Restless Legs Syndrome: Treatment Strategies and Agents to Avoid

Educational Objectives

The goal of this program is to improve the management of restless legs syndrome. After hearing and assimilating this program, the clinician will be better able to:

1. Diagnose restless legs syndrome.
2. Select appropriate medications and treatment strategies for managing restless leg syndrome.
3. Identify risk factors involved in the pathophysiology of restless legs syndrome.

Summary

Restless legs syndrome (RLS): clinical diagnosis is based on history; diagnostic criteriafrom the International Restless Leg Syndrome study group — fundamental symptom is the urge to move legs (individuals may not be able to describe the sensation); symptoms occur or worsen exclusively at night and exacerbate with rest, ie, sitting for long periods of time or not moving legs; symptoms are relieved by movement and not solely accounted for by a secondary condition (eg, nocturnal leg cramps, peripheral neuropathy, arthritis, peripheral vascular disease, positional discomfort, restlessness, anxiousness, attention-deficit/hyperactivity disorder); epidemiology — global prevalence is 5% to 14%, with clinically significant symptoms in ≤50%; tends to be genetic and is more common in those of northern and western European ancestry; 2-fold more common in women than in men; occurs in 20% of pregnant women; increases with age, ie, different medications and comorbidities; symptoms — discomfort while lying down and trying to sleep; intolerance of sedentary activities, eg, sitting during plane flights; psychological symptoms, eg, anger, frustration, irritability, and anxiousness; trouble falling or returning to sleep; need for movement

Periodic limb movement (PLM): PLM in sleep is not RLS; ≤90% of patients with RLS have PLMs, but 45% of all adults >65 yr of age have PLM; also common with other conditions, eg, heart failure, chronic kidney disease, and spinal cord injury; PLM in sleep study may be supportive of RLS diagnosis but is not necessary or sufficient for RLS diagnosis; there is no evidence for treatment of PLM in sleep; PLM disorder is exceedingly rare

Pathophysiology of RLS: occurs at night as serum iron level drops 30% to 50% as iron accumulates in the bone marrow for hematopoiesis; iron is a cofactor in dopamine transport in the central nervous system; BTBD9 and MIZ1 (single-nucleotide polymorphisms) are the most common risk factors and are involved in dopamine and iron regulation in the brain; in RLS, iron levels are lower in the substantia nigra (primary region for dopamine production) and increase more slowly than in controls

Dopamine agonists (DAs): bypass the defective endogenous system; side effects include sleep attacks, nausea, and impulse control disorders (ICD); in a 2018 Parkinson study of patients on DA treatment, the 5-yr cumulative incidence of ICD was 46%; a 2010 Mayo Clinic study showed that 17% of RLS patients on DA had ICD; a study in Austria (2016) showed that nearly 50% of patients on DA had ICD and 6-fold increased risk with DA augmentation; in augmentation, RLS symptoms manifest in the afternoon and evening, spread to other areas (eg, torso, arms), and appear minutes after taking DA (paradoxical treatment response); in a 2004 study, 50% of all patients on DA developed augmentation over the course of 3 yr; one study of pramipexole showed that in <2 yr, 33% of patients developed augmentation; in a 5-yr study on transdermal rotigotine patch, 13% of patients developed augmentation; one study showed that >50% of patients were prescribed DA, and >50% were prescribed a DA plus α2δ ligand (2007-2009); the IRLSSG, EURLSSG, and RLS Foundation recommend consideration of medications, eg, α2δ ligands, for initial RLS treatment to prevent augmentation; recommended dosage — 0.125 mg of pramipexole; RLS patients requiring maximum doses of DA already have augmentation, ie, DA should be discontinued; mild RLS does not require treatment

Iron: consensus for starting an oral iron supplement is serum ferritin levels <75 μg/L; ferritin is often elevated because of infection or inflammation but is noncircadian; transferrin saturation is ≥20% when normal and is circadian, decreases at night, and elevates in the morning; blood should be tested in the early morning before levels start to rise; recent ingestion of iron raises transferrin levels; 1000 mg of intravenous (IV) ferric carboxymaltose or any stronger formulation of iron, and 65 mg oral iron supplementation for ferritin <300 μg/L is recommended; a 2019 randomized trial showed a statistically significant decrease in RLS score with iron treatment; iron absorption decreases with higher levels of iron; administer 56 mg ferrous bisglycinate or 65 mg ferrous sulfate (FeSO₄) for ferritin <50 μg/L; for ferritin 50 to 75 μg/L, 20 to 30 mg of elemental iron (eg, 28 mg ferrous bisglycinate, half of a FeSO₄, or one FeSO₄ every other day) is recommended; for ferritin >75 μg/L, infusion of low molecular-weight iron (eg, iron dextran ferumoxytol, monoferric derisomaltose, or ferric carboxymaltose) is recommended; a study in Korea showed that, with 1000 mg of low molecular-weight dextran, 32% of patients on medication had complete remission of RLS, 16% had complete remission and could stop all medication, and 32% saw no improvement; in another Korean study, ferritin increased from an average of 41 μg/L to 274 μg/L, and RLS scores dropped/improved by an average of 7 points with iron infusion; duration of effect of infusion depends on the capacity to absorb and lose iron

Gabapentin (GP): US Food and Drug Administration has approved GP enacarbil (GPE) for treatment of RLS; in one clinical trial, absolute relapse rate was 14% higher in those who switched to placebo compared with those receiving 1200 mg GPE; GPE is better absorbed (through high-capacity nutrient transporters) than GP; dosing with dinner is recommended; recommended dose (with dinner) is 300 to 1800 mg GPE or 300 to 600 mg GP plus 600 mg at bedtime to avoid side effects of dizziness and sedation during daytime

Pregabalin: one trial showed that pregabalin was more effective than 0.5 mg pramipexole; maximum recommended dose is 300 mg at night

Opioids: can be used in patients with normal iron levels who are intolerant to α2δ ligands; mechanism of action — deficiency of β-endorphins and met-enkephalins in the thalamus is observed in a postmortem RLS brain; sensory relay is significantly impaired; iron homeostasis has been found to be defective in μ-opioid receptor knockout mice with clinical RLS; drugs that target the N-methyl-D-aspartate system (methadone, buprenorphine) significantly improve RLS; opioids are considered second-line medication for RLS; buprenorphine — preferred as it is a controlled substance level 3, whereas most other opioids are schedule 2; side effects (particularly, respiratory depression) are minimal, with lower risk for central sleep apnea and other sleep conditions; codeine, hydrocodone, oxycodone — can be prescribed in patients with intermittent or occasional nighttime symptoms; tramadol — should be prescribed with caution as it has potentially serotoninergic and dopaminergic effects and chronic use causes augmentation

Management of augmentation: severe augmentation warrants referral to a sleep medicine specialist with expertise in RLS; an alternative is evaluation of iron and its aggressive infusion; if iron infusion is not available, an α2δ ligand can be initiated; opioids can be given to individuals who fail to improve with α2δ ligands; DAs should be slowly decreased (by 0.125 mg for pramipexole and 0.25–0.5 mg for ropinirole) every week as tolerated; midday and afternoon doses should be reduced first because fewer symptoms manifest during the day; second agent can be increased if withdrawal is not tolerated

Benzodiazepines (BZDs): considered fourth- or fifth-line treatment for RLS; believed to reduce sleep arousal associated with PLM; can reduce anxiety which can also reduce RLS, but the speaker does not recommend use in RLS

Readings

Allen RP. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med. 2004; 5:385-391; doi: 10.1016/j.sleep.2004.01.012; Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med. 2018; 41:27-44; doi: 10.1016/j.sleep.2017.11.1126; Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis–Ekbom disease diagnostic criteria: updated international restless legs syndrome study group (IRLSSG) consensus criteria – history, rationale, description, and significance. Sleep Med. 2014; 15:860-873; doi: 10.1016/j.sleep.2014.03.025; Avni T, Reich S, Lev N, et al. Iron supplementation for restless legs syndrome – a systematic review and meta-analysis. Eur J Intern Med. 2019; 63:34-41. doi:10.1016/j.ejim.2019.02.009; Cho YW, Allen RP, Earley CJ. Lower molecular weight intravenous iron dextran for restless legs syndrome. Sleep Med. 2013; 14:274-277; doi: 10.1016/j.sleep.2012.11.001; Cornelius JR, Tippmann-Peikert M, Slocumb NL, et al. Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: a case-control study. Sleep. 2010; 33:81-87; doi: 10.1093/sleep/33.1.81; Forbes A, Saini P, Rye DB. 0663 buprenorphine/naloxone treatment of refractory RLS. Sleep. 2019; 42:A264-A265; doi: 10.1093/sleep/zsz067.661; Heim B, Djamshidian A, Heidbreder A, et al. Augmentation and impulsive behaviors in restless legs syndrome: coexistence or association? Neurology. 2016; 87:36-40; doi: 10.1212/WNL.0000000000002803; Kushida CA, Walters AS, Becker P, et al. A randomized, double-blind, placebo-controlled, crossover study of XP13512/GSK1838262 in the treatment of patients with primary restless legs syndrome. Sleep. 2009; 32:159-168; doi: 10.1093/sleep/32.2.159; Lal R, Sukbuntherng J, Luo W, et al. Population pharmacokinetics and pharmacodynamics of gabapentin after administration of gabapentin enacarbil. J Clin Pharmacol. 2013; 53:29-40; doi: 10.1177/0091270012439209; Winkelman JW, Johnston L. Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS). Sleep Medicine. 2004; 5:9-14; doi: 10.1016/j.sleep.2003.07.005; Yang X, Yang B, Ming M, et al. Efficacy and tolerability of intravenous iron for patients with restless legs syndrome: evidence from randomized trials and observational studies. Sleep Med. 2019; 61:110-117; doi: 10.1016/j.sleep.2019.01.040.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, members of the faculty and planning committee reported nothing to disclose. In his lecture, Dr. Berkowski presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Berkowski was recorded virtually at the Sports Medicine for the Primary Care Physician and Fall Update in Family Medicine, held September 23-24, 2021, and presented by Michigan Medicine. For information on future CME activities from this presenter, please visit ww2.highmarksce.com. Audio Digest thanks the speakers and Michigan Medicine for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

FP694701

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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