough when present to require treatment but does not occur frequently enough to necessitate daily therapy (usually less than two or three times a week).

Treatment consists of dopamine precursors, dopamine agonists, opioids, opioid agonists, benzodiazepines and benzodiazepine agonists.

Warnings in regard to levodopa use

Problems with levodopa treatment include augmentation and rebound.

  • Augmentation is defined as a worsening of RLS symptoms earlier in the day after an evening dose of medication, including earlier onset of symptoms, increased intensity of symptoms, or spread of symptoms to the arms. Up to 70% of patients taking levodopa daily will develop augmentation, and the risk increases with daily doses of 200 mg or more. The risk of augmentation may be lower with intermittent use, such as fewer than three times a week, but this has not been established firmly. If augmentation occurs, the drug should be discontinued and another agent substituted. 
  • Rebound, the recurrence of RLS in the early morning, occurs in 20% to 35% of patients taking levodopa.

Considerations in regard to the use of dopamine agonists: The action of dopamine agonists generally commences 90 to 120 minutes after ingestion; thus, these agents cannot be used effectively once symptoms have started.

Choice of benzodiazepines/benzodiazepine agonists: Short-acting agents, such as triazolam or zolpidem, are helpful for sleep-onset insomnia caused by RLS; intermediate-acting agents, such as temazepam, are helpful for RLS that awakens the patient later in the night.

Click Here further reading  Australia's best online pharmacy


Yee B, Killick R, Wong K. Restless leg syndrome. Australian Family Physician. may 2009; 38 (5): 296-300.

The International Restless Legs Syndrome Study Group (Arthur S. Walters MD -- Group Organizer and Correspondent). Towards a better definition of the Restless Legs Syndrome. Mov Disord. 1995;10:634-642.

Allen R, Picchietti D, Hening W, Trenkwalder C, Walters A, Montplaisir J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003;4:101–19.

Rajaram SS, Walters AS, England SJ, et al. Some children with growing pains may actually have RLS. Sleep 2004;27:767–73.

Cortese S, Konofal E, Lecendreux M, et al. RLS and attention-deficit/hyperactivity disorder: a review of the literature. Sleep 2005;28:722–8.

Desai AV, Cherkas LF, Spector TD, Williams AJ. Genetic influences in self-reported symptoms of obstructive sleep apnoea and restless legs: A twin study. Twin Res 2004;7:589–95.

Chen S, Ondo WG, Rao S, Li L, Chen Q, Wang Q. Genome wide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. Am J Hum Genet 2004;74:876–85.

Winkelmann J, Muller-Myhsok B, Wittchen HU, et al. Complex segregation analysis of restless legs syndrome provides evidence for an autosomal dominant mode of inheritance in early age at onset families. Ann Neurol 2002;52:297–302.

Bonati MT, Ferini-Strambi L, Aridon P, Oldani A, Zucconi M, Casari G. Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain 2003;126:1485–92.

Desautels A, Turecki G, Montplaisir J, Sequeira A, Verner A, Rouleau GA. Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q. Am J Hum Genet 2001;69:1266–70.

Restless legs syndrome. detection and management in primary care. National Heart, Lung, and Blood Institute Working Group on Restless Legs Syndrome. Am Fam Phys. Jul 1 2000;62(1):108-14.

Evidente VG, Adler CH. How to help patients with restless legs syndrome. Discerning the indescribable and relaxing the restless. Postgrad Med. Mar 1999;105(3):59-61, 65-6, 73-4.

Bozorg AM. Restless leg syndrome. Medscape. (n.d.) Accessed 27 July 2014.

Grote L, Leissner L, Hedner J, Ulfberg J. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord. Jul 30 2009;24(10):1445-52.

Shinno H, Yamanaka M, Ishikawa I, Danjo S, Nakamura Y, Inami Y. Successful treatment of restless legs syndrome with the herbal prescription Yokukansan. Prog Neuropsychopharmacol Biol Psychiatry. Feb 1 2010;34(1):252-3.

Oscroft NS, Smith IE. Oral glucocorticosteroids: effective in a case of restless legs syndrome resistant to other therapies. Sleep Med. Jun 2010;11(6):596.

Giannaki CD, Hadjigeorgiou GM, Karatzaferi C, Maridaki MD, Koutedakis Y, Founta P, et al. A single-blind randomized controlled trial to evaluate the effect of 6 months of progressive aerobic exercise training in patients with uraemic restless legs syndrome. Nephrol Dial Transplant. Aug 8 2013.

Restless leg syndrome fact sheet. National Institute of Neurologic Disorders and Stroke. NIH Publication No. 10-4847. 25 July 2014. Accessed 26 July 2014.

Zarcone VP Jr. Sleep hygiene. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia: WB Saunders; 2000:657-661.

Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless legs syndrome. Mayo Clin Proc. 2004;79:916-922.

Allen, RP and Earley, CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep. 1996; 19: 205–213.

Earley, CJ and Allen, RP. Pergolide and carbidopa/levodopa treatment of the restless legs syndrome and periodic leg movements in sleep in a consecutive series of patients. Sleep. 1996; 19: 801–810.

Guilleminault, C, Cetel, M, and Philip, P. Dopaminergic treatment of restless legs and rebound phenomenon. Neurology. 1993; 43: 445.

Hening, W, Allen, R, Earley, C, Kushida, C, Picchietti, D, and Silber, M. The treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine Review. Sleep. 1999; 22: 970–999.

Hening, WA, Allen, RP, Earley, CJ, Picchietti, DL, Silber, MH, and Restless Legs Syndrome Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 2004; 27: 560–583.

Silber, MH, Girish, M, and Izurieta, R. Pramipexole in the management of restless legs syndrome: an extended study. Sleep. 2003; 26: 819–821.

Winkelman, JW and Johnston, L. Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS). Sleep Med. 2004; 5: 9–14.

Trenkwalder C, Benes H, Poewe W, et al. Efficacy of rotigotine for treatment of moderate-to-severe RLS: a randomized, double-blinded, placebo-controlled trial. Lancet Neurol 2008;7:595–604.

backBack to Blog Home