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Do Treatments Address Sleep and Pain Issues in RLS William Ondo, MD Pain in RLS (prevalence) • 20% report “pain” 1 • 80% report “pain” occasionally 2 • IRLS correlates with McGill pain inventory (r2=0.52, p<0.05) 3 • Qualitatively different – Annoying, tiring, tingling, nagging • IRLS does not correlate with visual analogue pain scale (r2=0.11, NS) 1. Ondo W. 1996, 2. Winkelmann J. 2000, 3. Bentley A. 2007 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 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 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 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.) Gabapentin, XP13512 (Solzira), Pregabalin • Used in numerous pain conditions • Mechanism thought to be inhibition of the alpha 2-delta subunit of L-type voltageregulated calcium channels – Abundant in the dorsal root ganglia – Altered Brain fMRI Gabapentin RLS Patient Studies First Author (Year) Trial Design N Baseline Results for GBP-Treated Patients RLS Severity Decrease in RLS severity in all patients† Improvements in sleep quality,‡ sleep latency,‡ and sleep duration‡ Decrease in RLS severity in all patients† Reduction in PLMS† Micozkadioglu (2004)1 RCT, OL 14* Moderate Happe (2003)2 RCT, OL 16 Moderate to severe 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, 13* CO Not defined 12 of 13 patients had relief of RLS symptoms# Happe (2001)5 OL 9 Moderate to severe Adler (1997)6 OL 8 Not defined 8 of 9 patients had relief of RLS symptoms,** increased sleep quality,** and decreased daytime sleepiness†† Reduction in PLMS‡‡ 4 of 8 patients had relief of RLS symptoms patients; †p0.05; ‡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. *Hemodialysis 1Micozkadioglu H, et al. Ren Fail. 2004;26:393-397. 2Happe S, et al. Neuropsychobiology. 2003;48:82-86. 3Garcia-Borreguero D, et al. Neurology. 2002;59:1573-1579. 4Thorp ML, et al. Am J Kidney Dis. 2001;38:104-108. 5Happe S, et al. Neurology. 2001;57:1717-1719. 6Adler CH. Clin Neuropharmacol. 1997;20:148-151. XP13512 - Overview • Gabapentin prodrug, O H N O O which is actively transported by MCT1 and SMVT O O • 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 Mean Concentrations of Gabapentin in Blood After Oral NearEqual XP13512 SR or Neurontin Doses in Healthy Adults Gabapentin Concentration (g/mL) 6 Neurontin 600 mg (n=11) 5 XP13512 SR 1200 mg (n=10) • 2-fold increase in AUC • 3-fold delay in Tmax • Bioavailability, 75% 4 3 2 1 0 0 6 12 18 24 Time (h) 2 mg of XP13512 produces ~1 mg of gabapentin. AUC indicates the area under the plasma concentration-time curve; Tmax, time to maximum plasma concentration. XenoPort, Inc., Study XP022, data on file. Pain Score From Solzira®: Baseline to the End of Week 2 3.1 Placebo 4.6 Pain reported at baseline: • 84.4% - XP13512 1200 mg group 4.7 2.2 XP13512 600 mg 0 No pain 1 • 60.6% - placebo group 4.5 1.3 XP13512 1200 mg • 72.4% - XP13512 600 mg group 2 3 4 5 Baseline pain score 6 7 8 9 Pain Score After at Baseline 2 Weeks • Pain is commonly associated with RLS, occurring as the most troubling symptom in 19% of patients1 1Allen RP, et al. Arch Intern Med. 2005;165:1286-1292. 10 Most intense pain 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 Sleep Abnormalities in RLS REST Study: Sleep Burden Time Required for Patients to Fall Asleep* 68.6%† Number of Patients 250 35.9% 200 150 22.3% 17.4% 100 8.5% 7.3% 50 8.0% 0.5% 0 <15 mins 15–30 mins 30–60 mins 1–2 hours 2–3 hours >3 No answer hours given 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. Hening et al. Sleep Med. 2004;5:237-246. With permission. REST Study: Sleep Burden Number of Times Patients Awaken per Night* 60.1%† 150 24.5% 22.9% Number of Patients 125 17.1% 100 18.5% 75 50 6.9% 5.3% 4.9% 25 0 None Once (not woken) Twice 3 times 4 times >4 No answer times given * 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. Hening et al. Sleep Med. 2004;5:237-246. With permission. ) Sleep Differences Between Patients With and Without RLS Multivariate Odds Ratio for Difference Between Patients With/Without RLS 4.7; CI 1.5-14.8 3.8; CI 2.8-5.3 Not Refreshed at Awakening 5; CI 1.5-15.9 Disturbed Sleep 3.1; CI 2.2-4.4 3.7; CI 1.0-12.9 3; CI 2.1-4.3 Problems Maintaining Sleep Women Men 2.6; CI 0.8-8.1 3.2; CI 2.3-4.6 Problems Initiating Sleep 0 1 2 3 4 5 6 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. Sleep Differences Between Patients With and Without RLS (cont’d) Multivariate Odds Ratio for Difference Between Patients With/Without RLS >10 on Epworth Scale 2.9; CI 0.9-9.0 1.6; CI 1.1-2.3 Daytime Headache 4.8; CI 1.4-16.0 2.8; CI 1,8-4.2 Women Men 5.3; CI 1.3-21.6 Social Isolation 2.6; CI 1.6-4.2 9.4; CI 1.9-45.7 Sleepiness 3.0; CI 1.9-4.5 0 2 4 6 8 10 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. 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 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 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 Pergolide Sleep Studies (Wetter et al. Neurology 1999;52:944-950) • DBPCCO, N = 28, Dur = 28 days • Results: Pergolide (0.51 mg) Placebo – PLMS/hr 5.7 54.9 – TST 373 min 261 min – Subjective (0-30) 2.6 (1.2) 18.0 (2.8) Pramipexole Sleep Results (Saletu et al. Eur Arch Psych 2002;252:185) Placebo Pramipexole Wicoxon (0.28 mg) TST 30191 37750 0.02 Efficiency 6720 8411 0.002 Latency 125 88 0.08 PLMS/hr 4343 1811 0.005 PLMA/hr 7239 4429 0.02 Apnea/hr 6.34.9 2.82.3 0.01 Ropinirole Sleep Studies (Saletu et al. Neuropsychobiology 2000;41:190 Placebo Ropinirole P value PLMS/hr 39.7 (20.5) 10.3 (8.3) 0.01 PLMS arousal 65.7 (35.8) 39.6 (20.5) 0.01 TST 326 (73) 369 (41) 0.05 Stage II 105 (54) 155 (54) 0.05 Sleep efficiency 73.2 (16.7) 82.0 (8.7) 0.05 PLMS After Pramipexole Montplaisir J. 1999 Gabapentin Drugs Effect on Sleep • Increase slow wave sleep • Decrease sleep latency 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 XP-13512: PSG Sleep Time by Stage Baseline 45.6 214.3 56.0 77.2 Placebo 46.0 209.6 57.4 79.6 XP13512 35.9 228.2 0 50 100 150 78.7 200 250 Minutes *p<0.0001, ANOVA. †p=0.0179, ANOVA. ‡p=0.0002, ANOVA. REM indicates rapid eye movement. 300 Stage 1* † Stage 2 ‡ Stage 3/4 REM 74.9 350 400 450 PSG (8 Hours): Periodic Leg Movements 300 Baseline Placebo XP13512 254.6 261.4 Number of PLMs 250 200 185.7* 144.4 150 *p=0.0334, ANOVA †p=0.0082, ANOVA ‡p=0.0172, ANOVA 135.4 123.8 100 58.6 46.3 50 29.4† 5.6 PLM Index 0 31.8 32.7 23.2 Total PLMs 22.3 20.7 17.4 9.2 PLMS 7.4 4.3 PLMA 0.9 5.9 3.8‡ 1.0 0.6 PLMAW Type of PLM 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. XP-13512: PSG Sleep Measures Sleep efficiency, % Number of awakenings Number of entries to stage 1 Total sleep time, min Baseline (N=34) Placebo XP13512 p Value (ANOVA) 81.9 81.8 87.1 0.0309 8.0 8.5 6.0 <0.0001 20.6 22.4 16.5 <0.0001 393.2 392.6 417.7 0.0317 ANOVA indicates analysis of variance. PSG analysis by Tom Roth, PhD, Sleep Disorders Center, Henry Ford Hospital, Detroit, Michigan, and staff. 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 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 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 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 Thank You William Ondo, MD