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Latest Guidelines and Advances for Treatment of Restless Legs Syndrome

Christopher J. Earley, MBBCh, PhD, FRCPI

Department of Neurology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland

Supported by an educational grant from UCB, Inc.

Restless legs syndrome (RLS), also referred to as Willis-Ekbom disease, is a common disorder that can have a considerable impact on a patient’s functioning and quality of life. Clinicians must be familiar with available treatments to help their patients with RLS achieve optimal outcomes.

Selection and Sequencing of Treatments

AV 1. Selecting and Sequencing RLS Treatments

AV 1. Selecting and Sequencing RLS Treatments

The pharmacologic armamentarium for RLS consists primarily of dopamine agonists, α-2δ agents, opioids, and benzodiazepine receptor agonists.1–3 Each of these types of drugs has strengths and limitations, and clinicians should base their treatment selection on the frequency of the patient’s RLS symptoms and whether or not the RLS is accompanied by pain (AV 1). In addition, iron therapy is a treatment option for patients with low iron levels.2

Dopamine Agonists

Dopamine agonists include immediate-release agents such as ropinirole and pramipexole, as well as extended-release agents and a 24-hour rotigotine transdermal patch. For patients who experience RLS symptoms throughout the day, extended-release agents or the rotigotine patch may be appropriate; the patch provides stable 24-hour steady-state plasma concentrations of medication4 and is particularly effective for alleviating daytime symptoms of RLS.5 Less is known, however, about the long-term effects of these treatments than of the immediate-release agents.

Delayed effects with chronic use of dopamine agonists. Patients who use dopamine agonists chronically may experience hypersomnia,6 which could manifest as daytime sleepiness, sleep attacks, or a condition resembling narcolepsy. Patients may experience excessive sleepiness or sedation within 15 to 20 minutes of taking the medication, which may last for 1 to 2 hours, often followed by a period of insomnia.

AV 2. Dopaminergic Augmentation of RLS Symptom Severity

AV 2. Dopaminergic Augmentation of RLS Symptom Severity

Chronic dopamine agonist use has also been associated with compulsive behaviors such as eating, shopping, gambling, or sexual activity.6 Patients should be assessed for any type of compulsive behavior at each visit. Because patients often lack insight into the behavior, clinicians should also discuss this issue with a family member or significant other.

Exacerbation of RLS symptoms, which is called augmentation, is the most serious side effect associated with chronic dopamine agonist use (AV 2).7 If a patient’s symptoms appear to be getting worse after he or she has been taking a dopamine agonist for several months, clinicians should consider dopaminergic augmentation of symptom severity as a cause.7 Augmentation of symptom severity is believed to occur because chronic use of dopamine agonists leads to a desensitization of the intrinsic dopaminergic system and thus a decrease in dopaminergic activity. If the dose of medication is increased, there will be an initial improvement in symptoms, as the increase will compensate for the degree of desensitization. However, the dose increase, over weeks or months, will only increase further the desensitization process and lead to advancement in symptom severity.

Definitive or probable augmentation of symptom severity has been found to affect more than 20% of patients, at a rate of about 8% per year, who have used dopamine agonists to treat RLS.8 A study9 of patients being treated for RLS for up to 10 years found that the incidence of augmentation resulting from dopamine agonist treatment is relatively constant over the duration of drug use, with the rate of augmentation occurring at a near-constant rate of about 7% per year.

To treat dopaminergic augmentation of symptoms, clinicians must decide how to compensate for the body’s decreasing dopamine activity. One option is to maintain the current dose at bedtime as long as the patient can sleep at night and the RLS symptoms that occur earlier in the evening are mild and are relieved by walking around. Another option is to continue the same medication but increase the dose to cover the new symptoms, perhaps adding a low evening dose in addition to the bedtime dose. If this option is chosen, an upper limit on the total daily amount of dopamine agonist that will be used needs to be defined. In my practice, the recommendations for maximum total daily dose are the following: pramipexole, 0.75 mg; ropinirole, 1.5 mg; and rotigotine, 4.0 mg. The final option is to taper off the dopamine agonist. This strategy, although initially leading to severe rebound of symptoms, will lead to improvement in symptom severity and duration in the large majority of patients if a 10-day, drug-free period is adhered to by the patient.

One withdrawal strategy is to taper the original dopamine agonist while substituting a different one, such as pramipexole for a patient taking ropinirole. The pharmacologic profiles of these drugs are different enough to cause the dopaminergic dysregulation to abate somewhat following the switch. Based on clinical experience, a useful guideline when switching is an 8:1 ratio. Thus, if the patient is taking 4 mg/d of ropinirole, add 0.5 mg/d of pramipexole, stop the ropinirole, and then slowly reduce the pramipexole dose. Another option is to taper the dopamine agonist while providing coverage with an opioid to prevent withdrawal symptoms, but this strategy does not resolve the underlying altered dopaminergic state. Furthermore, if the patient then stops opioid treatment and develops withdrawal symptoms, he or she may believe that the symptoms are related to the opioid rather than the dopamine agonist. The option I choose is to gradually remove the patient from the dopamine agonist without adding coverage from another drug.

α-2δ Ligands

The α-2δ agents pregabalin, gabapentin, and gabapentin enacarbil should be considered first-line treatments for patients experiencing RLS, particularly when pain is present.3 A 1-year study10 found pregabalin to be superior to both placebo and pramipexole for treating RLS, with lower rates of augmentation than 0.5 mg/d of pramipexole. Although physicians are used to prescribing pregabalin or gabapentin in 2 or 3 doses per day, the dosing schedule should be structured to cover only the period of time that the patient has significant symptoms, which for most patients is late evening or bedtime. If the patient also experiences symptoms in the afternoon or evening and/or has underlying chronic pain, gabapentin enacarbil has value because it is a long-acting agent.3

Opioids

Opioids were first reported to be effective in treating RLS symptoms by Willis11 in 1685, and opioids remain a very effective and thus valuable treatment option in difficult cases of RLS.1 There is no indication of symptom augmentation occurring with chronic opioid use. In a study of patients taking methadone for up to 10 years, no significant drug tolerance developed.6 Opioids have different metabolic and pharmacokinetic profiles, so if a patient does not respond to one, another can be tried. For dual opioid therapy, agents should be selected from different classes, such as a synthetic opioid and a morphine derivative.

Iron

The presence of low iron in key areas of the brain has been implicated in the pathophysiology of RLS. Iron therapy, therefore, may be beneficial for treating RLS. Iron therapy can be either oral or intravenous. In a 12-week, randomized, double-blind trial of oral iron (ferrous sulphate, 325 mg/bid) versus placebo in patients with RLS who had ferritin levels between approximately 15 and 75 ng/mL, the oral iron treatment resulted in a significant improvement in RLS symptoms (P = .01).12 Thus, oral iron may be an important treatment option for patients with low or low-normal iron levels.

A number of studies have investigated intravenous iron for RLS. A recent study13 enrolled patients with moderate-to-severe RLS and low-to-normal iron levels; current RLS treatments were discontinued. The study found that the patients receiving treatment with a newer formulation of intravenous iron, ferric carboxymaltose, experienced significant improvement in RLS scores (P = .04), and 25% required no RLS medications at 24 weeks after the iron treatment. No significant adverse events were reported.

All patients with RLS should have their iron levels assessed using appropriate serum indicators such as ferritin levels, percentage of iron saturation, total iron-binding capacity, and early-morning fasting iron levels. Serum hemoglobin level is an insensitive indicator of iron deficiency. Low hemoglobin levels can indicate anemia, but an individual can be severely iron deficient for months or years before becoming anemic. Serum ferritin levels can be deceptive, too, because they increase with age, decreasing renal function, and inflammation.

Symptom improvement probably will not fully occur until 4 to 6 weeks after the iron infusion is given, so any decisions about the effectiveness of iron treatment or whether to discontinue other RLS treatments should not be made until this point. Clinicians should attempt to determine the serum ferritin level at which a patient’s RLS symptoms are most improved and then monitor the patient’s RLS symptoms over time, re-checking ferritin levels if symptoms worsen. Ferritin levels should be checked about 8 weeks after infusion, and 2 additional readings should be taken at 4-week intervals. In this way, the clinician can get an idea of whether the patient maintains a fairly stable iron status or loses iron rapidly. As long as the patient’s ferritin level is below 300 ng/mL, intravenous iron treatments can be repeated as needed to address symptoms. Based on clinical experience, a rough guide for determining an appropriate dose of intravenous iron is that every 100 mg of infused iron should increase the patient’s serum ferritin level by 10 to 12 ng/mL.

Conclusion

Many treatment options are available for patients with RLS. By selecting appropriate treatments on the basis of symptom frequency and pain and effectively managing adverse events, clinicians can help patients experience relief from the symptoms of RLS. Evaluating patients’ iron levels and treating any deficiency may also alleviate RLS symptoms.

Clinical Points
  • Select RLS treatments based on the frequency of the patient’s symptoms and any accompanying pain
  • Assess all patients being treated with a dopamine agonist for dopaminergic augmentation of RLS symptom severity
  • Assess iron levels in all RLS patients and consider iron supplementation for any patient with low to low-normal iron levels
Drug Names

ferric carboxymaltose (Injectafer), gabapentin (Neurontin, Gralise, and others), gabapentin enacarbil (Horizant), methadone (Methadose, Dolophine, and others), pramipexole (Mirapex and others), pregabalin (Lyrica and others), ropinirole (Requip and others), rotigotine (Neupro)

Abbreviations

BzRA = benzodiazepine receptor agonist
DA = dopamine
RLS = restless legs syndrome

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References
  1. 1. Silber MH, Becker PM, Earley C, et al. Willis-Ekbom disease foundation revised consensus statement on the management of restless legs syndrome. Mayo Clin Proc. 2013;88(9):977–986. PubMed
  2. 2. Aurora RN, Kristo DA, Bista SR, 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.
    Sleep. 2012;35(8):1039–1062. PubMed
  3. 3. García-Borreguero D, Kohnen R, Silber MH, et al. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med. 2013;14(7):675–684. PubMed
  4. 4. Elshoff JP, Braun M, Andreas JO, et al. Steady-state plasma concentration profile of transdermal rotigotine: an integrated analysis of three, open-label, randomized, phase I multiple dose studies. Clin Ther. 2012;34(4):966–978. PubMed
  5. 5. Stiasny-Kolster K, Berg D, Hofmann WE, et al. Effectiveness and tolerability of rotigotine transdermal patch for the treatment of restless legs syndrome in a routine clinical practice setting in Germany. Sleep Med. 2013;14(6):475–481. PubMed
  6. 6. Earley CJ, Silber MH. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med. 2010;11(9):807–815. PubMed
  7. 7. García-Borreguero D, Allen RP, Kohnen R, et al. Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute. Sleep Med. 2007;8(5):520–530. PubMed
  8. 8. Allen RP, Ondo WG, Ball E, et al. Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample. Sleep Med. 2011;12(5):431–439. PubMed
  9. 9. Silver N, Allen RP, Senerth J, et al. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med. 2011;12(5):440–444. PubMed
  10. 10. García-Borreguero D. Long-term efficacy and augmentation assessment of a dopamine agonist (pramipexole) compared with an alpha-2-delta ligand (pregabalin) in restless legs syndrome: results of a randomized, double-blinded, placebo-controlled trial. Emerging Science Abstract presented at: 64th Annual Meeting of the American Academy of Neurology; April 25, 2012; New Orleans, LA.
  11. 11. Willis T. The London Practice of Physick. London: Bassett and Crooke; 1685.
  12. 12. Wang J, O’Reilly B, Venkataraman R, et al. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: a randomized, double-blind, placebo-controlled study. Sleep Med. 2009;10(9):973–975. PubMed
  13. 13. Allen RP, Adler CH, Du W, et al. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centred, placebo-controlled preliminary clinical trial. Sleep Med. 2011;12(9):906–913. PubMed
From the Series:
Restless Legs Syndrome: Recognition, Diagnosis, and Treatment of a Common Sleep Disorder

Supported by an educational grant from UCB, Inc.

CME Background Information

Supported by an educational grant from UCB, Inc.

Objective

After completing this educational activity, you should be able to:

  • Develop a treatment plan that incorporates the appropriate therapies for patients with RLS

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr Earley has received honoraria from the Maryland Sleep Society.

The Chair for this activity, Richard P. Allen, PhD, is a consultant for Xenoport, UCB, Pfizer, and Impax; has received grant/research support from Pharmacosmos, GlaxoSmithKline, and NIH; and has received honoraria from UCB.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hours of Category I credit for completing this program.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Release, Review, and Expiration Dates

This Neurology Report activity was published in January 2014 and is eligible for AMA PRA Category 1 Credit™ through January 31, 2017. The latest review of this material was November 2013.

Statement of Need and Purpose

Restless legs syndrome (RLS) is a common neurologic disorder of unknown etiology that causes significant distress. The symptoms of RLS—uncomfortable sensations that create an urge to move the legs that worsen during periods of rest and are relieved temporarily by movement—can severely disrupt sleep, leading to a reduced quality of life, daytime tiredness, a lack of energy, a disturbance of daily activities, and a tendency to become depressed. The prevalence and severity of RLS increase with age, and, due to the aging of the population, the personal and societal burden of RLS will become ever greater in coming years, increasing the need for prompt and effective treatment. Due to the nature of RLS symptoms, patients may seek treatment from a variety of health care providers, including primary care physicians, psychiatrists, and neurologists. However, even though diagnostic criteria for RLS have been established, patients are often misdiagnosed. In many cases, patients should be screened for RLS even though they do not directly report RLS symptoms. Health care providers should also be aware that the majority of people with insomnia never discuss sleep problems with their physicians and patients should, therefore, be routinely screened for sleep disturbances. Once RLS has been diagnosed, treatment is generally pharmacologic because sleep hygiene behaviors that promote relaxation or comfort may worsen or trigger RLS symptoms. However, mild exercise may relieve the symptoms long enough to let the patient get to sleep. Unfortunately, many patients are currently prescribed therapies not known to be effective in RLS, including analgesics, anti-inflammatories, and medications for gout and cramps. Clinicians need education on recognizing and assessing RLS symptoms in clinical practice and then treating RLS effectively to improve patients’ outcomes and quality of life. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on RLS.

Disclosure of Off-Label Usage

Dr Earley has determined that, to the best of his knowledge, ferric carboxymaltose, gabapentin, pregabalin, and levodopa are not approved by the US Food and Drug Administration for the treatment of restless legs syndrome.

Review Process

The entire faculty of the series discussed the content at a peer-reviewed planning session, the Chair reviewed the activity for accuracy and fair balance, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.

Acknowledgment

This Neurology Report is derived from the planning teleconference series “Restless Legs Syndrome: Recognition, Diagnosis, and Treatment of a Common Sleep Disorder,” which was held in June and July 2013 and supported by an educational grant from UCB, Inc. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.