1. Efficacia dell’acido lipoico nel dolore neuropatico diabetico
Incontro Nazionale Neurofisiologia:
Nuove Strategie  
“Controversie sulla diagnosi e terapia del dolore neuropatico”
Opinioni a confronto
Efficacia dell’acido lipoico nel dolore neuropatico diabetico
Damiano Gullo
UO Endocrinologia
Ospedale Garibaldi-Nesima
Catania
Palermo, novembre 2012
Palermo, novembre 2012
Palazzo dei Normanni
Palermo, novembre 2012
Palazzo dei Normanni
Palermo, novembre 2012
Palazzo dei Normanni
Palermo, novembre 2012
Palazzo dei Normanni

2. 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.
Diabetic complications can be classified broadly as microvascular or macrovascular disease.
Microvascular complications include neuropathy (nerve damage), nephropathy (kidney disease) and vision disorders (eg retinopathy, glaucoma, cataract and corneal disease).
Diabetic peripheral neuropathy (DPN) is a “diagnosis of exclusion.

3. Da un punto di vista anatomopatologico, la neuropatia diabetica è caratterizzata da un danno assonale con perdita delle fibre mieliniche e amieliniche,
Peripheral Neuropathy (PN) results from damage to the nerves of the Peripheral Nervous System (PNS). (Sistema Nervoso Periferico (SNP)
I nervi sono strutture anatomiche del sistema nervoso periferico formate da fasci di assoni (provenienti da un gruppo di neuroni) che trasportano informazioni da o verso il sistema nervoso centrale. Il nervo contiene, inoltre, vasi sanguigni utili al rifornimento di ossigeno e nutrienti. Nel nervo sono presenti guaine di tessuto connettivo che si fanno via via più piccole, ricoprendo prima l'intero nervo poi fasci e fascetti di assoni (epinervio, perinervio ed endonervio). Il colore dei nervi può variare dal bianco al grigio, a seconda della prevalenza di fibre mieliniche o amieliniche.
danno di tipo ischemico per microangiopatia dei vasa nervorum,

4. Incidence of sensory and autonomic neuropathy in diabetic patients can be as high as 50% and leads to incapacitating pain, digestive abnormalities, erectile dysfunction, heart arrhythmia, sensory loss, foot ulceration (up to 2 million Americans have this complaint), infection, gangrene and poor wound healing. The end result is often lower extremity amputation that accounts for approximately 80,000 cases each year in the USA and in rare cases sudden death, presumably on a cardiac basis.

5. Neuropathies Clinical Classification
Focal
Diffuse
Proximal
Distal
large-fiber
small-fiber
Peripheral Neuropathy (PN) results from damage to the nerves of the Peripheral Nervous System (PNS).

6. 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.
Shortcomings of available treatments
There are several drawbacks to the currently available treatments, including: failure to counteract progressive -cell dysfunction, concerns over weight gain and hypoglycaemia, regimen complexity and tolerability issues. Overcoming these shortcomings is important in improving diabetes therapy.

7. Antioxidants Nutrients
Peripheral Neuropathy (PN) results from damage to the nerves of the Peripheral Nervous System (PNS).
Oxidative stress contributes to diabetic neuropathy
It is generally believed that oxidative stress is the key pathological process inducing nerve damage in diabetes [19,20]. Oxidative stress, possibly triggered by vascular abnormalities and associated microangiopathy in the nerve [1,21,22], is a key pathological process inducing nerve damage in diabetes in humans and experimental models [19,20,22]. Diabetes-induced oxidative stress in animal models of in type 1, type 2 and pre-diabetes in sensory neurons and peripheral nerve is demonstrated by increased production of reactive oxygen species (ROS) [23–27], lipid peroxidation [28–30] and protein nitrosylation [29–32], and diminished levels of reduced glutathione [28,33] and ascorbate [28]. Treatment with anti-oxidants such as α-lipoic acid, γ-linolenic acid and aldose reductase inhibitors prevent many indices of neuropathy in STZ-diabetic rats [19,20,25,27]. The neurons and Schwann cells do initiate protective mechanisms involving up-regulation of antioxidant pathways [34–36], however, the neurodegenerative outcome is energy failure in the nerve, observed as a decrease in high energy intermediates (e.g. phosphocreatine) [19,20], impaired axonal transport of proteins [37] and sub-optimal ion pumping [38–41].

8. EVIDENCE-BASED GUIDELINE: TREATMENT OF PAINFUL DIABETIC NEUROPATHY—
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
Shortcomings of available treatments
There are several drawbacks to the currently available treatments, including: failure to counteract progressive -cell dysfunction, concerns over weight gain and hypoglycaemia, regimen complexity and tolerability issues. Overcoming these shortcomings is important in improving diabetes therapy.

9. 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).
One Class I and two Class II studies showed benefit from alpha-lipoic acid in reducing pain in PDN, but pain was not a predefined endpoint in these studies.e11–e13 The effect size in pain reduc- tion was moderate (20–24% superior to placebo).
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).
A recent "Special Editorial" in Neurology addressed the rating system used by the American Academy of Neurology (AAN) in its evidence-based guidelines. Apparently, many readers have expressed frustration with the Level "U" recommendation. The article states that "U" stands for "insufficient data to support or refute use of a particular treatment or diagnostic test," not unimportant or useless. The article emphasizes, "...a Level U guideline recommendation is not synonymous with a negative recommendation."
American Academy of Neurology Classification of Recommendations
A=Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specific population (Level A rating requires at least two consistent Class I studies.) 
B= Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specific population. (Level B rating requires at least one Class I study or two consistent Class II studies.)
C=Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)
U= Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

10. 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.
Shortcomings of available treatments
There are several drawbacks to the currently available treatments, including: failure to counteract progressive -cell dysfunction, concerns over weight gain and hypoglycaemia, regimen complexity and tolerability issues. Overcoming these shortcomings is important in improving diabetes therapy.

11. 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 ( 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).

12. 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 insulin-stimulated glucose transport and metabolism in skeletal muscle, and R-LA 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.

13. Mean TSS levels on a weekly basis during the placebo run-in and the randomized double-blind period of the trial. *P < 0.05 for ALA600, ALA 1200, and ALA1800 vs. placebo; **P < 0.05 for ALA1800 vs. placebo.
Mean TSS levels on a weekly basis during the placebo run-in and the randomized double-blind 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:
Copyright © 2011 American Diabetes Association, Inc.

14. 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 Diabetes. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy.
Ametov Aset al. Diabetes Care The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial.
Ziegler D et al. Diabetes Care Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial.
Int J Endocrinol. 2012;

15. Meta-Analysis. pooled standardized mean difference -all trials
Peripheral Neuropathy (PN) results from damage to the nerves of the Peripheral Nervous System (PNS).
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 = ) in favour of alpha lipoic acid administration (Table 4)
Int J Endocrinol. 2012; 2012:

16. 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:
Published online 2012 January 26. doi:  /2012/456279

17. 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.

18. Fine