Fighting the URGE: Optimizing the
Treatment of Restless Leg Syndrome
pmiCME Updates
November 15, 2012
Boston, Massachusetts
Faculty:
David B. Rye, MD, PhD
Ana Krieger, MD, MPH
Educational Partner
The Institute for Continuing
Healthcare Education
Session 6: Fighting the URGE:
Optimizing the Treatment of Restless Leg Syndrome
Learning Objectives
1. Evaluate the underlying etiology and pathophysiology of RLS and determine how these may impact diagnosis and
treatment.
2. Apply current guidelines for the treatment of RLS into practice, thereby improving rates of appropriate diagnosis.
3. Analyze current guidelines for the management of RLS and employ in clinical practice those that may improve
patient outcomes.
4. Assess the efficacy and side effect profiles of pharmacologic treatments for RLS, and utilize those that minimize
patient symptoms and maximize quality of life.
Faculty
David B. Rye, MD, PhD
Professor of Neurology
Emory University School of Medicine
Atlanta, Georgia
David Rye, MD, PhD, is a professor of neurology at Emory University’s School of Medicine and the director of research for
Emory Healthcare’s program in sleep medicine. He is an internationally recognized expert in narcolepsy and related
disorders of excessive daytime sleepiness and movement disorders in sleep, particularly RLS.
Dr Rye is the former chair of the RLS medical advisory board and is on the medical advisory board of the Narcolepsy
Network. He is a past recipient of the American Academy of Neurology’s Sleep Science Award (2008) and the Sleep
Research Society’s Outstanding Scientific Achievement Award (2009). He also is the recipient of numerous grant awards
from the National Institutes of Health.
Ana Krieger, MD, MPH
Medical Director
Weill Cornell Center for Sleep Medicine
New York, New York
Ana C. Krieger, MD, MPH, is an associate professor of clinical medicine in the departments of medicine, neurology, and
neuroscience. She is a board certified specialist in sleep medicine by the American Academy of Sleep Medicine and the
medical director of the Weill Cornell Center for Sleep Medicine.
Over the past 14 years, Dr Krieger has been actively involved in patient care, training of sleep specialists, and sleep disorders
education and research. Besides her clinical activities, Dr Krieger is a clinician scientist, the principal investigator on
National Institutes of Health-sponsored translational research projects investigating the mechanisms of cardiovascular
disease and thrombosis in sleep apnea, and is involved in multiple other collaborative multidisciplinary research projects in
sleep medicine.
Faculty Financial Disclosure Statements
The presenting faculty reports the following:
David B. Rye, MD, PhD, is a consultant and on the advisory board for UCB; is on the external data monitoring committee
for Merck; and is on the advisory board for Impax Laboratories and Jazz Pharmaceuticals.
Ana C. Krieger, MD, MPH, has no financial relationships to disclose.
Education Partner Financial Disclosure Statement
The content collaborators at the Institute for Continuing Healthcare Education have reported the following:
Cathy Pagano, CCMEP, President; Allison A. Muller, PharmD, D.ABAT, Medical Director; Scott Kober, MBA, CCMEP,
Director, Content Development; April Reynolds, MS, ELS, Content Editor; Sandra Davidson, Director, Project
Suggested Reading List
Allen RP, Bharmal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome: results of a general
population survey in the United States. Mov Disord. 2011;26(1):114-120.
Allen RP, Picchietti D, Hening WA, et al. 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(2):101-119.
Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study.
Arch Intern Med. 2005;165(11):1286-1292.
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: an American
Academy of Sleep Medicine Clinical Practice Guideline. SLEEP. 2012;35:1039-1062.
Berger K, Luedemann J, Trenkwalder C, et al. Sex and the risk of restless legs syndrome in the general population. Arch
Intern Med. 2004;164:196-202.
Byrne R, Sinha S, Chaudhuri KR. Restless legs syndrome: diagnosis and review of management options. Neuropsychiatr Dis
Treat. 2006;2:155-164.
Earley CJ, Silber MH. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med.
2010;11(9):807-815.
Gamaldo CE, Earley CJ. Restless legs syndrome: a clinical update. CHEST. 2006;130:1596-1604.
Hening W, Walters AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care
population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med. 2004;5(3):237-246.
Merlino G, Valente M, Serafini A, et al. Restless legs syndrome: diagnosis, epidemiology, classification and consequences.
Neurol Sci. 2007;28:S37-S46.
Nichols DA, Allen RP, Grauke JH, et al. Restless legs syndrome symptoms in primary care: a prevalence study. Arch Intern
Med. 2003;163(19):2323-2329.
Scholz H, Trenkwalder C, Kohnen R, et al. Dopamine agonists for restless legs syndrome. Cochrane Database Syst Rev.
2011(3):CD006009.
Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless legs syndrome.
Mayo Clin Proc.
Session 6
3:30 PM - 4:45 PM
Fighting the URGE: Optimizing the Treatment of Restless Leg Syndrome
Speakers: David B. Rye, MD, PhD Ana Krieger, MD, MPH
Presenter Disclosure Information
The following relationships exist related to this presentation:• David B. Rye, MD, PhD, is a consultant and on the advisory board for UCB; is on the external data monitoring committee for Merck; and is on the advisory board for Impax Laboratories and Jazz Pharmaceuticals.
• Ana C. Krieger, MD, MPH, has no financial relationships to disclose.
Off-Label/Investigational Discussion
In accordance with pmiCME policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.
Generic Name Brand Name Pramipexole Mirapex Pergolide Permax Cabergoline Dostinex Pregabalin Lyrica Gabapentin enacarbil Horizant Rotigotine Neupro Alprazolam Niravam, Xanax Ropinirole Requip Iron dextran Dexferrum, Imferon, INFeD Iron sucrose Venofer Ferric gluconate Ferrlecit, Nulecit Ferric carboxymaltose Ferinject Levodopa Dopar, Larodopa Gabapentin Fanatrex, Gabarone, Neogab, Gralise, Neurontin, Nupentin Clonazepam Ceberclon, Klonopin, Klonopin Wafer Citalopram Celexa Zolpidem Ambien, Ambien CR, Edluar, Intermezzo, Stilnox, Sublinox, Zolpimist Pharmacologics Within This Presentation
Learning Objectives
• Evaluate the underlying etiology and pathophysiology of restless legs syndrome (RLS) and determine how these may impact diagnosis and treatment • Apply current guidelines for the treatment of RLS into practice, thereby improving rates of appropriate diagnosis • Analyze current guidelines for the management of RLS and employ into clinical practice those that may improve patient outcomes • Assess the efficacy and side effect profiles of pharmacologic treatments for RLS, and utilize those that minimize patient symptoms and maximize quality of lifePlease indicate the number of patients
you see each week with RLS
1. 0‐5 2. 6‐10 3. 11‐15 4. 16‐20 5. 21‐25 6. 25‐30 7. >30?
Activity Pre‐Test
1. UT, a 32‐year‐old female complaining of frequent migraines 2. PA, a 57‐year‐old male with renal failure 3. JK, a 45‐year‐old male with a recent knee replacement 4. TY, a 75‐year‐old female with multiple sclerosis 5. SS, a 24‐year‐old HIV‐positive male
In which of the following patients would you
suspect a greater than average possibility of the
presence of RLS (choose all that apply)?
?
1. Pramipexole 2. Folic acid supplementation 3. Pregabalin 4. Gabapentin enacarbil 5. Ropinerole 6. Rotigotine For a pregnant 29‐year‐old patient in her third trimester who presents with severe RLS‐related symptoms, which of the following agents would best combine safety and efficacy??
1. Symptoms occurring only between the hours of 2‐5 a.m. 2. Significant worsening of symptoms with decrease in medication dosage 3. Spread of symptoms to previously unaffected areas 4. Significant improvement in symptoms with increase in medication dosageWhich of the following might lead you to
conclude that your RLS patient is suffering
from augmentation?
?
1. Fluid retention 2. Sleepiness 3. Morning drug hangover 4. Skin irritation/infectionIn an RLS patient being treated with rotigotine,
which of the following potential side effects
would you be most concerned about?
?
Epidemiology and Diagnostic Considerations
David Rye, MD, PhD Professor of Neurology Emory University Atlanta, GA • Defining RLS • Epidemiology of RLS: comorbidities and factors influencing trait expressivity • Tools and clinical pearls to help recognize RLS • Pathophysiology of RLS 1) Iron 2) Spinal sensorimotor systems 3) Molecular geneticsWhat We’ll Cover
The Burden of RLS is Significant
• 5‐10 million Americans clinically significantly affected • Quality of life is negatively impacted to a degree comparable to other common, complex, chronic diseases • Higher cross‐sectional rates of mood disorders – Major depressive disorder (odds ratio [OR]=4.7, range: 1.6‐14.5) – Panic disorder (OR=12.9, range: 3.6‐46.0) • Higher cross‐sectional rates of cardiovascular problems – Hypertension (OR=1.5, range: 0.9‐2.4) – Heart disease (OR=2.5, range: 1.4‐4.3) Allen RP et al. Arch Intern Med. 2005;165:1286‐92; Kushida CA et al. Am J Med. 2007;120(1 Suppl 1):S4; Lee HB et al. J Neuropsychiatry Clin Neurosci. 2008;20:101; Ulfberg J et al. Movement Disorders. 2001;16:1159‐1163.IRLSSG/NIH Essential Diagnostic Criteria for RLS
• An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations • Onset or worsening of symptoms at rest or inactivity, such as when lying or sitting • Relief with movement—partial or total relief from discomfort by activities such as walking or stretching • Worsening of symptoms in the evening and at night Allen RP et al. Sleep Med. 2003;4:101‐119. IRLSSG=International RLS Study Group A Multitude of Descriptors are Chosen by Patients to Describe Their Sensory RLS Experience (N=360 respondents) • “Creepy, crawly” 43.6% • “Aching” 39.4% • “Tingling” 28.3% • “Electric” 27.8% • “Painful” 24.2% • “Indescribable” 23.9% • “Like worms” 20.0% Rye DW et al. Unpublished data. <20%: “pins & needles”; “pulling”; “tugging”; “asleep”; “numbness”; “itching”; “burning”“Do You Experience Your
Sensory Symptoms as ‘Painful?’”
• Percentage who answered in the affirmative – 35% of a population‐based sample of Icelanders (N=951) – 35%‐56% of smaller RLS cohorts reported by others Ekbom K. Acta Med Scand Suppl. 1945;158:1; Bassetti CL et al. European Neurol. 2001;45:67; Holmes R et al. J Neural Transm. 2007;114:929.Supportive Features
• Family History – 30%‐65% • Symptom amelioration with dopaminergics (80%‐ 90%) • Periodic limb movements of sleep (~90%) Allen RP et al. Sleep Med. 2003;4:101‐119. 11.3% 11.3% 5% 3.6% 7.9% 1.5-4.0% 2.0% 0.2% 6.8-11.5% 5-10% 0%?? 3.5%RLS prevalence is high and
influenced by ethnicity
2.5-4.0% 0.9-1.5% 18.3%(F) Allen RP et al. Arch Intern Med. 2005;165:1286‐92; Tan E et al. Mov Disord. 2001;16:577; Cho SJ et al. Sleep. 2009;32:1069; Castillo PR et al. Mayo Clinic Proceedings. 2006;81:1345; Sevim S et al. Neurology. 2003;61:1562; Inoue Y et al. J New Rem Clim. 2000;49:244; Ulfberg J et al. Mov Disord. 2001;16(6):1159; Tison F et al. Neurology. 2005;65(2):239‐246; Cho SJ et al. Sleep. 2009;32(8):1069‐76; Benediktsdottir B et al. Sleep Med. 2010;11(10):1043; Lavigne GJ et al. Sleep. 1994;17(8):739.RLS Expressivity is Also Affected by the ‘Environment’ (ie, Other Medical Conditions)
Condition Prevalence of RLS Blood donation 25% (women) 15% (men) Iron deficiency (without anemia) ~40% Pregnancy (esp. 3rdtrimester) 26% Renal failure/hemodialysis 50% (African‐Americans) 70% (Caucasians) Ulfberg J et al. Sleep Med. 2004;5(2):115‐8; Akyol A et al. Clin Neurol Neurosurg. 2003;106:23‐27; Manconi M et al. Neurology. 2004;63:1065‐69; Kutner NG et al. Sleep Med. 2002;3:497‐500.
RLS Occurs at Greater Frequency Than
Expected by Chance in Many Conditions
• Rheumatologic disorders • Diabetes • Pulmonary hypertension • Chronic obstructive pulmonary disease (COPD) • Chronic liver disease • Crohn’s disease • Celiac disease • Gastric bypass surgery • Irritable bowel syndrome • Migraine Hening et al. Sem Arthritis Rheum. 2008;38:55; Merlino G et al. SLEEP. 2007;30:866; Minai OA. J Heart Lung Transplant. 2008;27:335; Kaplan Y. Can J Neurol Sci. 2008;35:352; Lo Coco D et al. Sleep Med. 2009;10:572; Franco RA. J Clin Sleep Med. 2008;4:45; Weinstock LB. Inflamm Bowel Dis. 2010;16(2):275‐9; Manchanda S et al. Sleep Med. 2009;10:763; Weinstock LB et al. Dig Dis Sci. 2009 (in press); Banerji et al. Br Med Journal. 1970;4:774; Weinstock LB et al. Dig Dis Sci. 2008;53:1252; Cologno D et al. Neurological Sciences. 2008;29(Suppl 1): S166; Rhode AM et al. Cephalalgia. 2007;27:1255.Neurological Conditions in Which
RLS Occurs at High Frequencies
Condition Prevalence of RLS
Parkinson’s disease 11%‐24% Spinocerebellar ataxias (SCA‐3) 45% Multiple sclerosis 33% Myelopathy ~40% Peralta CM et al. Mov Disord. 2009;24(14):2076‐80; Verbaan D et al. Mov Disord. 2010;25(13):2142‐147.; Schöls L et al. Neurology. 1998;51:1603; Manconi M et al. European J Neurol. 2007;14:534; Trotti LM et al. Sleep. 2007;30:A306.
Periodic Limb Movement (PLM) and RLS Are Often,
But Not Always, Overlapping Conditions
PLMs RLS Scofield H et al. Sleep. 2008:31(9):1221‐1227; Trotti LM et al. Sleep Med. 2009;10:668‐671; Chervin RD et al. Am J Respir Crit Care Med. 2001;164:1454‐1458. Trotti LM et al. Sleep Medicine. 2009;10:668‐671. PLMI = Periodic Limb Movement IndexIron Impacts RLS Symptomatology,
But it is NOT a Sine Qua Non
• RLS occurs in ~40% of subjects with iron deficiency (ie, iron deficiency by itself is insufficient to cause RLS)• In vivo and in vitro iron depletion occurs in some patients in dopamine‐rich brain regions of RLS patients • Iron deficiency adversely affects dopamine signaling • Intravenous iron can ameliorate RLS symptoms, although recent controlled studies demonstrate less consistent and less dramatic clinical responses Akyol A et al. Clin Neurol Neurosurg. 2003;106:23; Allen RP et al. Neurology. 2001;56:263; Connor JR et al. Neurology. 2003;61:304; Allen RP et al. Sleep Med. 2004;5:385; Earley CJ et al. Sleep Med. 2004;5:231; Earley CJ et al. Sleep Med. 2009;10:206; Grote L et al. Mov Disord. 2009;24:1445.
Iron Deficiency is Not Necessary for RLS Diagnosis
(Iron measures in a clinic‐based RLS sample) • % RLS patients ferritin <20 ug/dL =22%
– Of whom only 1 in 3 are anemic • % RLS patients ferritin 21‐40 ug/dL =20%
– Of whom only 1 in 6 are anemic Personal observations on 360 consecutive RLS referrals. Unpublished data.RLS Has a Significant Genetic Component
• 30%‐65% of RLS patients have a first‐degree relative with the disorder • High (54%‐83%) concordance in identical twins • Most pedigrees described exhibit an autosomal dominant inheritance pattern • “Anticipation” in some families • Genetic linkage studies have been largely uninformative Winkelmann J et al. Mov Disord. 2007;22(Suppl 18):S449; Trotti L et al. Curr Neurol Neurosci Rep. 2008;8:281.Case Study #1
Our Pa ent ― CC
• 27‐year‐old male presenting for the evaluation of restless legs and intermittent insomnia • Recently married, no children • Past history of depression (associated with the death of his father and brother) and anxiety, stable off medications for 4 years • Patient reports nail biting and skin picking • Patient is a writer, drinks 1 cup of coffee in the morning • No other medical problems are presentCC’s RLS‐Related History
• Childhood history of “growing pains” in both legs, mostly at night, described as a uncomfortable, “tingling‐like” sensation associated with an urge to move them • As a teenager, leg discomfort started to interfere with sleep onset • Recently married; leg movements at bedtime keep his wife awake • Current complains are leg discomfort at night that delay onset of sleep by at least 30 minutes and interfere with his wife’s sleep • Has not been previously diagnosed or treated for RLSYour Call
What would you recommend at this point?
1. Prescribe hypnotics at bedtime 2. Iron supplementation 3. Recommend melatonin at bedtime 4. Initiate dopaminergic agents 5. No treatment?
Your Call
Would you order a ferritin level in this patient?
1. Yes 2. No?
Your Call
Would you order an overnight sleep study
in this patient?
1. Yes 2. No?
Panel Discussion
• Should we check ferritin levels in every patient?
• At which point should we recommend iron
supplementation?
• When should we order a sleep study?
Case Study #2
Our Patient — JD
● 62‐year‐old female ● Small‐business owner ● History of anxiety and arthritis ● Exercises regularly, does not smoke ● Drinks 1 cup of coffee each morning ● Medications include daily multivitamin, ibuprofen as needed, and alprazolam as needed during the day for anxiety (average use = twice a week)JD’s RLS‐Related History
• 2003: Husband noticed her legs were restless while laying quietly in bed prior to going to sleep. Despite feeling somewhat uncomfortable in the legs, patient did not consider it a problem • 2009‐2010: Leg discomfort increased, causing difficulty falling asleep. Patient started walking around the room to get some relief, worsening her anxietyJD’s RLS‐Related Treatment History
● June 2011: Started on ropinerole 0.5 mg at 9 p.m. daily with adequate clinical response ● October 2011: Seen for follow‐up with primary care physician. Patient described earlier onset of symptoms, occurring in the late afternoon. Dosage was increased to 1 mg and timing changed to 5 p.m. with adequate response ● December 2011: Break‐through bedtime leg discomfort. Dosage increased to 1.5 mg at 5 p.m. with partial improvement ● January 2012: Early afternoon tingling sensation occurring in the arms, not improved after increasing dosage to 2 then 3 mg at 5 p.m. Leg discomfort at night feels worse than baseline symptomsYour Call
Which of the following would you choose as the next step in the management of this patient? 1. Continue to increase ropinirole dosage 2. Change the time of the medication to lunchtime 3. Add a second dose of ropinirole at noon 4. Switch to long‐acting ropinirole 5. Continue ropinirole and add another medication 6. Decrease the dosage of ropinirole?
Panel Discussion
● What may be the reason for this patient’s worsening symptoms? ● With which signs of augmentation did she present? ● Would you have treated her RLS differently during the initial 8 months? ● Would you have considered checking ferritin levels? ● What would be your next treatment option(s)?Treatment Considerations for RLS
Ana C. Krieger, MD, MPH, FCCP, FAASM Associate Professor Weill Cornell Medical College Cornell UniversityWhen to Consider Treatment
• When symptoms are severe enough based on: – Subjective sensation – Sleep disruption – Impact on social or professional performance – Changes in quality of life Garcia‐Borreguero et al. BMC Neurology. 2011;11:28.What to Consider in RLS Treatment
• Primary vs. secondary RLS • Concurrent medical problems/medications • Presence of overlapping PLMs in sleep • Severity, duration, and timing of symptoms – Circadian rhythmicity of symptoms Garcia‐Borreguero et al. BMC Neurology. 2011;11:28.Approaches to Treatment
• Consider the need for further testing – Polysomnography (REM sleep behavior disorder, PLMs) – Blood draw (hemoglobin, transferrin saturation and ferritin, vitamins B12, D, and folate) – Neurological assessment • Treat underlying conditions – Sleep apnea, hypoventilation – Diabetes mellitus, renal failure, electrolyte imbalance Garcia‐Borreguero D et al. BMC Neurology. 2011;11:28.Focused RLS Treatment Approach
• Supportive • Pharmacological GOALS • Reduce symptoms (based on IRLS score) • Improve Clinical Global Impression (CGI) scores • Improve quality of life • Improve sleep (if altered)Supportive Treatment for RLS
• Iron supplementa on ― if ferri n <45 ng/mL • Exercise, yoga • Also suggested: – Vitamin supplementation: C, D, E – Leg compression – Cold/warm packs • No clear evidence that melatonin helps Aukerman M et al. J Am Board Fam Med. 2006:19:487‐93; Innes K et al. BMC Complementary and Alternative Medicine. 2012;12;P212.Iron Supplementation
• May be used in conjunction with other treatments, including pharmacotherapy • Route: – Oral • Several weeks (low rate of transport across the intestinal wall) • GI‐related side effects (constipation) – IV • One or two doses • Potential side effects (anaphylactic/anaphylactoid reactions) MacDougall I. Kidney International. 1999;55:S61‐66.IV Iron Treatment
• Iron dextran: – Low molecular weight – fewer side effects – High molecular weight – effective, low cost, more side effects • Iron sucrose • Ferric gluconate • Ferric carboxymaltose Side effects if high molecular weight avoided <1:200,000 include dyspnea, hypotension, nausea, flushing, pruritus, anaphylaxis MacDougall I. Kidney International. 1999;55:S61‐66.IV Iron Treatment
• Ferric carboxymaltose: 1 dose, 500 mg IV • N=20, ferritin <45 ng/mL • 12/20 responders after 7 days • IRLS ↓10 points in responder group Hornyak M. Sleep Medicine. 2012;13:732‐5. (3 weeks) Hornyak M. Sleep Med. 2012;13:732‐735.IV Iron Treatment
• Randomized, placebo controlled • N= 46, off RLS therapy • IV ferric carboxymaltose: 1 dose 1000 mg = 500 mg IV 5 days apart • 45% responded, 29% remitted (IRLS ≤10) • 25% free of other RLS treatments at 24 weeks • IRLS ↓8.9 points vs. ↓4 placebo Allen R et al. Sleep Med. 2011;12::906‐13.Pharmacotherapy
• Not recommended in pregnancy • Medications can be given intermittently or daily • FDA‐approved drugs: – Dopamine agonists (oral) • Pramipexole (D2/D3 receptor agonist) • Ropinirole – Dopamine agonists (skin patch) • Rotigotine – α2δ agonists • Gabapentin enacarbilPharmacotherapy
• Off‐label (FDA approved but not for RLS): – Dopamine agonists • Levodopa – α2δ ligands* • Pregabalin • Gabapentin – Opioids* – Benzodiazepines * Useful to manage associated pain in neuropathy Aurora RN et al. SLEEP. 2012;35(8):1039‐1062.Practice Parameter with High Body of Evidence Harm/Burden Assessment Clinicians should treat patients
with RLS with pramipexole or ropinirole
Benefits clearly outweigh harms FDA Approved for RLS
Clinicians can treat patients with RLS with gabapentin enacarbil or rotigotine Uncertainty in balance between benefits and harms FDA Approved for RLS Clinicians can treat RLS patients with levodopa with dopa decarboxylase inhibitor Benefits closely balanced with harms. This is particularly true for those with intermittent RLS who use this medication sporadically Off‐label use Clinicians can treat RLS patients with cabergoline only if other recommended agents have been tried first and failed, and close clinical follow‐up is provided Benefits closely associated with harms Off‐label use Aurora RN et al. SLEEP. 2012;35(8):1039‐1062.
Recommended Medications
Pramipexole in RLS*
• Double‐blind, randomized, placebo‐controlled • N=234, 26 weeks follow‐up • IRLS scale >15, ferritin >30 ng/mL • Dosage: 0.125‐0.75 mg/day • Efficacy: – IRLS score ↓13.7 vs. 11.1 (p=0.008) – IRLS score ≤50% baseline in 59% vs. 43% (p=0.004) • Augmentation: 9% vs. 6% placebo • Side effects: nausea (15%), spasms (6%), arthralgia (5%) Hogl B. Sleep Medicine. 2011;12:351‐60. * Only trial over 12 weeks in durationPramipexole in RLS
Adjusted mean change in IRLS scores (N=321) Hogl B. Sleep Med. 2011;12:351‐360. ap<0.001bp<0.01Ropinirole in RLS
• Randomized, single/double‐blinded, placebo‐controlled • Single‐blind enrollment phase: N=202, Primary RLS, IRLS score ≥15 for 24 weeks – Mean IRLS score ↓12.8 • Dosage: 0.25‐4 mg (mean=2 mg/d) • Efficacy in double‐blind phase (N=92, 12 weeks): – IRLS score compared to single‐blind pre‐enrollment: ↓8.7 ropinirole vs. 4.6 placebo – CGI much/very much improved in 69% vs. 47% (p=0.03) – Side effects: nausea (18%), headache (11%), upper respiratory tract infection (2%) Montplaisir J et al. Mov Dis. 2006;21:1627‐35.Rotigotine in RLS
1 • Moderate to severe RLS, N=295, age 58±10 years • 2‐year, open‐label, follow‐up study: mean daily dose=3 mg • Efficacy: – 95% much/very much improved CGI – 17±9 improvement on IRLS score • Safety: 1% nausea (29%2), 2.3% fatigue • Local reaction: 16% (52%2) • Augmentation: 2.4% (2.7%2) 1. Hogl B et al. BMC Neurology. 2010;10:86; 2. Inoue Y et al. Prog Neurophsychopharm Biol Psych. 2012 [Epub ahead of print].Gabapentin Enacarbil in RLS
• Randomized, double‐blind, placebo‐controlled, 12 weeks • Primary RLS, off treatment, ferritin >20 ng/mL • n=115 (600 mg), n=113 (1200 mg) and n=97 (placebo) • Efficacy – 600 mg dose – IRLS ↓14 , CGI 73% – 1200 mg dose – IRLS ↓13, CGI 78% – Placebo – IRLS ↓10, CGI 45% • Compliance: >94% • Responders: 64% (600 mg), 58% (1200 mg), 40% (placebo) • Side effects: somnolence (22% 600 mg; 18% 1200 mg), dizziness (10% 600 mg; 24% 1200 mg) Lee D et al. J Clin Sleep Med. 2011;7;282‐92.Gabapentin Enacarbil in RLS
Lee D et al. J Clin Sleep Med. 2011;7;282‐292. Subjects Free of RLS Reprinted with permissionGabapentin in RLS
• Randomized, crossover, double‐blind study (n=24) • Dose: 600 mg to 2400 mg • Baseline: – 56% patients with pain – Excluded ferritin <20 ng/mL • Gabapentin side effects: – 26% malaise – 9% somnolence Garcia‐Borreguero et al. Neurology. 2002;59:1573‐9. *p<0.1,**p< 0.01Pregabalin in RLS
• Double‐blind, placebo‐controlled, randomized study • 12 weeks, N=98 – Excluded if ferritin <10 ng/mL • IRLS ↓12 pregabalin vs. ↓10 in placebo (p<0.005) • Mean dose: 322 mg • Side effects: unsteadiness (50%), daytime sleepiness (43%), headache (13%) Garcia‐Borreguero D et al. Neurology. 2010;74:1897‐1904.Medications Dosages
:
Medication Dose Range Half‐Life Titration Schedule Ropinirole 0.25–4 mg 6 h 4‐10 d Pramipexole 0.125–0.54 mg 8‐12 h 1‐4 d Rotigotine 1–3 mg patches 5‐7 h 7 d Gabapentin enacarbil 600 or 1200 mg 7‐9 h 5‐10 d Gabapentin 300–2700 mg 5‐7 h 3‐6 d Pregabalin 25–300 mg 10 h 3‐6 d Clonazepam 0.5–2 mg 30‐40 h 1‐3 d Garcia‐Borreguero D et al. BMC Neurology. 2011;11:28; Lee D et al. J Clin Sleep Med. 2011;7;282‐92.
Potential Side Effects
Drug Side Effects Ropinirole Nausea, low blood pressure, dizziness, headache, nasal congestion Pramipexole Nausea, low blood pressure, dizziness, headache, nasal congestion, heart failure (possible association) Rotigotine Skin irritation, nausea, low blood pressure, dizziness,headache, nasal congestion Gabapentin enacarbil Dizziness, somnolence, fatigue
Gabapentin Sleepiness, dizziness, fluid retention
Pregabalin Sleepiness, dizziness, headache, fluid retention
Clonazepam Sleepiness, dizziness, morning drug hangover
Garcia‐Borreguero D et al. BMC Neurology. 2011;11:28; Lee D et al. J Clin Sleep Med. 2011;7;282‐92; Renoux C et al. Pharmacoepidemiol Drug Saf. 2012;21:34‐41.
Monitoring Therapy
• Symptoms improvement/resolution If daytime symptoms: – Consider rotigotine patches as extended‐release dopamine agonists are not FDA approved for RLS European Restless Legs Study Group. Available at EURLSSG.ORG.Monitoring Therapy
• Side effects • Improvement in sleep/quality of life • Follow‐up visits every 6 to 12 months • Watch for augmentationAugmentation
Allen RP. Sleep Medicine. 2003;4:101‐119. Earlier onset of symptoms (≥2 hours) OR 2 of the following: 1. Intensity increase with increasing dose 2. Decreased intensity with decreasing dose 3. Shorter rest time to provoke symptoms than before treatment 4. RLS symptoms occur in previously unaffected limbs or body parts 5. Shorter duration of treatment benefit than with initial treatment 6. PLMS or PLM while awake (PLMW) occur for the first time or are worse than either before treatment of after initial treatmentAugmentation
• Associated with low ferritin1,2 • Problem with dopaminergic agents – Levodopa = 60% (up to 80% if >300 mg)3 – Pramipexole = 9%‐24%4 – Rotigotine = 13%4 – Ropinirole = 3%‐4%5; may accumulate yearly up to 20%6 1. Frauscher B et al. Sleep Med. 2009;10:611‐5; 2. Trenkwalder C et al. Sleep Med. 2008;9:572‐4; 3. Hogl B et al. J Neurol. 2010; 257:230‐7; 4. Garcia‐Borreguero et al. Eur J Neur. 2012;19:1385‐96; 5. Garcia‐Borreguero et al. Mov Dis. 2012; 27:277; 6. Silver N. et al. Sleep Med. 2011;12:440‐4.Managing Augmentation
• Differential diagnosis: – Progression of disease – Early AM rebound – Tolerance • Prevention: keep dopamine doses as low as possible • Treatment: if clinically relevant – Reduce or discontinue use of dopamine agents – Change to other drug category – Use longer‐acting drugs – Treat low ferritin Trenkwalder C et al. Sleep Med. 2008;9:572‐4.Placebo Effect in RLS Treatment
• Approximately 40% in many studies • Consider other symptoms and problems prior to selecting therapy Fulda S. Brain. 2008;131:902‐17.When to Refer to a Specialist
• Patient requires maximal recommended dose for symptom control (any meds) • Symptoms refractory to treatment – Not improved after 1 dopa and 1 non‐dopa drug • Intolerable/unusual side effects/augmentation • Children or elderly patients (>75 years)Summary
• Treatment is symptomatic and considered on an individual basis according to: – Severity of disease – Underlying medications – Co‐morbidities • In pregnant patients, only iron and folic acid supplementation are considered safeSummary II
• Medications should be carefully monitored to: – Keep the lowest effective dosage – Avoid (or quickly detect) augmentation • With the exception of rotigotine, medications should be taken just prior to patients’ usual onset of symptomsImportant Final Consideration
• Impulse control disorders with dopamine agonists: – Compulsive behavior (sexual, gambling, eating, shopping) – Associated with higher doses • In Parkinson’s disease: – Dopamine agonist withdrawal syndrome (DAWS): • Risk factor: impulse control disorder • Symptoms similar to drug addiction withdrawal – Depression, fatigue, anxiety, insomnia, irritability, panic, diaphoresis • Prevention: slow weaning of high doses • Recovery: 60% in 6 months, additional 23% in 12 months • About 15% unable to discontinue dopamine agonists Voon V et al. BMC Neurol. 2011;11:117; Edwards MJ. J Neurol Neurosurg Psych. 2012. [Epub ahead of print]; Pondal M et al. J Neurol Neurosurg Psych. 2012. [Epub ahead of print].Further Information
European RLS Study Group: www.eurlssg.org – RLS information – Symptom diary – Diagnostic algorithm (online) – Latest references – LinksCase Study #3
Our Pa ent ― TJ
• 63‐year‐old female • RLS symptoms first emerged at age 27 during third trimester of pregnancy • Resolved after delivery but re‐emerged sporadically for the next 3 decades • Exacerbation at age 59, resulting in initiation of pramipexole • Son, maternal uncle, and cousin have all been diagnosed with RLS • Relevant medical history • Disc herniation and right L5‐radiculopathy treated surgically in 1978 • C5‐C6 herniated disc repair in 1999 • Hysterectomy as a result of uterine cancer in 2008TJ’s Initial Presentation
• Current medications • Pramipexole 0.25 mg daily for RLS • Citalopram 20 mg daily for panic attacks and anxiety • Zolpidem 5 mg PRN for psychophysiological insomnia • Lansoprazole 15 mg daily for gastroesophageal reflux • Clinical exam • Patient demonstrates tolerance to pramipexole and symptom augmentation • Flexor withdrawal‐like, non‐volitional movements in her right big toe and ankle • 3+ tendon reflexes throughout • No pathological spread • Laboratory results • Iron= 56 µg/dL, ferritin=22 ng/mL, transferrin saturation=17%Your Call
What would you recommend for TJ at this point? 1. Decrease the dosage of pramiprexole to 0.125 mg daily 2. Stop the pramiprexole and initiate treatment with ropinirole 1 mg daily 3. Consider adding new medication class (eg, gabapentinoid or opioid) 4. Introduce iron supplementation and split or increase the pramipexole dose (eg, to 0.125 mg twice a day or 0.25 mg twice a day)?
Six Years Later…
Patient has tried and failed multiple treatment regimens: • Ropinerole 1 mg daily • Ropinirole 1 mg daily + carbidopa‐levodopa 25/100 PRN + oral iron supplementation • Ropinirole 3 mg daily + carbidopa‐levodopa 25/100 PRN + oral iron supplementation • Pramiprexole 0.125 mg twice daily + oral iron supplementation • Pramiprexole 0.25 mg three times daily + oral iron supplementation • Pramiprexole 0.25 mg twice daily + gabapentin enacarbil 600 mg daily + oral iron supplementationToday’s Clinical Presentation
• IRLS Group Rating Scale = 21 (out of 40) • Augmentation has largely resolved but patient sometimes has early day symptoms when she “forgets” to take her early doses of pramipexole • Patient experiences additional “breakthrough” RLS in the middle of the day even when remembering to take her medication • Patient notes improvements in sleep quality and overall RLS symptoms • Clinical exam • PLM while awake is less obvious than upon initial presentation • Diffuse hyper‐reflexia remains • Laboratory results • Iron=109 ug/dL, ferritin=78 ng/mL, transferrin saturation=39%Your Call
What would you recommend for TJ at this point? 1. Continue with the current treatment regimen until symptoms significantly worsen 2. Consider initiation of rotigotine transdermal patch to simplify medication regimen (discontinuing other RLS medications) and avoid variability in symptoms 3. Further increase dosage of pramipexole to 1.0‐1.25 mg 4. Add an additional medication class, such as an opioid?
Activity Post‐Test
1. UT, a 32‐year‐old female complaining of frequent migraines 2. PA, a 57‐year‐old male with renal failure 3. JK, a 45‐year‐old male with a recent knee replacement 4. TY, a 75‐year‐old female with multiple sclerosis 5. SS, a 24‐year‐old HIV positive maleIn which of the following patients would you
suspect a greater than average possibility of
the presence of RLS (choose all that apply)?
?
1. Pramipexole 2. Folic acid supplementation 3. Pregabalin 4. Gabapentin enacarbil 5. Ropinerole 6. Rotigotine For a pregnant 29‐year‐old patient in her third trimester who presents with severe RLS‐related symptoms, which of the following agents would best combine safety and efficacy??
1. Symptoms occurring only between the hours of 2‐5 a.m. 2. Significant worsening of symptoms with decrease in medication dosage 3. Spread of symptoms to previously unaffected areas 4. Significant improvement in symptoms with increase in medication dosageWhich of the following might lead you to
conclude that your RLS patient is suffering
from augmentation?
?
1. Fluid retention 2. Sleepiness 3. Morning drug hangover 4. Skin irritation/infection
