NO Acido lipoico e dolore neuropatico diabetico Domenico A. Restivo Incontro Nazionale Neurofisiologia: Nuove Strategie   “Controversie sulla diagnosi e terapia del dolore neuropatico” Opinioni a confronto NO Acido lipoico e dolore neuropatico diabetico Domenico A. Restivo U.O. di Neurologia P.O. “Nuovo Garibaldi”, Catania

AANEM GUIDELINES - 2011 There is insufficient evidence to support or refute the usefulness of vitamins and alpha-lipoic acid in the treatment of PDN (Level U). BRIL ET AL., 2011

ALA AND NEUROPATHIC PAIN Golbidi et al., 2011

Misure di outcome inappropriate per valutare il dolore neuropatico ALA RCTs ALADIN I ALADIN III SYDNEY NATHAN II SYDNEY 2 NATHAN I Misure di outcome inappropriate per valutare il dolore neuropatico

OUTCOME MEASURES IN ALA RCTs TSS (Total symptoms Score: points: 0-14.64): Sensory symptoms (Ziegler et al., 2004) Neuropathy TSS: Sensory symptoms (Bastyr et al., 2002) TNS (Total Neuropathy Score): Sensory, motor, and autonomic symptoms; Sensory and motor signs; reflexes; QST (vibration); sensory and motor NCS. (Cornblath et al., 1999) NSS (Neuropathy Symptoms Score): Sensory, motor, and autonomic Symptoms (Dyck et al., 1988) NIS (Neuropathy Impairment Score): NIS LL: Sensory and motor signs; Reflexes in the lower limbs; NIS LL + 4: Sensory and motor signs; Reflexes in the lower limbs + motor NCS; NIS LL + 5: Sensory and motor signs; Reflexes in the lower limbs + motor NCS + QST (vibration); NIS LL + 7: Sensory and motor signs; Reflexes in the lower limbs + sensory and motor NCS + QST (vibration) + AFT (Dyck et al., 1997)

TSS Patients: 328 Outcome primario: TSS Outcome secondario: NSS, Neuropathy Disability Score Results: improvement in TSS

ALADIN TSS Significant changes in TSS score

Patienti: 509 Outcome primario: TSS Outcome secondario:NIS, NIS-LL Risuatati: No miglioramento in TSS; SI NIS

NO IMPROVEMENT IN QST Pazienti: 60 vs 60 controlli Outcome primario: TSS Outcome secondario: NIS, NSC, NCS, QST, AF test Risultati: miglioramento significativo in TTS, NIS, NCS

Patients: 181 Primary Outcome: TSS Secondary Outcome :individual symptoms of TSS, NIS, NSC, Patient’s Global Assessment (PGA) Results: improvement in TSS, individual symptoms of TSS, NSC, PGA

Primary outcome Secondary outcomes

Results: no significant improvement in the primary endpoints Patients: 460 Primary outcome: NIS-LL 7 Secondary outcome: NIS, NIS-LL, NCS, QST

EFFECTS OF ALA ON DIFFERENT OUTCOME MEASURES 20 DPNP PTS Restivo et al., unpublished data

NPSI: SIGNIFICANT IMPROVEMENT ONLY FOR ALA NPSI 20 DPNP PTS NPSI: SIGNIFICANT IMPROVEMENT ONLY FOR DEEP SPONTANEOUS PAIN (PRESSING) AND PARESTHESIA/DYSESTHESIA QUESTO DATO POTREBBE IN QUALCHE MODO SPIEGARE L’ASSENZA DI MIGLIORAMENTO DEL QST DOPO ALA

Neuropatie Dolorose in corso di Diabete PoliNPT sensitiva dolorosa associata a ridotta tolleranza al Glc NPT da iperglicemia o funzionale NPT acuta dolorosa precipitata dal controllo glicemico PoliNPT prevalentemente sensitiva distale e simmetrica NPT delle fibre di piccolo calibro NPT cachettica o NPT dolorosa acuta Anoressia con neuropatia dolorosa acuta Mononeuropatie singole o multiple Radicolopatia toracica multipla dolorosa Radicolo-plessopatia lombosacrale dolorosa acuta Mononeuropatie da intrappolamento NPT oftalmoplegica

Risposta migliore nei pz con polineuropatia simmetrica POTREBBE L’EFFETTO DELL’ALA DIPENDERE DAL TIPO DI NEUROPATIA ? BPI ALA 15 SFDN PTS; 22 DSP PTS Risposta migliore nei pz con polineuropatia simmetrica sensitiva distale Scarsa risposta in pz con neuropatia prevalentemente a carico delle piccole fibre

Stimulation of distal sensory axons to study the neural impulse generation in individual nerve fibers by-passing the receptor organ The absolute refractory periods (ARP) of single sensory axons is significantly shorter in diabetic patients (Mackel and Brink 2003) The shorter ARP in diabetic nerves may be consistent with reduced nodal Na+ currents (Quasthoff, 1998), which is a consequence of reduction of Na+-K+ ATPase activity, which play an important role in the pathophysiology of DN (Distal Simmetric Polyneuropathy)

No correlation between ARP increase and BPI changes The absolute refractory period is the shortest interpulse interval at which an action potential is generated and propagated in response to a second stimulus ALA INCREASE ARP IN DISTAL SIMMETRIC POLYNEUROPATHY ARP No correlation between ARP increase and BPI changes in patients with diabetic distal sensory neuropathy and pain 12 PTS

??? COSTI “TANTO NON FA MALE…” IN ITALIA LA TERAPIA PER UN MESE CON ACIDO LIPOICO COSTA CIRCA 20 EURO… HA UN SENSO SOTTOPORRE IL PAZIENTE AD UNA SPESA, NON SEMPRE DA TUTTI SOSTENIBILE, IN ASSENZA DI SICURI BENEFICI E/O SOLO SULLA BASE DEL PRESUPPOSTO CHE: “TANTO NON FA MALE…” ???

CONCLUSIONI NON VI SONO SUFFICIENTI EVIDENZE CHE L’ACIDO LIPOICO POSSA MIGLIORARE IL DOLORE NEUROPATICO ASSOCIATO A DIABETE MELLITO ULTERIORI STUDI RANDOMIZZATI-CONTROLLATI CHE UTILIZZINO MISURE DI OUTCOME PIU’ “SPECIFICHE” SONO NECESSARI PRIMA DI UN SICURO E DEFINITIVO UTILIZZO DELL’ALA SUL DPNP