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
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
9
20 DPNP PTS
8
7
6
5
TSS
BPI
4
3
2
1
0
baseline
week1
week2
week3
Restivo et al., unpublished data
ALA
NPSI
10
9
20 DPNP PTS
8
7
Burning
6
Pressing
5
Paroxysm al
4
Evoked
3
Par/Dysesth
2
1
0
baseline
week1
week2
week3
week4
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
POTREBBE L’EFFETTO DELL’ALA DIPENDERE DAL TIPO DI NEUROPATIA ?
BPI
8
7
6
5
ALA
SF
4
DSP
3
2
15 SFDN PTS; 22 DSP PTS
1
0
baseline
week1
week2
week3
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)
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
4
3.5
Effects of ALA on ARP
ARP
3
4
3.5
2.5
2
1.5
1
3
No correlation between ARP
increase and BPI changes
2.5
2
DN
in patients with diabetic 1.5
distal
sensory neuropathy and pain
1
0.5
0.5
0
Normals
DN
12 PTS
0
baseline
week1
week2
week3
week4
COSTI
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