Fighting the URGE: Optimizing the Treatment of Restless Leg Syndrome

Transcription

1 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

2 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 Management; and Tina Chiu, MED, Project Manager, have no financial relationships to disclose. Session 6

3 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): 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): Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med. 2005;165(11): 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: 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: Byrne R, Sinha S, Chaudhuri KR. Restless legs syndrome: diagnosis and review of management options. Neuropsychiatr Dis Treat. 2006;2: Earley CJ, Silber MH. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med. 2010;11(9): Gamaldo CE, Earley CJ. Restless legs syndrome: a clinical update. CHEST. 2006;130: 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): 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): Scholz H, Trenkwalder C, Kohnen R, et al. Dopamine agonists for restless legs syndrome. Cochrane Database Syst Rev. 2011(3):CD Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless legs syndrome. Mayo Clin Proc. 2004;79: Session 6

4 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. Pharmacologics Within This Presentation 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 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 life Please indicate the number of patients you see each week with RLS >30 Activity Pre Test 1

5 In which of the following patients would you suspect a greater than average possibility of the presence of RLS (choose all that apply) 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 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. Pramipexole 2. Folic acid supplementation 3. Pregabalin 4. Gabapentin enacarbil 5. Ropinerole 6. Rotigotine Which of the following might lead you to conclude that your RLS patient is suffering from augmentation In an RLS patient being treated with rotigotine, which of the following potential side effects would you be most concerned about 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 dosage 1. Fluid retention 2. Sleepiness 3. Morning drug hangover 4. Skin irritation/infection What We ll Cover 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 genetics 2

6 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: ) Panic disorder (OR=12.9, range: ) Higher cross sectional rates of cardiovascular problems Hypertension (OR=1.5, range: ) Heart disease (OR=2.5, range: ) 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. Arch Intern Med. 2005;165: ; 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: IRLSSG=International RLS Study Group Allen RP et al. Sleep Med. 2003;4: 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% 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 <20%: pins & needles ; pulling ; tugging ; asleep ; numbness ; itching ; burning Rye DW et al. Unpublished data. 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%) 5-10% 11.3% % 18.3%(F) % 11.3% 7.9% 5% 3.6% 3.5% 0% 2.0% 0.2% % % Allen RP et al. Sleep Med. 2003;4: RLS prevalence is high and influenced by ethnicity Allen RP et al. Arch Intern Med. 2005;165: ; 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): ; Cho SJ et al. Sleep. 2009;32(8): ; Benediktsdottir B et al. Sleep Med. 2010;11(10):1043; Lavigne GJ et al. Sleep. 1994;17(8):739. 3

7 Condition Blood donation RLS Expressivity is Also Affected by the Environment (ie, Other Medical Conditions) Prevalence of RLS 25% (women) 15% (men) Iron deficiency (without anemia) ~40% Pregnancy (esp. 3 rd trimester) 26% Renal failure/hemodialysis 50% (African Americans) 70% (Caucasians) 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 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: ; Kutner NG et al. Sleep Med. 2002;3: 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 (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 Periodic Limb Movement (PLM) and RLS Are Often, But Not Always, Overlapping Conditions Parkinson s disease 11% 24% Spinocerebellar ataxias (SCA 3) 45% Multiple sclerosis 33% Myelopathy ~40% RLS PLMs Peralta CM et al. Mov Disord. 2009;24(14): ; Verbaan D et al. Mov Disord. 2010;25(13): ; 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. Scofield H et al. Sleep. 2008:31(9): ; Trotti LM et al. Sleep Med. 2009;10: ; Chervin RD et al. Am J Respir Crit Care Med. 2001;164: Iron 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 PLMI = Periodic Limb Movement Index Trotti LM et al. Sleep Medicine. 2009;10: 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:

8 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 ug/dl = 20% Of whom only 1 in 6 are anemic 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 Personal observations on 360 consecutive RLS referrals. Unpublished data. Winkelmann J et al. Mov Disord. 2007;22(Suppl 18):S449; Trotti L et al. Curr Neurol Neurosci Rep. 2008;8:281. Our Pa ent CC Case Study #1 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 present CC 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 RLS Your 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 5

9 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 : Leg discomfort increased, causing difficulty falling asleep. Patient started walking around the room to get some relief, worsening her anxiety 6

10 JD 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 symptoms Your 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 University When 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 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. Garcia Borreguero et al. BMC Neurology. 2011;11:28. 7

11 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 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) 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. MacDougall I. Kidney International. 1999;55:S 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:S 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 (3 weeks) Hornyak M. Sleep Medicine. 2012;13: Hornyak M. Sleep Med. 2012;13:

12 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 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 α 2 δ agonists Gabapentin enacarbil Allen R et al. Sleep Med. 2011;12:: Pharmacotherapy Off label (FDA approved but not for RLS): Dopamine agonists Levodopa α 2 δ ligands* Pregabalin Gabapentin Opioids* Benzodiazepines * Useful to manage associated pain in neuropathy Aurora RN et al. SLEEP. 2012;35(8): Recommended Medications Practice Parameter with High Body of Evidence Clinicians should treat patients with RLS with pramipexole or ropinirole Clinicians can treat patients with RLS with gabapentin enacarbil or rotigotine Clinicians can treat RLS patients with levodopa with dopa decarboxylase inhibitor 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 Harm/Burden Assessment Benefits clearly outweigh harms FDA Approved for RLS Uncertainty in balance between benefits and harms FDA Approved for RLS Benefits closely balanced with harms. This is particularly true for those with intermittent RLS who use this medication sporadically Off label use Benefits closely associated with harms Off label use Aurora RN et al. SLEEP. 2012;35(8): Pramipexole in RLS* Double blind, randomized, placebo controlled N=234, 26 weeks follow up IRLS scale >15, ferritin >30 ng/ml Dosage: mg/day Efficacy: IRLS score 13.7 vs (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%) Pramipexole in RLS Adjusted mean change in IRLS scores (N=321) a p<0.001 b p<0.01 * Only trial over 12 weeks in duration Hogl B. Sleep Medicine. 2011;12: Hogl B. Sleep Med. 2011;12:

13 Ropinirole 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: 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: 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 [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; Gabapentin Enacarbil in RLS Subjects Free of RLS Reprinted with permission Lee D et al. J Clin Sleep Med. 2011;7; Gabapentin 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 *p<0.1,**p< 0.01 Garcia Borreguero et al. Neurology. 2002;59: Pregabalin 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:

14 Medications Dosages Medication Dose Range Half Life Titration : Schedule Ropinirole mg 6 h 4 10 d Pramipexole mg 8 12 h 1 4 d Rotigotine 1 3 mg patches 5 7 h 7 d Gabapentin 600 or 1200 mg 7 9 h 5 10 d enacarbil Gabapentin mg 5 7 h 3 6 d Pregabalin mg 10 h 3 6 d Clonazepam mg h 1 3 d Garcia Borreguero D et al. BMC Neurology. 2011;11:28; Lee D et al. J Clin Sleep Med. 2011;7; Ropinirole Pramipexole Rotigotine Drug Gabapentin enacarbil Gabapentin Pregabalin Clonazepam Potential Side Effects Side Effects Nausea, low blood pressure, dizziness, headache, nasal congestion Nausea, low blood pressure, dizziness, headache, nasal congestion, heart failure (possible association) Skin irritation, nausea, low blood pressure, dizziness, headache, nasal congestion Dizziness, somnolence, fatigue Sleepiness, dizziness, fluid retention Sleepiness, dizziness, headache, fluid retention 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: Monitoring Therapy Symptoms improvement/resolution Monitoring Therapy Side effects Improvement in sleep/quality of life Follow up visits every 6 to 12 months Watch for augmentation 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. Augmentation 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 treatment Allen RP. Sleep Medicine. 2003;4: Augmentation Associated with low ferritin 1,2 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: ; 5. Garcia Borreguero et al. Mov Dis. 2012; 27:277; 6. Silver N. et al. Sleep Med. 2011;12:

15 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: Placebo Effect in RLS Treatment Approximately 40% in many studies Consider other symptoms and problems prior to selecting therapy Fulda S. Brain. 2008;131: 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 safe Summary 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 symptoms Important 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 [Epub ahead of print]; Pondal M et al. J Neurol Neurosurg Psych [Epub ahead of print]. 12

16 Further Information European RLS Study Group: RLS information Symptom diary Diagnostic algorithm (online) Latest references Links Case 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 2008 TJ 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 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 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 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 supplementation 13

17 Today 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 mg 4. Add an additional medication class, such as an opioid Activity Post Test In which of the following patients would you suspect a greater than average possibility of the presence of RLS (choose all that apply) 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 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. Pramipexole 2. Folic acid supplementation 3. Pregabalin 4. Gabapentin enacarbil 5. Ropinerole 6. Rotigotine Which of the following might lead you to conclude that your RLS patient is suffering from augmentation 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 dosage 14

18 In an RLS patient being treated with rotigotine, which of the following potential side effects would you be most concerned about 1. Fluid retention 2. Sleepiness 3. Morning drug hangover 4. Skin irritation/infection Questions & Answers 15