Hilton/Irvine Orange County Airport Irvine, California March 29, 2008

1. St Hilton/Irvine Orange County Airport Irvine, California March 29, 2008 2008 Symposia Series 1 1

2. Restless Legs Syndrome: Recent Learnings and Strategies Robert J. Werra, MD Associate Clinical Professor Department of Family and Community Medicine University of California, San Francisco San Francisco, California

3. 0 How many RLS patients have youtreated or referred in the last month? • 0-5 • 5-10 • 10-20 • >20 Use your keypad to vote now! RLS = restless legs syndrome

4. Faculty Disclosure • Dr Werra: consultant: Boehringer Ingelheim, GlaxoSmithKline; speakers bureau: Boehringer Ingelheim

5. Learning Objectives • Identify the 4 primary clinical characteristics of RLS • Design an individualized RLS management strategy based on disease severity • Counsel patients on the nonpharmacologic and pharmacologic approaches to the management of RLS • List the safety and efficacy profiles of pharmacologic agents available for the treatment of RLS

6. RLS: Definition • RLS is a neurologic disorder characterized by an uncontrollable urge to move the legs that usually is associated with unpleasant sensations • Sensations range in severity from uncomfortable to irritating to painful

7. RLS: Core Symptoms—URGE Courtesy of Philip M. Becker, MD. Allen RP, et al. Sleep Med. 2003;4:101-119; Walters AS. Mov Disord. 1995;10:634-642. Urge to move limbs, usually accompanied or caused by uncomfortable and unpleasant feelings in the limbs Rest or inactivity precipitates or worsens symptoms Getting up or moving improves the sensation Evening or nighttime appearance or worsening of symptoms

8. RLS: Prevalence 8 • Overall prevalence: 5%-15% • Lower in Asian populations • Higher in women • Up to 25% of patients in primary care have RLS symptoms • Prevalence increases linearly with age • Mean age of onset: 34  20 years • Can appear in childhood RLS Patients (n = 416) All 6 Men Women 4 Prevalence (%) 2 0 20-29 30-39 40-49 50-59 60-69 70-79 80 Age Group (years) 16,202 adults in the United States and5 European countries Allen R, et al. Arch Intern Med. 2005;165:1286-1292; Hening W, et al. Sleep Med. 2004;5:237-246; Kageyama T, et al. Psychiatry Clin Neurosci. 2000;54:296-298; Nichols D, et al. Arch Intern Med. 2003;163:2323-2329; Ondo W, Jankovic J. Neurology. 1996;47:1435; Phillips B, et al. Arch Intern Med. 2000;160:2137-2141; Ulfberg J, et al. Eur Neurol. 2001;46:17-19.

9. RLS SleepMultiMedia, Sleep Multimedia, Inc., Scarsdale, NY.

10. RLS: Underdiagnosed in Primary Care 70 64.8% Reported RLS 60 64.8% Received diagnosis 50 37.9% 40 Patients (%) 37.9% 30 24.9% 20 12.9% 24.9% 10 12.9% 0 Reported by Patients Reported by Physicians Hening W, et al. Sleep Med. 2004;5:237-246.

11. Commonly Misdiagnosed • Lack of understanding of RLS contributes to misdiagnosis • May be tendency to attribute symptoms to better-recognized conditions • Poor circulation • Arthritis • Back/spinal injury or problem • Varicose veins • Depression/anxiety • Nerve compression Allen RP, et al. Arch Intern Med. 2005;165:1286-1292.

12. 2005 Sleep in America PollCorrelates of RLS • Individuals with RLS were significantly more likely to: • Be unemployed • Be cigarette smokers • Have concomitant medical conditions: Net: At least 1 condition 61% High blood pressure 29% Arthritis 28% Heartburn or GERD 19% Depression 18% Anxiety disorder 12% Diabetes 11% Heart disease 10% Lung disease 5% None of these 39% 0% 20% 40% 60% 80% 100% GERD = gastroesophageal reflux disease. National Sleep Foundation. Sleep in America Poll. 2005. Available at: www.sleepfoundation.org; Accessed March 6, 2008.

13. Scope of the Problem

14. Burden of Illness • Discomfort and pain • Major cause of sleep disturbance • Trouble falling asleep, decreased hours of sleep • May lead to daytime fatigue/sleepiness • Poor functioning at home or job • Trouble sitting still, restless • Impaired social interactions • Feelings of frustration, anxiety, depression, embarrassment Allen R, et al. Presented at 7th Congress of the European Federation of Neurological Societies. Abstract 576; Fehnel S, et al. 7th Congress of the European Federation of Neurological Societies. Abstract 677; Hening W, et al. 7th Congress of the European Federation of Neurological Societies. Abstract 605.

15. REST General Population StudyRLS: Impact on Quality of Life vs Age- and Sex-Adjusted US Norms RLS patients 100 Age- and sex-adjusted norms for the US general population (n = 2474) 80 * * * 60 * * Mean Score * * * 40 20 0 PhysicalFunctioning RolePhysical BodilyPain GeneralHealth Energy/Vitality SocialFunctioning RoleEmotional MentalHealth SF-36 Health Survey Domain *Scores for RLS sufferer groups were significantly below the norms for all 8 dimensions. REST = RLS Epidemiology, Symptoms, and Treatment. Allen R, et al. Arch Intern Med. 2005;165:1286-1292.

16. REST General Population StudyRLS: Impact on Quality of Life Comparable to Chronic Conditions RLS Patients (n = 158)Patients in the US General Population With Type 2 diabetes mellitus (n = 541) Osteoarthritis with hypertension (n = 175) Depression (n = 502) 100 80 60 Mean Score 40 20 0 PhysicalFunctioning RolePhysical BodilyPain GeneralHealth Energy/Vitality SocialFunctioning RoleEmotional MentalHealth SF-36 Health Survey Domain Allen R, et al. Arch Intern Med. 2005;165:1286-1292.

17. 2005 Sleep in America Poll RLS: Impact on Daytime Function Drive Drowsy Participants at risk for RLS Missed Events Participants with no RLS risk Errors at Work Missed Work P <.05, at risk of RLS vsnot at risk of RLS Late to Work Fatigue 0% 20% 40% 60% 80% National Sleep Foundation. Sleep in America Poll. 2005. Available at: www.sleepfoundation.org. Accessed March 6, 2008.

18. Sleep Heart StudyRLS: Associated With CAD and CVD CAD = coronary artery disease; CVD = cardiovascular disease. Winkelman JW, et al. Neurology.2008;70:35-42.

19. Pathophysiology

20. RLS: Pathophysiology • Serendipitous finding that low doses of levodopa provide relief from RLS • Hypothesis: RLS is associated with dopaminergic (DA) dysfunction in the CNS at the subcortical level CNS = central nervous system.

21. RLS: What We Know About Its Pathophysiology PET/SPECT = positron emission tomography/single-photon emission computed tomography. Allen RP, et al. J Clin Neurophysiol. 2001;18:128-147; Bogan RK. Expert Opin Pharmacother. 2008;9:611-623; Walters AS. Sleep Med. 2002;3:301-304.

22. RLS Pathophysiology: Iron-Dopamine Model of RLS Brain: Iron Insufficiency CNS: Dopamine Abnormalities RLS Allen RP, et al. J Clin Neurophysiol. 2001;18:128-147.

23. RLS: Primary vs Secondary • Primary (idiopathic) • Accounts for most cases • Majority are hereditary (mainly autosomal dominant) • Highly significant gene associations on chromosomes 6 and 2 • Secondary causes of RLS include • Iron-deficiency anemia (~25% of patients) • Pregnancy (~20% of pregnant women) • End-stage renal disease/dialysis (up to 60%) • Medications • Diabetes • Rheumatoid arthritis • Peripheral neuropathy Bonati MT, et al. Brain. 2003;126:1485-1492; Desautels A, et al. Am J Hum Genet. 2001;69:1266-1270; Earley CJ, et al. J Neurosci Res. 2000;62:623-628; Hui DS, et al. Am J Kidney Dis. 2000;36:783-788 Lee KA, et al. J Women’s Health Gend Based Med. 2001;10:335-341; National Heart, Lung, and Blood Institute Working Group on Restless Leg Syndrome. Am Fam Physician. 2000;62:108-114; Tan EK, et al. Am J Med Sci. 2000;319:397-403.

24. Agents That May Precipitate RLS • Medications • Antihistamines • Dopamine antagonists • Lithium • Monoamine oxidase inhibitors (MAOIs) • Selective serotonin reuptake inhibitors (SSRIs) • Tricyclic antidepressants • Other • Alcohol • Caffeine • Smoking Parker KP, Rye DB. Nurs Clin North Am. 2002;37:655-673; Stiasny K, et al. Sleep Med Rev. 2002;6:253-265.

25. Diagnosis

26. 0 Which of the following is necessary to establish a diagnosis of RLS? • Brain MRI study • History and physical exam • Overnight polysomnogram (sleep study) • Serum ferritin level Use your keypad to vote now! MRI = magnetic resonance imaging

27. RLS: Assessment • Patient history is essential • Physical examination, including neurologic and vascular • Will be normal if RLS is idiopathic • Laboratory tests • CBC • Serum ferritin • Percent iron saturation • Folate • Chemistries (BUN/creatinine ratio) • FBG • A1c BUN = blood urea nitrogen; CBC = complete blood count; FBG = fasting blood glucose. Allen R, et al. Sleep Med. 2003;4:101-119; Parker KP, et al. Nurs Clin North Am. 2002;37:655-673.

28. RLS: Core Symptoms—URGE • Urge to move limbs, usually accompanied or caused by uncomfortable and unpleasant feelings in the limbs • Rest or inactivity precipitates or worsens symptoms • Getting up or moving improves the sensation • Evening or nighttime appearance or worsening of symptoms Courtesy of Philip M. Becker, MD. Allen RP, et al. Sleep Med. 2003;4:101-119; Walters AS. Mov Disord. 1995;10:634-642.

29. The Simple Question • The Sleep Research Society and American Academy of Sleep Medicine have devised the following question to determine which patients are likely to have RLS: • When you try to relax in the evening or sleep at night, do you ever have unpleasant, restless feelings in your legs that can be relieved by walking or movement? • If your patient answers, “Yes,” he or she probably has RLS Ferri R, et al. Eur J Neurol. 2007;14:1016-1021.

30. Differential Diagnosis • Periodic limb movement disorder (PLMD) • Semirhythmic leg movements during sleep • Peripheral neuropathy • More constant pain/discomfort; not usually relieved by movement • Nocturnal leg cramps • Akathisia • Excessive movement without specific sensory complaints • History of dopamine antagonist use; no nighttime worsening • Vascular disease • Varicose veins • Sleep disorders • Sleep apnea or REM behavioral disorder Earley CJ. N Engl J Med. 2003;348:2103-2109; Garcia-Borreguero D, et al. Acta Neurol Scand. 2004;109:303-317; Stiasny K, et al.Sleep Med Rev. 2002;6:253-265.

31. RLS: Primary Features • Symptom descriptions • Creepy, crawly, tingly • Painful, burning, achy • “Like worms or bugs crawling deep in leg muscle” • “Like water running under the skin” • “Like soda water in the veins” • Muscle ache or tension • Compelling urge to move • Usually affects both legs simultaneously • Can be unilateral or alternating • Arms and trunk may become involved • Many patients experience daily symptoms • Rest (sitting or lying down) provokes symptom onset • Getting up (activity) can immediately, and at least partially, relieve discomfort

32. RLS: Primary Features (cont’d) Earley CJ. N Engl J Med. 2003;348:2103-2109. • Circadian pattern to symptoms • Peak symptom severity between midnight and 4:00 AM • Often marked relief between 6:00 AM and 10:00 AM • Persists even in “unconventional” sleep/wake cycles (eg, shift work) • Frequently associated features • Involuntary limb movements while patient is awake • Periodic limb movements (PLM) while patient sleeps • Characterized by periodic episodes of repetitive/highly stereotyped limb movements; episodes of muscle contraction last from 0.5-5 seconds, interval ~20-40 seconds • Loss of restful sleep; contributes to daytime sleepiness

33. RLS: When to Refer • Consider referral to neurologist for EMG/NCV • If peripheral neuropathy is suspected • Consider referral to sleep center for polysomnography • In children • If coexisting obstructive sleep apnea or narcolepsy is suspected • If sleep disturbance continues after treatment EMG/NCV = electromyography/nerve conduction velocity studies. Earley CJ. N Engl J Med. 2003;348:2103-2109; Parker KP, et al. Nurs Clin North Am. 2002;37:655-673; Stiasny K, et al.Sleep Med Rev. 2002;6:253-265.

34. Treatment

35. RLS: Treatment Considerations • Clinical history • Patient’s age • Potential aggravators • Frequency, severity, and timing of symptoms • Comorbid conditions

36. RLS: Treatment Considerations (cont’d) • RLS severity and frequency will vary from patient to patient • Mild, moderate, severe • Intermittent, frequent, daily, refractory • Treatment often is individualized • Need to determine optimal medication or combination of medications, dosages, and nonpharmacologic treatments

37. RLS: Treatment Goals • Provide adequate restorative sleep that occurs at desirable and appropriate times • Allows relief and/or resolution of daytime symptoms (fatigue, lack of concentration, sleepiness, and depression) • Enable patients to enjoy quiet, relaxing, passive activities that have evoked symptoms (reading, watching television, attending the theater, travel by car or plane) Hening WA. Am J Med. 2007;120:522-527.

38. RLS: Treatment Strategies—Nonpharmacologic • Remove potential aggravators • Sleep deprivation • Alcohol • Exercise (too much vs too little) • Caffeine • Smoking • Consider discontinuing medications that can worsen RLS • SSRIs (eg, paroxetine, fluoxetine, sertraline) • Tricyclics (eg, amitriptyline, nortriptyline) • Dopamine antagonists (eg, clozapine, risperidone) • Antihistamines • Treat secondary causes • Iron deficiency • Renal disease Hening W, et al. Sleep. 1999;22:970-999; Hening WA. Am J Med. 2007;120:522-527; Phillips B, et al. Arch Intern Med. 2000;160:2137-2141; Stiasny K, et al.Sleep Med Rev. 2002;6:253-265.

39. RLS: Treatment Strategies—Nonpharmacologic (cont’d) • Improve sleep hygiene • Regular bedtime and wake time • Restrict bed to sleep and intimacy • Avoid perturbing activities immediately before sleep • Moderate exercise • Neither daytime inactivity nor unusual and excessive exercise • Reduced nighttime exercise • Brief walk before bedtime • Relaxation techniques • Baths (cold, warm, hot) • Leg vibration/massage • Games Parker KP, Rye DB. Nurs Clin North Am. 2002;37:655-673; Hening W, et al. Sleep. 1999;22:970-999; Hening WA. Am J Med. 2007;120:522-527; Hu J. J Tradit Chin Med. 2001;21:312-316; Rajaram SS, et al. Sleep Med. 2005;6:101-106.

40. RLS: Treatment Strategies—Symptom Severity Hening WA. Am J Med. 2007;120:522-527.

41. 0 Which agent do you most commonly prescribe for your patients with RLS? • Benzodiazapine • Gabapentin • Levodopa • Pramipexole • Ropinirole Use your keypad to vote now!

42. RLS: Treatment Strategies— Pharmacologic by Symptom Severity Hening WA. Am J Med. 2007;120:522-527.

43. RLS: Pharmacologic Therapy—Dose Ranges of Common Medications Hening WA. Am J Med. 2007;120:522-527.

44. RLS: Treatment Strategies— Pharmacologic *FDA-approved agents for treatment of RLS. GI = gastrointestinal. Earley CJ. N Engl J Med. 2003;348:2103-2109; Quilici S, et al. Sleep Med. 2008; Jan 26 [Epub]; Stiasny K, et al.Sleep Med Rev. 2002;6:253-265.

45. TREAT RLS US Ropinirole: Efficacy Mean IRLS Rating Scale Total Score at Each Visit 25 Week 12 LOCF P <.0001 20 * IRLS Rating Scale Total Score (mean) 15 Placebo (n = 193) † 10 † † † † † † † † 5 Ropinirole (n = 187) 0 Baseline Day 3 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 8 Week 10 Week 12 Time Point (OC) *P = .003. †P <.001. A decrease in score denotes improvement IRLS = International Restless Legs Syndrome; LOCF = Last observation carried forward; OC = observed case. Data on file, GlaxoSmithKline (TREAT RLS US).

46. Pramipexole: Efficacy Total IRLS Score *P <.0001 †P = .00001 Adjusted Mean Change From Baseline n = 21 n = 86 n = 114 n = 224 n = 85 n = 254 Partinen M, et al. Poster presented at Second World Congress of the World Association of Sleep Medicine. February 4-8, 2007; Oertel WH, et al. Pramipexole RLS Study Group. Mov Disord. 2007;22:213-219; Winkelman JW, et al. Neurology. 2006;67:1034-1039.

47. RLS: Treatment Strategies— Pharmacologic None of the agents presented on this slide are FDA approved for RLS. Earley CJ. N Engl J Med. 2003;348:2103-2109; Stiasny K, et al.Sleep Med Rev. 2002;6:253-265.

48. RLS: Pharmacologic Management—Clinical Considerations • Evidence-based and clinical guidelines identify dopamine agonists as a first-line treatment for RLS • Start with lowest medication dose and slowly increase to effective dose • Start dose at bedtime • If necessary, add an evening dose then tailor to patient’s symptoms • Watch for augmentation and rebound Littner M, et al. Sleep. 2004;27:557-559.

49. Augmentation and Rebound • Augmentation • Defined by a combination of earlier onset of RLS symptoms, increase of symptom severity, and involvement of other limbs • Time shift of symptoms from bedtime to early evening, then to daytime • Seen in up to 82% of patients with RLS receiving levodopa • Rebound • Wearing off of drug effect, typically in the morning • Seen in up to 25% of RLS patients receiving levodopa Allen RP, Earley CJ. J Clin Neurophysiol. 2001;18:128-147; Allen RP, Earley CJ. Sleep. 1996;19:205-213; Guilleminault C, et al. Neurology. 1993;43:445.

50. Iron-Deficiency RLS Treatment • Consider if serum ferritin <50 µg/L or iron saturation <16% • Ferrous gluconate • 325 mg + 100 mg vitamin C 1-3x/d on an empty stomach • Vitamin C improves absorption • May take significant length of time for benefit • Iron dextran (IV) is an option for patients with a proven iron deficiency • Single 1-g iron infusion Davis BJ , et al. Eur Neurol. 2000;43:70-75;Earley CJ. N Engl J Med. 2003;348:2103-2109; Earley CJ, et al. Sleep Med. 2004;5:231-235.