Transcript 73737373 - Restless Legs Syndrome Foundation

RLS: The role of Opioids and
Alpha-2-delta Systems in RLS
William Ondo, MD
Alpha-2-delta Systems
•Gabapentin and XP13512
(Solzira) effective in RLS
Gabapentin and XP13512 (Solzira)
• 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 evoked changes in functional activity in nociceptive
regions in the brain of the anaesthetized rat: an fMRI study
R J M Governo, P G Morris, C A Marsden and V Chapman
• Methods: Changes in blood oxygen level dependent (BOLD)
haemodynamic signal following intravenous infusion of GBP
(equivalent to 30 mg kg-1 p.o., followed by 100 mg kg-1 p.o.),
compared to saline control, were studied in isofluorane anaesthetized
rats (n=8 per group).
• Results:
– Significant (P<0.001) increases in BOLD signal intensity in several brain
regions, including the thalamus and periaqueductal grey (PAG).
– Significant (P<0.001) decreases in BOLD signal intensity in the amygdala and
the entorhinal cortex.
• Conclusions: The activation of key areas involved in nociceptive
processing indicate a supraspinal site of action of GBP and this may
contribute to its well-described analgesic effects in animal models of
pain and clinical studies.
Opioids in RLS
• Background
• Clinical Response
– Opioid antagonist
– Opioid / Dopamine interactions
• Opioid Imaging
• RLS CNS Opioid Pathology
CNS Opioid Systems
• Opioid receptors all activated by neuropeptides:
– enkephalins, dynorphans, endorphin
• Diffuse distribution throughout CNS
– Highest peptide staining in thalamus
– Important receptor density in thalamus, hypothalamus,
peri-aqueductal grey, spinal cord (laminae I and II of
dorsal horn)
• Analgesia highest in periaqueductal grey matter and
rostral ventromedial medulla
– Descending inhibitory pathways
Mathews 1996
Opioid Receptor Types
Endogenous
Function
Other effects
Action
Spine
Thalamus
Cortex
Mu
enkephalin,
endorphine
Pain, reword
mechanisms,
dyskinesia
Respiratory
depression,
constipation
Opens
K+
channels
70
60
30
Delta
enkephalin,
endorphine
Pain, anxiety,
depression
Respiratory
stimulation
Opens
K+
channels
24
30
40
Kappa
dynorphin
psychotrophic
Opens
Ca++
channels
6
10
30
Clinical Efficacy of Opioids
• Used by Willis (1685)
• Open label efficacy of:
– Morphine, codeine, oxycodone, hydroxycodone,
methadone, propoxyphene, levorphenol,
hydromorphone
– Meperidine not effective
• Controlled trial efficacy:
– Oxycodone, propoxyphene
• Opioids also improve PLMS
Walters 1993, Kaplan 1993
Comparative Efficacy of Opioids
• Retrospective review:
– Levophanal>hydromorphone>hydrocodone>
propoxyphene
• Mu opioid agonist probably most potent
Becker. Sleep 2001;24(supple1)
Effects of Opioid Antagonist
• Naloxone had little effect on drug naive RLS
subjects (sensory or PLM) 1,2,3
• Naloxone immediately reverses beneficial
effects of opioids in opioid treated patients
(sensory and PLMS)
1. Walters 1986, 2. Hening 1986, 3. Winkelmann 2001
Dopamine Interactions
• Dopamine antagonists result in:
– Delayed and modest worsening of RLS in drug naïve
patients
– More acute and marked worsening in dopamine agonist
treated patients (no published data)
Winkelmann 2001, Akpinar 1987
Opioid / Dopamine Interactions
• Naloxone does not reduce dopamine agonist efficacy
• Dopamine antagonists (pimozide) does reduce opioid
efficacy (sensory and PLMS)
• Therefore opioids may work through dopaminergic
pathways
– Mu opioid receptors on dopamine receptors potentiate the
dopamine receptors
– Mu agonists increase dopamine release in nuc accumens
Akpinar1987, Montplaisir 1991, Hagelberg 2004, Di Chiara 1988
Opioid Treatment Summary
• Effective as monotherapy and adjunctive
therapy (DA)
– Mu agonists possibly more effective
• Dependency, tolerance and addiction not
usually a problem
• Effective in secondary RLS
– uremic, neuropathic
• May work via D2/D3 receptors
[11C]diprenorphine PET Study
(von Spiczak et al. Brain 2005;128:906-917)
• [11C]diprenorphine
– Non-specific opioid receptor ligand
– Mu, Kappa, Delta
• Decreased binding suggests increased endogenous
opioid activity or internalization or down regulation
of receptors
• Binding Decreased:
– Rheumatoid arthritis, trigeminal neuralgia, post-Stroke
pain,
– Striatum: Huntington’s chorea, PD dyskinesia
Opioid Receptor Ligands
Henriksen, G. et al. Brain 2008 131:1171-1196; doi:10.1093/brain/awm255
Methods
• 15 with idiopathic RLS and 12 age
matched controls
– Demographics, IRLS, McGill pain
questionnaire, PSG, NCV/EMG
• Scans done during day
• Patients off RLS medications for 48 hours
– No opioid treatment
Patient Demographics
Sex
Age
Onset
Duration
Fam. Hx.
Medications
F
24
14
10
+
–
M
64
7
57
+
Pergolide 2 mg
M
62
47
15
+
Cabergoline 3 mg
F
47
42
5
–
–
F
23
16
7
–
L-Dopa on demand
F
34
24
10
+
–
F
63
40
23
+
Pergolide 0.5 mg
M
62
26
36
+
–
F
49
35
14
+
–
M
43
23
20
+
–
F
53
23
30
+
L-Dopa 100 mg + L-dopa retard 100 mg
F
30
28
2
+
–
F
49
45
4
+
–
M
25
5
20
+
–
F
67
45
22
+
L-Dopa 100 mg + L-dopa retard 100 mg
45.2 ± 15.8
29 ± 13.9 18.3 ± 14.5
Results
• No difference between RLS patients and
controls
• Within the RLS groups some areas
correlated with severity of RLS
symptoms (IRLS)
• Some areas correlated with severity of
McGill pain survey
Localized clusters of significant negative correlations between
[11C]diprenorphine uptake ratios (n = 15) and RLS severity (IRLS) at
P < 0.05 uncorrected threshold, cluster extent of 50 voxels
von Spiczak, S. et al. Brain 2005 128:906-917; doi:10.1093/brain/awh441
Effect sizes for correlations between [11C]diprenorphine
uptake (Vd) and RLS severity (IRLS scores)
Conclusion
• RLS inversely correlated (increased endogenous release or
receptor down regulation) with binding in the medial
“affective” pain system
– Projects to frontal and insular cortex, anterior cingulate gyrus
– Role in affective and motivational aspects of pain
– Higher opioid receptor levels than lateral pain system
• Lateral system = sensory discriminative
• Projects to primary sensory cortex
Jones AK, 1991
Afferent Pain System
ACC, anterior cingulate cortex; CL, centrolateral nucleus; MDvc, ventrocaudal part of medial
dorsal nucleus; Pf, parafascicular nucleus; SI, primary somatosensory cortex; SII, secondary
somatosensory cortex; VMpo, posterior part of ventromedial nucleus; VPI, ventral posterior inferior
nucleus; VPL, ventral posterior lateral nucleus; VPM, ventral posterior medial nucleus.
Pathology
Is the Restless Legs Syndrome mediated through a defect
in the endogenous opioid system? Decreases in Beta
endorphin and Met enkephalin in the thalamus of patients
with Restless Legs Syndrome compared to controls: a
post-mortem study
Arthur S. Walters, MD, William G Ondo, MD, Wen Zhu,
PhD ,Weidong Le, PhD
Methods
• Post-mortum staining of the thalamus and substantia
nigra
• Antibodies to Beta-endorphine, Met-enkephalin,
Leu-enkephalin
• Stained for Tyrosine Hydroxylase
• Cell counts
Age
Sex
Opioids IRLS Medical History
C
O
N
T
R
O
L
75
F
74
F
LF, RF
74
F
COPD, GERD, CHF, Anem, SVT, HTthy
80
F
COPD, GERD, Afib, Chol.
77
M
None
78
F
CAD, HTN, cat.
R
L
S
77
F
+
36
DM, RF, CAD, HTN, Anem, Br CA, HTthy
77
F
+
32
HTN, CAD, Dep
77
F
87
F
83
F
+
DM, HTN, PN, MI, RF, Anem
Dep, Skin CA
+
29
HTN, CAD
32
GERD, CAD, CHF, Afib, Chol, HTN, PM, PN
DM = Diabetes Mellitus, HTN = Hypertension, PN = Peripheral Neuropathy, MI = Myocardial Infarction, RF = Renal
Failure, COPD= Chronic Obstructive Pulmonary Disease, GERD = Gastroesophageal Reflux Disease, Hthy =
Hypothyroidism, Afib = Atrial Fibrillation, CHF = Congestive Heart Failure, SVT = Supraventricular Tachycardia, Inc
Chol = Increased Cholesterol, CAD = Coronary Artery Disease, Br CA= Breast Cancer, PM = Polymyalgia Rheumatica
Beta-endorphin Positive Cells in Thalamus
Met-enkephalin Staining Cells in Thalamus
Results
• Thalamus
– Beta-endorphin and met-enkephalin cells reduced
– No difference in Leu-enkephalin
• Substantia Nigra:
– No difference in tyrosine hydroxylase, or endorphin /
enkephalin stains
• No correlation between age or previous opioid
treatment and cell counts
Conclusions
• Some alteration in thalamic endogenous opioid cells
– Primary
– Secondary
• Endogenous opioid inhibit cell firing
• Consistent with increased thalamic activity in fMRI
• Consistent with increased thalamic activity in
H2[15O] PET
Bucher 1997, San Pedro 1998
Is the thalamus primarily involved,
secondarily involved, or an
epiphenomenon ?
Thank You
William Ondo, MD