Transcript Catania 25 marzo 2011

Incontro Nazionale Neurofisiologia:
Nuove Strategie
Efficacia dell’acido lipoico
“Controversie sulla diagnosi e terapia del dolore neuropatico”
Opinioni a confronto
nel dolore neuropatico
diabetico
Palermo, 29-30 novembre 2012
Damiano Gullo
UO Endocrinologia
Ospedale Garibaldi-Nesima
Catania
Diabetic neuropathy (DN)
• Neuropathy is a microvascular complication of diabetes
mellitus that leads to considerable morbidity and a
decreased quality of life.
• DN is a term indicating all signs and symptoms of peripheral
nerve dysfunction in diabetic patients in whom other causes
of neuropathy have been excluded.
• DN is a major public health problem, affecting approximately
13–26% of diabetic patients.
Neuropathies
Clinical Classification
Focal
Diffuse
 Proximal
 Distal
 large-fiber
 small-fiber
Neuropathic pain
• Neuropathic pain is difficult to treat, and standard analgesics
are usually not effective enough.
• The medications which are currently used to treat diabetic
neuropathic pain include mainly antidepressants,
antiepileptics, and opioids.
• These medications are limited in their effectiveness, they
have considerable side effects, and they have no effect on
the processes by which hyperglycaemia leads to cell
damage.
2011
EVIDENCE-BASED
GUIDELINE: TREATMENT
OF PAINFUL DIABETIC
NEUROPATHY—
REPORT OF THE
AMERICAN ASSOCIATION
OF NEUROMUSCULAR
AND
ELECTRODIAGNOSTIC
MEDICINE, THE
AMERICAN ACADEMY OF
NEUROLOGY, AND THE
AMERICAN ACADEMY OF
PHYSICAL MEDICINE &
REHABILITATION
Bril et al. 2011
What about lipoic acid..anyone?
Other Pharmacological Agents.
Recommendations:
1. Capsaicin and isosorbide dinitrate spray should be considered for the
treatment of PDN (Level B).
2. Clonidine, pentoxifylline, and mexiletine should probably not be
considered for the treatment of PDN (Level B).
3. The lidoderm patch may be considered for the treatment of PDN (Level
C).
4. There is insufficient evidence to support or refute the
usefulness of vitamins and alpha-lipoic acid in the treatment
of PDN (Level U).
History of lipoic acid
• Discovered in 1937 by Snell et al., who found that certain bacteria
needed a compound from potato extract for growth.
• In 1951, the so-called potato-growth factor was isolated by Reed and
colleagues, and lipoic acid was discovered as a molecule that assists in
acyl-group transfer and as a co-enzyme in the Krebs cycle.
• In the 1980s, alpha-lipoic acid was recognized as a powerful antioxidant.
It is produced by animals and humans, and can be found in liver, skeletal
muscle, potatoes, and broccoli.
• Intravenous and oral LA are approved for the treatment of diabetic
neuropathy in Germany.
Food Sources of LA
Supplements
• R-LA occurs naturally in foods covalently bound to lysine in proteins
(lipoyl lysine). Animal tissues rich in lipoyllysine (~1-3 mcg/g dry wt)
include kidney, heart, and liver, while vegetables rich in lipoyllysine
include spinach and broccoli.
• LA in supplements is not bound to proteins.
The amounts of LA available in dietary supplements (200-600 mg)
are as much as 1,000 times greater than the amounts obtained in the
diet.
• Most LA supplements contain a (50/50) mixture of R-LA and S-LA.
• Since taking LA with a meal decreases its bioavailability, it is
generally recommended that LA be taken on an empty stomach (one
hour before or two hours after eating).
Racemic vs. R-LA Supplements
• R-LA is the isomer that is synthesized by plants and animals and
functions as a cofactor for mithocondrial enzymes.
• After oral dosing with LA, peak plasma concentrations of R-LA were
found to be 40%-50% higher than S-LA, suggesting R-LA is better
absorbed than S-LA.
• In rats, R-LA was more effective than S-LA in enhancing insulinstimulated glucose transport and metabolism in skeletal muscle, and RLA was more effective than LA and S-LA in preventing cataracts.
• However, virtually all of the published studies of LA supplementation in
humans have used LA. At present, it is not clear whether R-LA
supplements are more effective than LA supplements in humans.
Mean TSS levels on a weekly basis during the placebo run-in and the randomized doubleblind period of the trial. *P < 0.05 for ALA600, ALA 1200, and ALA1800 vs. placebo; **P < 0.05
for ALA1800 vs. placebo.
Ziegler D et al. Diabetes Care 2006;29:2365-2370
Copyright © 2011 American Diabetes Association, Inc.
Randomized, placebo-controlled studies with alpha lipoic acid in
persons with symptomatic peripheral diabetic neuropathy.
•
Ziegler et al 1995 Diabetologia. Treatment of symptomatic diabetic peripheral
neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre
randomized controlled trial (ALADIN Study).
•
Ruhnau KJ at al. 1999. Diabetes. Effects of 3-week oral treatment with the
antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic
polyneuropathy.
•
Ametov Aset al. Diabetes Care 2003. The sensory symptoms of diabetic
polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial.
•
Ziegler D et al. Diabetes Care 2006. Oral treatment with alpha-lipoic acid
improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial.
Int J Endocrinol. 2012;
Meta-Analysis. pooled standardized mean
difference -all trials
Meta-Analysis. Overall, the pooled standardized mean difference estimated from all trials revealed a
reduction in TSS scores of −2.26 (CI: −3.12 to −1.41; P = 0.00001) in favour of alpha lipoic acid
administration (Table 4)
Int J Endocrinol. 2012; 2012: 456279.
Conclusions
• Based on the four level 1b randomized, placebo-controlled
studies, there is evidence to support that alpha lipoic acid
causes a significant and clinically relevant decrease in
neuropathic pain when administered for a period of three
weeks at a dosage of 600 mg per day (grade of
recommendation A)
• Intravenous administration of alpha lipoic acid leads to
significant and clinically relevant improvements of symptomatic
peripheral diabetic neuropathy in the short term.
Int J Endocrinol. 2012; 2012: 456279.
Published online 2012 January 26. doi: 10.1155/2012/456279
Safety & Dangers of Alpha Lipoic Acid
In general, alpha lipoic acid (ALA) is considered a safe supplement.
• Anaphylactoid reactions, including laryngospasm, were reported after
intravenous LA administration. The most frequently reported side effects of oral LA
supplementation are allergic reactions affecting the skin, including rashes, and
itching.
• Abdominal pain, nausea, vomiting, diarrhea, and vertigo have also been
reported, and one trial found that the incidence of nausea, vomiting, and
vertigo was dose-dependent.
• Malodorous urine has been noted by people taking 1,200 mg/day of LA orally.
• In rare circumstances, alpha lipoic acid may cause insulin autoimmune
syndrome; also known as Hirata disease, a condition characterized by
hypoglycemia and very high levels of insulin.
Fine