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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