1. John Winkelman, MD, PhD Medical Director, Sleep Health Center Brigham and Women's Hospital Harvard Medical School Boston, Massachusetts Past, Present, and Future of Scientific Research in Restless Legs Syndrome: What has been done, what should be done and how do we make up the difference Section VII. The Science Behind the Treatments Used in RLS Discussant

2. Substantial recent progress in RLS treatment research Of 36 placebo-controlled treatment trials in RLS, two-thirds have been done since 2000 Temporal patterns: –80’s-90’s: benzodiazepines, anticonvulsants –90’s-00’s: dopaminergics –10’s: ??

3. RLS treatments RLS treatments are generally –very effective –have low side effect burden –have low stigma

4. RLS treatments are very effective Parameter No. of studiesNo. of SubjectsEffect size [95% CI] ES ratio IRLS 1411662.62 [2.27–2.97]*0.56 Other RLS Scores: Parallel group trials 53681.48 [0.98–1.99]*0.52 Cross-over trials 71021.57 [0.94–2.21]*0.16 Quality of Life 77250.83 [0.58–1.09]*0.60 Daytime Sleepiness 1313550.63 [0.46–0.80]*0.57 Sleep Quality 1211300.84 [0.63–1.04]*0.32 Total Sleep Time 5850.37 [0.25–0.49]0.65 Sleep Duration 78060.35 [0.23–0.47]*0.37 PLMS index 144450.88 [0.71–1.06]*0.13 Sleep Efficiency 6960.37 [0.26–0.49]0.19 Fulda and Wetter, 2008

5. RLS treatments are very effective globally Parameter No. of studiesNo. of SubjectsEffect size [95% CI] ES ratio IRLS 1411662.62 [2.27–2.97]*0.56 Other RLS Scores: Parallel group trials 53681.48 [0.98–1.99]*0.52 Cross-over trials 71021.57 [0.94–2.21]*0.16 Fulda and Wetter, 2008

6. RLS treatments are fairly effective for subjective sleep measures Parameter No. of studiesNo. of SubjectsEffect size [95% CI] ES ratio Sleep Quality 1211300.84 [0.63–1.04]*0.32 Sleep Duration 78060.35 [0.23–0.47]*0.37 Fulda and Wetter, 2008

7. RLS treatments are very effective for PLMS but not sleep architecture Parameter No. of studiesNo. of SubjectsEffect size [95% CI] ES ratio Total Sleep Time 5850.37 [0.25–0.49]0.65 PLMS index 144450.88 [0.71–1.06]*0.13 Sleep Efficiency 6960.37 [0.26–0.49]0.19 Fulda and Wetter, 2008

8. What are the problems and how can we do better? Outcomes Drug development and testing Individualized treatment Special populations

9. Hening et al. Sleep Med 2004:5;237-46. 15.8 6 9.3 11.1 10.2 11.8 21.4 27 43.4 051015202530354045 Daytime sleepiness Twitching / or jerks of the legs Inability to get comfortable Exhaustion/fatigue Inability to stay still/urge to move Pain Uncomfortable feelings in the legs Sleep-related symptoms Patients (%) No symptoms indicated What are the most important outcomes in RLS?

10. Outcome problems in RLS RLS treatments do well for global reductions in RLS and sleep quality, but not so well for improving sleep duration or objectively recorded sleep (what are we missing?) Little emphasis on mood or daytime functioning in RLS Interactions between these “correlates” (sleep, mood) and global RLS severity needs to be better understood

11. Long term outcomes in RLS Clinicians have become “addicted” to the predictable, rapid, and nearly complete response seen in our patients with DA Increasing concern in RLS community that dopaminergic agents are “addictive”: –create a need for medication at times you didn’t beforehand (augmentation) –increasing doses (tolerance) –Rebound symptoms (withdrawal)

12. Outcomes to be employed in future studies with DA agents Assess DA, placebo and active comparator rates of augmentation over long-term (>12 months) Assess rate of dose escalation (tolerance) Incorporate assessment of rebound RLS into trials

13. Drug development in RLS Most treatment advances from serendipity (dopaminergics, opioids, anticonvulsants) Some treatments from clinical observation of secondary RLS (Iron) However, no treatment (yet) has derived from an understanding of the pathophysiology of RLS (“translational”)

14. Impediments to translational developments Fundamentally, there is not an understanding of the pathophysiology of RLS No high throughput assay to assess early drug candidates in Phase I and II trials –No animal model for RLS –Unclear association of endophenotypes (eg PLMS) to RLS

15. Dopaminergic agents Are there specific DA receptors which are more likely to produce benefit, AEs, augmentation? Is continuous dopaminergic stimulation helpful or harmful increase risk of augmentation? What are the predictors of augmentation (eg dose, pharmacogenetics)? Are there dopaminergic/opioid agents which produce better benefits, short and long-term? Is elimination of PLMS necessary for optimal treatment of RLS? Does addition of hypnotic agent lead to better treatment of RLS?

16. Specific questions for drug development/treatment Are there specific DA receptors which are more likely to produce benefit, reduce AEs, augmentation? –Dramatic reduction of tardive dyskinesia with atypical antipsychotics Can we identify predictors of augmentation (eg dose, pharmacogenetics)? Does continuous dopaminergic stimulation increase/decrease risk of augmentation?

17. Specific questions for drug development/treatment Are there dopaminergic+opioid agents which produce better benefits, short and long-term? Can we modify circadian or arousal systems through melatonin or hypocretin/orexin? Is elimination of PLMS necessary for optimal treatment of RLS? Does addition of hypnotic agent lead to better treatment of RLS?

18. Placebo effect has hampered Phase II and III development of RLS treatments Need to manage placebo effect better so as to limit size of trials –Placebo run-in –Shorter trials –Crossover trial –Real time measures of RLS severity

19. Individualized and subgroup treatment of RLS Most clinical trials have addressed moderate to severe primary RLS with single agents compared to placebo We have been spoiled by the success of our treatments (70-80% response rates) As RLS treatment matures, predictors of RLS treatment success and specialized treatment groups will play a larger role in clinical trials and practice

20. Individualized treatment of RLS Individualized treatment already exists for “secondary” RLS –Low ferritin PO iron –Neuropathy + RLS anticonvulsant –ESRD + RLS kidney tx Can this be expanded? –CNS iron contentIV iron – Predictors of augmentationnon- dopaminergic treatment

21. Treatment of special RLS cohorts Secondary RLS Refractory RLS Intermittent RLS “Comorbid” RLS: eg with neuropathic pain, depression, sleep apnea

23. Developmental perspective RLS treatment has developed substantially in the last 20 years It is no longer in its infancy, but it is clearly not a mature field We have been spoiled by early success Harder questions and more complex tasks await us