1. Do Treatments Address Sleep and Pain Issues in RLS William Ondo, MD

2. Pain in RLS (prevalence) 20% report “pain” 1 80% report “pain” occasionally 2 IRLS correlates with McGill pain inventory (r 2 =0.52, p<0.05) 3 Qualitatively different –Annoying, tiring, tingling, nagging IRLS does not correlate with visual analogue pain scale (r 2 =0.11, NS) 1. Ondo W. 1996, 2. Winkelmann J. 2000, 3. Bentley A. 2007

3. Pain Types in RLS Pain as part of the description within the diagnosis of primary RLS –“50% pain and 50% urge to move” Pain as a separate issue in addition to RLS –Neuropathic pain Pain as a description of learned helplessness –psychological Pain as a consequence of augmentation Pain first noticed after treatment of urge to move

4. Dopaminergic Treatments of RLS Pain usually not assessed in RLS trials No consistent evidence that dopaminergic medications have clinical analgesic properties in humans Some evidence in animal that destruction of descending dopaminergic tracts reduce pain threshold (descending inhibition) Complex interaction between dopaminergic and opioid systems Lindval O. 1983, Fleetwood Walker 1988, Hagelberg N. 2002

5. Hyperalgesia in RLS 11 patients (age 60 +/- 10 years) with 'primary' restless leg syndrome (RLS) (disease duration 18 +/- 15 years) pin-prick pain ratings abnormal in RLS (static hyperalgesia) –Day and night Gentle pressure, allodynia (dynamic mechanical hyperalgesia) was normal Stiasny-Kolster, 2004

6. Response to L-dopa for RLS Associated Hyperalgesia Single dose of L-dopa did not improve hyperalgesia 12 months later 6/11 were retested after chronic and successful therapy with dopaminergics –IRLS: 27.5 6.3 to 10.2 6.7 –L-dopa and carbergoline –Hyperalgesia improved in all 6 subjects Is this dopamine or a non-specific effect resulting from improved RLS (better sleep, etc.)

7. Gabapentin, XP13512 (Solzira), Pregabalin Used in numerous pain conditions Mechanism thought to be inhibition of the alpha 2-delta subunit of L-type voltage- regulated calcium channels –Abundant in the dorsal root ganglia –Altered Brain fMRI

8. Gabapentin RLS Patient Studies First Author (Year) Trial Design N Baseline RLS Severity Results for GBP-Treated Patients Micozkadioglu (2004) 1 RCT, OL14 * Moderate Decrease in RLS severity in all patients † Improvements in sleep quality, ‡ sleep latency, ‡ and sleep duration ‡ Happe (2003) 2 RCT, OL16 Moderate to severe Decrease in RLS severity in all patients † Reduction in PLMS † Garcia-Borreguero (2002) 3 RCT, DB, CO 22 Moderate to severe Decrease in RLS severity § and stage 1 sleep † Reduction in PLMS † and improvements in increased total sleep time, ║ sleep efficiency, ¶ and slow wave sleep † Thorp (2001) 4 RCT, DB, CO 13 * Not defined12 of 13 patients had relief of RLS symptoms # Happe (2001) 5 OL9 Moderate to severe 8 of 9 patients had relief of RLS symptoms, ** increased sleep quality, ** and decreased daytime sleepiness †† Reduction in PLMS ‡‡ Adler (1997) 6 OL8Not defined4 of 8 patients had relief of RLS symptoms * Hemodialysis patients; † p  0.05; ‡ p<0.001; § p<0.0005; ║ p=0.01; ¶ p<0.0001; # p<0.01; ** p=0.004; †† p=0.034; ‡‡ p=0.003. Abbreviations: GBP indicates gabapentin; RCT, randomized controlled trial; OL, open-label; PLMS, periodic leg movements of sleep; DB, double-blind; CO, cross-over. 1 Micozkadioglu H, et al. Ren Fail. 2004;26:393-397. 2 Happe S, et al. Neuropsychobiology. 2003;48:82-86. 3 Garcia-Borreguero D, et al. Neurology. 2002;59:1573-1579. 4 Thorp ML, et al. Am J Kidney Dis. 2001;38:104-108. 5 Happe S, et al. Neurology. 2001;57:1717-1719. 6 Adler CH. Clin Neuropharmacol. 1997;20:148-151.

9. Gabapentin prodrug, which is actively transported by MCT1 and SMVT Well absorbed throughout gastrointestinal (GI) tract Immediately releases gabapentin in blood Linear pharmacokinetics (no saturable absorption of gabapentin) Successfully formulated for sustained release (SR) 2 mg of XP13512 produces ~1 mg of gabapentin MCT1 indicates monocarboxylate transporter type 1; SMVT, sodium-dependent multivitamin transporter. OH O O O O O HNHN XP13512 - Overview

10. 2 mg of XP13512 produces ~1 mg of gabapentin. Time (h) Gabapentin Concentration (  g/mL) 06121824 0 1 2 3 4 5 6 XP13512 SR 1200 mg (n=10) Neurontin 600 mg (n=11) 2-fold increase in AUC 3-fold delay in T max Bioavailability, 75% Mean Concentrations of Gabapentin in Blood After Oral Near- Equal XP13512 SR or Neurontin  Doses in Healthy Adults AUC indicates the area under the plasma concentration-time curve; T max, time to maximum plasma concentration. XenoPort, Inc., Study XP022, data on file.

11. Pain Score From Solzira ® : Baseline to the End of Week 2 1 Allen RP, et al. Arch Intern Med. 2005;165:1286-1292. Pain is commonly associated with RLS, occurring as the most troubling symptom in 19% of patients 1 012345678910 Placebo XP13512 600 mg XP13512 1200 mg No pain Most intense pain 4.7 4.6 4.5 Pain Score at Baseline 2.2 1.3 3.1 Baseline pain score Pain Score After 2 Weeks Pain reported at baseline: 84.4% - XP13512 1200 mg group 72.4% - XP13512 600 mg group 60.6% - placebo group

12. Clinical Efficacy of Opioids Used by Willis (1685) Open label efficacy of: –Morphine, codeine, oxycodone, hydroxycodone, methadone, propoxyphene, levorphenol, hydromorphone –Meperidine not effective –More potent Mu agonists are most effective Opioids also improve PLMS Pain not usually assessed Walters 1993, Kaplan 1993

13. Sleep Abnormalities in RLS

14. REST Study: Sleep Burden Time Required for Patients to Fall Asleep* Hening et al. Sleep Med. 2004;5:237-246. With permission. 0 50 100 150 200 250 <15 mins 15–30 mins 30–60 mins 1–2 hours 2–3 hours >3 hours No answer given 8.5% 22.3% 35.9% 17.4% 7.3% 8.0% 0.5% Number of Patients 68.6% † 43.2% of patients reported excess daytime sleepiness. 8.5% stated that they had to miss work due to feelings of tiredness. *n=551 RLS patients with at least twice-weekly RLS symptoms and some or high negative impact of these symptoms on quality of life. † Indicates the range of values considered abnormal and representing insomnia.

15. REST Study: Sleep Burden Number of Times Patients Awaken per Night* Number of Patients 0 25 50 75 100 125 150 None (not woken) OnceTwice3 times 4 times >4 times No answer given 4.9% 6.9% 22.9% 24.5% 17.1% 18.5% 5.3% 60.1% † Hening et al. Sleep Med. 2004;5:237-246. With permission. *n=551 RLS patients with at least twice-weekly RLS symptoms and some or high negative impact of these symptoms on quality of life. † Indicates the range of values considered abnormal and representing insomnia.

16. Sleep Differences Between Patients With and Without RLS Women, n=16 with RLS, n=124 without RLS; men, n=181 with RLS; n=2427 without RLS. Ulfberg et al. Eur Neurol. 2001;46:17-19. Ulfberg et al. Mov Disord. 2001;16:1159-1163. )

17. Sleep Differences Between Patients With and Without RLS (cont’d) Women, n=16 with RLS, n=124 without RLS; men, n=181 with RLS; n=2427 without RLS. Ulfberg et al. Eur Neurol. 2001;46:17-19. Ulfberg et al. Mov Disord. 2001;16:1159-1163.

18. Polysomnographic Data in RLS PLMS –>80% Reduced sleep efficiency Increased awakening PLMS associated with sleep apnea in some studies Increased K-alpha complexes Sleep architecture otherwise normal Allan R. 2001, Montplaisir J. 1997, Montplaisir J. 2006

19. Effects of Exogenous Dopaminergic Stimulation on Sleep Unclear !!! Depends on: –Species –Dose –Receptor (D1 vs. D2 family) –Disease state –Time of day –Baseline arousal state

20. Dopaminergic Treatment of RLS: Effect on Sleep Most studies show subjective benefit –MOS, Pittsburg sleep inventory, etc. PSG data mixed –+/- improved sleep efficacy, decreased latency, decreased awakening –No overall change in sleep architecture –Dramatic benefit in PLMS

21. Ropinirole: Subjective change from Baseline in Domains of MOS Sleep Scale at Week 12 (LOCF) † *p<0.01 Sleep Quantity 0 1 * Mean change from baseline (hours) Sleep Disturbance Sleep Adequacy Daytime Somnolence * * * Mean change from baseline (%) † LOCF=last observation carried forward

22. Pergolide Sleep Studies (Wetter et al. Neurology 1999;52:944-950) DBPCCO, N = 28, Dur = 28 days Results: Pergolide (0.51 mg) Placebo –PLMS/hr5.754.9 –TST373 min261 min –Subjective ( 0-30 ) 2.6 (1.2)18.0 (2.8)

23. Pramipexole Sleep Results (Saletu et al. Eur Arch Psych 2002;252:185) PlaceboPramipexole (0.28 mg) Wicoxon TST 301  91377  50 0.02 Efficiency 67  2084  11 0.002 Latency 12  58888 0.08 PLMS/hr 43  4318  11 0.005 PLMA/hr 72  3944  29 0.02 Apnea/hr 6.3  4.92.8  2.3 0.01

24. Ropinirole Sleep Studies ( Saletu et al. Neuropsychobiology 2000;41:190 PlaceboRopiniroleP value PLMS/hr39.7 (20.5)10.3 (8.3)0.01 PLMS arousal65.7 (35.8)39.6 (20.5)0.01 TST326 (73)369 (41)0.05 Stage II105 (54)155 (54)0.05 Sleep efficiency73.2 (16.7)82.0 (8.7)0.05

25. PLMS After Pramipexole Montplaisir J. 1999

26. Gabapentin Drugs Effect on Sleep Increase slow wave sleep Decrease sleep latency

27. Gabapentin Effect on Sleep in RLS N=24(16f), DBCO, dose 600-2,400 (1,855 mean) Results: –RLSRS 9.5(1.4) vs. 17.9(1.4), p<0.001 –Pittsburgh Sleep 1.8(0.3) vs. 2.9(0.3), p<0.01 –PLMS 31(3) vs. 12(3), p=0.05 –TST (p<0.01), SWS (p<0.05) Garcia-Borreguero D, Neurology, 2002

28. Stage 1 Stage 2 Stage 3/4 REM * p<0.0001, ANOVA. † p=0.0179, ANOVA. ‡ p=0.0002, ANOVA. * † ‡ Placebo XP13512 Baseline XP-13512: PSG Sleep Time by Stage REM indicates rapid eye movement.

29. PLMs indicates periodic leg movements; PLMS, period leg movements of sleep; PLMA, periodic leg movements of sleep with ≥3-second arousal; PLMAW, periodic leg movements of sleep with ≥30-second awakening. PSG (8 Hours): Periodic Leg Movements 254.6 144.4 58.6 5.6 261.4 135.4 46.3 5.9 185.7* 123.8 29.4 † 3.8 ‡ 0 50 100 150 200 250 300 Total PLMsPLMSPLMAPLMAW Type of PLM Number of PLMs Baseline Placebo XP13512 *p=0.0334, ANOVA † p=0.0082, ANOVA ‡ p=0.0172, ANOVA 31.832.723.222.320.717.49.27.44.30.91.00.6 PLM Index 

30. ANOVA indicates analysis of variance. PSG analysis by Tom Roth, PhD, Sleep Disorders Center, Henry Ford Hospital, Detroit, Michigan, and staff. Baseline (N=34) PlaceboXP13512 p Value (ANOVA) Sleep efficiency, % 81.9 81.8 87.1 0.0309 Number of awakenings 8.0 8.5 6.0<0.0001 Number of entries to stage 1 20.6 22.4 16.5<0.0001 Total sleep time, min393.2392.6417.7 0.0317 XP-13512: PSG Sleep Measures

31. Opioid Treatment of RLS: Effects on Sleep Few controlled trials –Improved PLMS (oxycodone) Not propoxyphene –Reduced awakenings –Improved sleep efficacy –Increased sleep apneas Kavey, N. 1988, Walters A. 1993

32. Opioid: Controlled Trials Walters: DBPCCT, N=11, 2 wks Oxycodone (mean dose 15.9 mg) Subjective scales: –leg sensation (p<0.009) –motor restlessness (p<0.006) –10/11 preferred oxycodone PLMS: (p<0.004) PLMS arousals: (p<0.009)

33. Benzodiazepines Used as sleep aides Reduce sleep latency Modestly increase TST –Mostly increase Stage I and II sleep Reduce PLMS –Possibly less in RLS / PLMS Doghramji K. 1991

34. Clonazepam: RLS Controlled Trials Montagna, DBPCCT, N=6, 1wk –improved subjective sleep, dysesthesia –5/6 preferred drug –PLMS unchanged Boghen, DBPCCT, N=6, 4 wks –No significant subject changes –No change in polysomnogram Saletu., DBCO, N=10, single nights –Improved sleep efficiency –No change in PLMS

35. Conclusions Medications usually help pain –Dopaminergics may be less effective for pain Medications usually help sleep –Sleep improvement may be delayed after RLS improves –Gabapentin drugs may improve SWS –Dopaminergics most robustly improve PLMS

36. Thank You William Ondo, MD