Restless Leg Syndrome (RLS)

Restless Leg Syndrome

by Elizabeth Papa, PharmD(c)
CareKinesis / Jefferson School of Pharmacy

Restless leg syndrome (RLS) is a neurological movement disorder that affects about 10% of adults in the United States.(1) RLS is typically described as crawling, throbbing, pins and needles, tingling, prickly, or an urge to move.  Roughly 80-90% of patients with RLS also have a concurrent periodic leg movement in sleep (PLMS) leading to disturbance in sleep and excessive daytime sleepiness.(2) The four key diagnostic features of RLS include: an urge to move the limbs that is usually associated with paresthesias or dysethesias (abnormal sensations), worsening of symptoms at rest, symptoms alleviated by movement, and worsening of symptoms in the evening or at night.  Risk factors for RLS include low iron levels, lower socio-economic status, poor health, age, Parkinson’s disease, mental health, and end stage renal disease.(3)

Treatment options for RLS include non-pharmacologic and pharmacologic strategies.  Non-pharmacologic options would be ideal to start with prior to placing patients on drug therapy to treat RLS.  Pharmacologic treatments options include dopaminergic agents, anticonvulsants, clonidine, opioids and iron supplementation.

Dopaminergic agents include: pramipexole (Mirapex®), ropinirole (Requip®), levodopa/carbidopa (Sinemet®).  Levodopa has been a mainstay of RLS treatment for many years; however concern regarding the higher occurrence of augmentation with levodopa compared to alternative dopaminergic agents has moved its use from the forefront of RLS therapy.  Because of the increased risk of augmentation, alternative dopaminergic agents such as pramipexole and ropinirole are now first-line standards in RLS that requires pharmacologic treatment.  Augmentation is essentially an increase in RLS symptom severity, including an onset of symptoms earlier in the day, increased symptoms, or spreading of symptoms to other body parts (e.g. arms).  Therefore, levodopa is recommended for use in patients with intermittent symptoms that may not require daily therapy.

Rotigotine (Neupro®) is an additional dopaminergic agent that was withdrawn from the market in 2008 and re-introduced in 2012 after the current guidelines were published.  It was originally withdrawn due to reports of rotigotine crystals forming in the patches, decreasing clinical effectiveness.  The patch has since been re-introduced with no reports of crystal formation and has an FDA-approved indication for RLS.

Anticonvulsants have also been used as alternative options in the treatment of RLS.  The only option with FDA approval is gabapentin enacarbil (Horizant®).  Other choices with off-label use include gabapentin (Neurontin®), pregabalin (Lyrica®), and carbamazepine (Tegretol®).  A high level of evidence exists supporting the use of gabapentin enacarbil for the treatment of RLS, however because the medication is relatively new compared to alternative agents, guidelines are recommending conservative use at this time.  A lower level of evidence exists for additional anticonvulsant options, causing these therapies to be considered alternatives as well.  Gabapentin has shown usefulness in patients complaining of pain.  Pregabalin has shown efficacy in initial trials but long-term follow-up data is warranted.  Carbamazepine was shown to be effective in earlier trials but no recent data has been published and concern regarding side effects and the risks versus benefits keep carbamazepine as a option rather than a standard treatment.

Clonidine has also been used as treatment for RLS.  Data supporting the use of clonidine is minimal and side effects are concerning.  Therefore guidelines suggest clonidine as an option that may be beneficial in patients with concomitant hypertension and RLS.  Opioids are a viable option in patients who have not responded to other therapies; a concern would be for the possibility of worsening or developing sleep apnea.  Iron supplementation has shown some benefit in patients with low ferritin levels and is therefore suggested as an option for the treatment of RLS in patients with low ferritin levels.

Please see this RLS Chart for more information.

References:
1.    Bayard M, Avonda T, Wadzinski J. Restless Leg Syndrome. Am Fam Physician. 2008;78(2):235-240.
2.    Aurora RN, Kristo DA, Bista SR, Rowley JA, Zak RS, et al. 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.  An American Academy of Sleep Medicine Clinical Practice Guideline. SLEEP. 2012;35(8):1039-1062.
3.    Yeh P, Walters AS, Tsuang JW. Restless legs syndrome: a comprehensive overview on its epidemiology, risk factors, and treatment. Sleep Breath. 2012;16:987-1007.