Transcript 73737373 - Restless Legs Syndrome Foundation

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; †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.
*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
30191
37750
0.02
Efficiency
6720
8411
0.002
Latency
125
88
0.08
PLMS/hr
4343
1811
0.005
PLMA/hr
7239
4429
0.02
Apnea/hr
6.34.9
2.82.3
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