Examining -lipoic acid for use in Diabetic Neuropathy as

an Effective Alternative to Current Therapy

Resident Pharmacotherapy Rounds

Kristle Green, PharmD
PGY1 Pharmacy Community Practice Resident
The University of Texas at Austin/HEB Pharmacy

Objectives:
1. Review the epidemiology, pathogenesis, goals, and treatment of diabetic neuropathic pain
2. Discuss -lipoic acid and its use for neuropathic pain
3. Discuss literature investigating the use of -lipoic acid for the treatment of diabetic neuropathic
pain
4. Provide recommendations regarding the future use of -lipoic acid in patients with diabetic
neuropathy

I.

Diabetic Neuropathy Introduction1-6

a. Defined as pain arising from the direct result of a lesion or disease affecting the
somatosensory system
b. The most common among the neuropathies are chronic diabetic sensorimotor
polyneuropathy (DSPN) and autonomic neuropathy
c. The diabetic neuropathies are heterogeneous with diverse clinical manifestations and may
be local or diffuse
i. DSPN represents a diffuse symmetric and length-dependent injury to peripheral
nerves that has major implications on quality of life and morbidity

II.

Background3-6
a. Oxidative stress and impaired antioxidant defense mechanisms have been implicated as
major pathogenic components
b. DSPN affects nearly 30% of diabetics in hospital care and 25% of those in the community
i. Painful diabetic neuropathy affects 16% of patients of diabetes
c. Significantly interferes with quality of life (QOL) and emotional well being
i. Associated with depression, anxiety, loss of sleep, and decreased physical activity
d. Specific treatment for the underlying never damage is currently unavailable
i. Improved glycemic control may help to control progression however it will not
reverse neuronal loss
e. Current treatments vary in response rates with many intolerable side effects
f. -lipoic acid has been indicated as a possible treatment option with limited side effects

III.

Pathogenesis 6-10
a. Exact etiology unknown but believed to be multifactorial
b. Accepted theories:
i. Chronic hyperglycemia and its metabolic effects (Figure 1)
1. Genesis of nerve damage; impaired glucose tolerance leads to the
development of both small and large nerve fiber damage and thus
neuropathic pain
2. Metabolic alterations including increased accumulation of advanced
glycation end products, oxidative stress, and lipid alteration
3. Association with increased formation of free radicals and decreased
antioxidant potential, leading to oxidative damage of cell components
4. Direct increase of reactive oxygen species (ROS) generation since glucose
undergoes antioxidation to generate hydroxide radicals
ii. The effect of ischemia on nerves in the periphery

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Figure 1. Mechanisms of Tissue Injury by Hyperglycemia12

Glycation
pathway

Glycated
proteins (i.e.
A1C)

Altered
function or
turnover
AGE

Hyperglycemia
Sorbitol
pathway

Sorbitol and
fructose

Receptor
mediated
cytokine
effects

Osmotic
effects
Oxidative
effects

c. The polyol pathway (Figure 2)

i. Implicated in metabolic changes that occur
ii. In hyperglycemia hexokinase is saturated resulting in increased flux of glucose into
this pathway
iii. Glucose is reduced to sorbitol which does not readily diffuse across the cell
membrane
iv. The increased amount of sorbitol in the membrane results in increased osmolality of
the membrane, leading to potential cell damage.
v. As a result of the increased sorbitol accumulation, compensatory depletion of
endoneurial osmolytes taurine and myo-inositol occurs to maintain osmotic balance
Figure 2. The polyol pathway12

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d. Protein Kinase Activation

i. Increased vascular permeability, impaired nitric oxide synthesis, and changes in
blood flow
e. Oxidatative Stress
i. Enhanced metabolism of glucose through the polyol pathway results in enhanced
production of oxygen and therefore oxidative stress
ii. Downregulates Na-K-ATPase activity and resulting in nerve ischemia
iii. Endoneurial hypoxia and microvascular damage may also occur from the
downstream inactivation of nitrous oxide and in turn increase vascular tension along
with decreased blood flow
1. Results in subsequent nerve dysfunction
iv. Indicated in causing program cell death when it results from hyperglycemia

Figure 3: Damage to Nerves and Blood Vessels due to DSPN3

IV.

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Diagnosis 5,11,13
a. Symptoms
i. Distal, symmetrical pain which is often associated with nocturnal exacerbations
ii. Pain commonly described as: prickling, deep aching, sharp like an electric shock,
burning with hyperalgesia and frequent allodynia upon examination
b. Screening
i. The American Diabetes Association (ADA) recommends that all patients be screened
annually for distal symmetric polyneuropathy (DPN) starting at diagnosis of type 2
diabetes and 5 years after diagnosis of type 1 diabetes
ii. Screening test may include pinprick sensation, vibration perception, 10-g
monofilament pressure, sensation at the distal plantar aspects of both the great
toes and metatarsal joints, and assessment of ankle reflexes
Page 4

c. Test
i. Many different approaches however many test fail to have reproducible results,
may falsely reassure practitioners when there is indeed mild neuropathy, and/or
may be to invasive (Table 1)
ii. Abnormal nerve conduction test (NCT) is usually the first objective quantitative
indication of the condition
iii. To confirm diagnosis, severity must be assessed either by nerve conduction (NC)
abnormality or grading (Table 2 and 3)
Table 1. Advantages and disadvantages for different tests of neuropathy
Method
Clinical/neurological examination
Electrophysiology

Advantage
Simple, easy to use
Sensitive, objective

Quantitative sensory tests (QST)

Evaluates both large and small nerve fibers

Sympathetic skin response (SSR)

Quantitative sudomotor axon reflex test
(QSART)
Autonomic testing

Simple, fast, objective

Sensitive, objective, reproducible

Nerve/skin biopsy

Quantitative, sensitive

Corneal confocal microscopy/Corneal

aesthesiometry

Rapid, noninvasive, reiterative, quantitative

Objective, quantitative

Disadvantage
Not sensitive or reproducible
Assesses only large fibers, requires special
equipment
Subjective, low reproducibility, requires
special equipment
Semi quantitative, low sensitivity
Requires special equipment , time consuming
Moderate sensitivity, requires special
equipment
Invasive, problems with wound healing,
specialist histological technique to quantify
intraepidermal nerve fiber
Requires special equipment and expertise

10

Grade 0
Grade 1a
Grade 1b
Grade 2a
Grade 2b

Table 2. Description of the Stages of Severity

No abnormality of NC
Abnormality of NC
NC abnormally of stage 1a plus neurologic signs typical of DSPN but without neuropathy symptoms
NC abnormality of stage 1a plus neurologic signs typical of DSPN but without neuropathy symptoms
NC abnormality of stage 1a, a moderate degree of weakness of ankle dorsiflexion with or without
neuropathy symptoms
10

Possible
DSPN

Probably
DSPN
Confirmed
DPSN

V.

Green

Table 3. Definitions of minimal criteria for typical DPN

The presence of symptoms or signs of DPSN including the following symptoms- decreased
sensation, positive neuropathic sensory symptoms predominantly in the toes, feet, or legs;
or signs- symmetric decrease of distal sensation or unequivocally decreased or absent
ankle reflexes
The presence of a combination of symptoms and signs of neuropathy include any two or
more of the following: neuropathic symptoms, decreased distal sensation, or unequivocally
decreased or absent ankle reflexes
The presence of an abnormality of NC and a symptom(s) or sign(s) of neuropathy confirms
DSPN. If NC is normal, a validated measure of small fiber neuropathy (SFN) may be used

Treatment3,5,9,10
a. Without treatment neuropathy is a chronic and progressive disease
b. Pharmacologic management mainly consists of symptomatic therapies
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c. Goals
i. Arrest progressive loss of nerve function
ii. Improve symptoms
iii. Improve glycemic control
d. ADA Recommendations
i. First line- Tricyclic Antidepressants
ii. Second line- Anticonvulsants
iii. Opioids
e. Diabetic Peripheral Neuropathic Pain Consensus Treatment Guidelines Advisory Boards
i. First Line
1. Duloxetine, controlled-released oxycodone, pregabalin, and tricyclic
antidepressants
ii. Second Line
1. Carbamazepine, gabapentin, lamotrigine, tramadol, venlafaxine ER
f. The American Academy of Neurology
i. First line- Pregabalin
ii. Second Line- venlafaxine, duloxetine, amitriptyline
iii. Probably effective- gabapentin, valproate, and opioids
g. Evidence from clinical trials suggest a maximum response rate of approximately 50% for any
monotherapy, however many of these therapies were found to have significant adverse
effects (Appendix A,Table 4)
i. Lack of efficacy should be judged after 2-4 weeks of treatment using an adequate
low dose
ii. Analgesic combinations may be useful to achieve this target
Table 4. Odds ratios for efficacy and withdrawal, numbers needed to treat (NNT) and numbers needed
to harm (NNH)3
Drug class
Odds ratio
Odds ratio
NNT
NNH
efficacy
withdrawal
(secondary to AE)
Tricyclics
22.2 (5.884.7)
2.3 (0.69.7)
1.53.5
2.717.0
Duloxetine
2.6 (1.64.8)
2.4 (1.15.4)
5.75.8
15.0
Traditional
5.3 (1.816.0)
1.5 (0.37.0)
2.13.2
2.73.0
anticonvulsants
New generation
3.3 (2.34.7)
3.0 (1.755.1)
2.94.3
26.1
anticonvulsants
Opioids
4.3 (2.37.8)
4.1 (1.214.2)
2.63.9
9.0
VI.

Green

-lipoic acid (ALA)5,8,10,11

a. Marketed as a dietary supplement
b. Synthesized enzymatically in plant and animal mitochondria
c. Unique in that possesses antioxidant activity in both hydrophilic and hydrophobic mediums
and in both its oxidized (lipoic acid) and reduced forms (dihydrolipoic acid)
d. Role in DSPN
i. An antioxidant and free radical scavenger shown to improve symptomatic diabetic
neuropathy
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ii. First used therapeutically in Germany to treat diabetes induced neuropathy

iii. Currently approved for the treatment of DSPN in Germany in both IV and oral
formulations
1. It is also used for treatment of diabetic retinopathy in Germany
e. Previous Trials (Appendix D)
i. ALADIN trials (alpha-lipoic acid in diabetic neuropathy) IV use of ALA
ii. SYDNEY I trial (symptoms of diabetic polyneuropathy) also investigated IV use of
ALA

VII. Literature Evaluation

Trial 1: Effects of 3-week oral treatment with the antioxidant thioctic (-lipoic acid) in symptomatic diabetic
polyneuropathy (ORPIL study). Ruhnaut K.J., Meissner H.P., Finn J.R., et al. Diabetic Medicine.1999 (16); 10401043
Design
Randomized, double-blind, placebo-controlled trial
Objective
To evaluate the efficacy and safety of short-term oral treatment with the antioxidant thioctic acid
(TA) or neuropathic symptoms and deficits in patients with T2DM with symptomatic polyneuropathy
Population
Type 2 diabetic outpatients with polyneuropathy recruited from the Berline Diabetes Academy
unit
Inclusion Criteria:
o Age 18-70 years
o Type 2 diabetes treated with diet, oral anti-diabetic agents and/or insulin
o Evidence of distal symmetrical polyneuropathy with at least moderate severity of one
or more of the typical symptoms in the feet equivalent to > 4 points in the TSS
Exclusion Criteria:
o Asymmetrical neuropathy of the trunk and proximal lower limbs
o Presence of foot ulcers
o Peripheral vascular disease
o Myopathy
o Causes of neuropathy other than diabetes and significant neurological diseases
o Participation in a study of any investigational drug for neuropathy within 3 months
before the study
o Use of antioxidants or vitamin B within 1 month before the study
o Severe concomitant diseases
o Pregnancy, lactation, or childbearing age without birth control devices
Primary Outcomes: TSS (pain, burning, paresthesiae, and numbness) in the feet were scored at
weekly intervals
Methods
Participants were randomly assigned to oral treatment with 600 mg of TA TID (n=12) or placebo
(n=12) for 3 weeks
The Hamburg Pain Adjective List (HPAL) and the Neuropathy Disability Score (NDS) were
assessed at baseline and day 19
Results
At baseline TSS, HPAL, and NDS were not significantly different between the groups
Significantly improved TSS pain and burning subscores
Change from baseline to Day 19
Placebo
Thioctic Acid (ALA)
TSS in feet
-1.94 + 1.50 (-24%)
-3.75 + 1.88 (-47%)
HPAL
-0.96 + 1.32 (-29%)
-2.20 + 1.65 (-60%)
NDS
+0.18 + 0.4
-0.27 + 0.47
*statistically significant

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P-value
P = 0.021*
P = 0.072
P = 0.025*

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Authors
Conclusion
Comments

Oral treatment with 600 mg of TA three times daily for 3 weeks may improve symptoms and
deficits resulting from polyneuropathy in type 2 diabetic patients without causing significant
adverse reactions
Strengths
Weaknesses
Randomized, double-blind, placebo
Small sample size, only 22 patients
controlled trial
completed the trial
Exclusion of patients currently or previously
Short duration of treatment
taking antioxidants one month before the
Never defined the severe concomitant
study
diseases excluded from trial
Concurrent administration of insulin and/or
oral anti-diabetic medication may have
influenced results
Anti-diabetic medications used during
treatment were not disclosed
Funded by the manufacture of ALA

Trial 2: Oral treatment with -lipoic acid improves symptomatic diabetic polyneuropathy: The SYDNEY 2 trial.
Ziegler D., Ametov A., Barinov A., et al. Diabetes Care 2006;29(11) 2365-2370.
Design
Multicenter, randomized, double-blind, placebo-controlled trial
Objective
To evaluate the effects of ALA on positive sensory symptoms and neuropathic deficits in diabetic
patients with distal symmetric polyneuropathy (DSP)
Population
Patients in Israel and Russia
Inclusion Criteria
o Age 18-74
o Diabetes type 1 or 2 defined by ADA criteria
o Duration of diabetes > 1 year
o HbA1C <10%
o Symptomatic DSP attributable to diabetes after thorough evaluation for other causes
or neuropathy
o TSS >7.5 points
o Neuropathic impairment score- lower limb (NIS-LL) > 2 points
o Pain sensation according to the pin-prick test absent or decreased
Exclusion Criteria
o Confounding neurologic disease or neuropathy
o Myopathy of any cause
o Peripheral vascular disease severe enough to cause intermittent claudication ischemic
ulcers or limb ischemia
o Significant hepatic or renal disease
o Antioxidant therapy or pentoxyphylline within the last month
o Use of > 50 mg ALA or use of gamma-linolenic acid containing substance with the last
3 months
Methods
Patients received once daily oral doses for 5 weeks:
o 600 mg ALA (n= 45)
o 1200 mg ALA (n= 47)
o 1800 mg ALA (n=46)
o Placebo (n= 43)
One week placebo run-in period
Primary outcome: change from baseline of the TSS, including stabbing pain, burning pain,

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Results

paresthesia, and asleep numbness of the feet

o TSS assessed at screening, baseline, before the state or the study treatment, and after
each week of treatment
Secondary outcome: individual symptoms of TSS, Neuropathy Symptoms and Change (NSC)
score, NIS, and patients global assessment of efficacy
181 diabetic patients in Russia and Israel randomized, only 166 completed the trial
All groups were comparable in age, gender, disease state, blood pressure, polyneuropathy
stage
Mean TSS did not differ significantly at baseline among treatment groups
Safety analysis showed dose dependent increase in nausea, vomiting, and vertigo
o Side effects reported by 27% of 600 mg group (P= 0.53), 43% of 1200 mg group (P=
0.03), and 54% of the 1800 mg group (P < 0.001)
Significant improvement in pain and burning subscores

Mean TSS
Response rate
Stabbing Pain
Burning Pain
Parethesiae
Numbness

NSC number
NSC severity
NSC change
NIS
NIS-LL
NIS-LL sensory
function

Authors
Conclusions

Comments

Green

Change from baseline after 5 weeks on treatment

ALA600
ALA1200
ALA1800
-4.9 (51%)*
-4.5 (48%)*
-4.7 (52%)*
62%
50%
56%
-1.40*
-1.56*
-1.46*
-1.32*
-1.09*
-1.15*
-1.16
-0.85
-1.12
-0.97
-0.99
-0.98

Placebo
-2.9 (32%)
26%
-0.83
-0.50
-0.80
-0.79

Changes from initial screening levels after 5 weeks

ALA600
ALA1200
ALA1800
-2.8*
-2.8*
-2.7
-7.4*
-7.2*
-7.6*
+8.6*
+8.5*
+9.5*
-3.80
-3.85
-3.85*
-3.75
-2.63
-2.70

Placebo
-1.7
-4.9
+5.4
-2.38
-2.08

-2.25*

-1.73

-1.55

-1.05

*statistically significant
Oral treatment with ALA for 5 weeks improve neuropathic symptoms and deficits in patients
with DSP
Effects were not dose dependent
ALA dosed at 600 mg once daily provided the optimum risk-to-benefit ratio
Strengths
Weaknesses
Randomized, double-blind placeboRelatively small study
controlled
Short duration of treatment
Safety analysis and adverse effects were
Self-report of symptom improvement
reported
Randomization method was not described
Inclusion of T1DM patients may have
confounded results

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Trial 3: Efficacy and safety of antioxidant treatment with -lipoic acid over 4 years in diabetic polyneuropathy:
The NATHAN I trial. Ziegler D., Low P.A., Litchy W.J., et al. Diabetes Care. 2011;34:2054-2060
Design
Multicenter randomized, double-blind parallel-group trial
Objective
To evaluate the efficacy and safety of alpha-lipoic acid (ALA) over 4 years in mild-moderate
diabetic distal symmetric sensorimotor polyneuropathy (DSPN)
Population
Patients with mild-moderate DSPN
Inclusion Criteria:
o Age 18-64 years
o Type 1 or type 2 diabetes defined by the ADA criteria
o Diabetes duration > 1 year
o Presence of stage 1 or 2a DSPN attributable diabetes
o Stable insulin regimen, weight, diet, and physical activity
th
o NIS-LL and seven nerve conduction test score > 97.5 percentile
o NIS-LL > 2 points
o One of two abnormalities:
th
Abnormal nerve conduction attributable in two separate nerves > 99
percentile for distal latency or < 1 percentile for nerve conduction velocity
or amplitude
st
Abnormal heart rate during deep breathing (HRDB) < 1 percentile or TSS in
the feet < 5 points
o Female patients had to be either surgically sterilized, > 1 year postmenopausal, or
practicing an acceptable method of contraception
Exclusion Criteria:
o Neuropathies other than DSPN
o Myopathy and other neurological diseases that may interfere with the assessment of
the severity of DSPN
o Previous bilateral sural nerve biopsies
o Peripheral vascular disease with intermittent claudication
o Foot ulcers
o High risk for visual loss
o Psychiatric, psychological or behavioral symptoms that would interfere with the
patients ability to participate in the trial
o Active neoplastic disease except basal cell carcinoma
o Uncontrolled atrial fibrillation
o Clinically significant cardiac, pulmonary, gastrointestinal, hematologic, or other
endocrine diseases
o Organ transplants
o Aspartate aminotransferase or alanine aminotransferase > 2 times normal
o Serum creatinine > 1.8 and > 1.6 mg/dL for men and women respectively
o Drug or alcohol abuse within the last year
o Use of investigational drug within the last 6 months
o Severe anaphylactic reaction to multiple drugs, sulfur products, or biologic products
o Ketoacidosis or hypoglycemia within the last three months resulting in hospital
admission
o Antioxidant therapy (> 400 IU vitamin E, > 200 mg vitamin C or > 30 mg/day beta
carotene) or pentoxyphylline within the last month
o Gamma linolenic acid and ALA >50 mg/day within the last 3 months
o History of use of medications or vitamins known to cause peripheral neuropathy
including but not limited to the use of phenytoin or carbamazepine > 15 years of use
or > 100 mg/day pyridoxine within the last 12 months
o Use of pain medication except for standard doses of salicylates, ibuprofen, indoles,
fenamates, oxicams, or pyrazoles

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Methods

2 week screening phase, 6 week placebo run-in phase, 4 year double-blind phase, and 4week washout phase
Patients were randomly assigned to oral treatment with 600 mg ALA once daily (n= 233) or
placebo (n= 227) for 4 years
Primary Outcome:
o Composite score (NIS-LL) and seven neurophysiologic tests
Secondary outcomes:
o NIS, NIS-LL
460 diabetic patients randomized
Improved NIS (P=0.028), NIS-LL (P=0.05), and NIS-LL muscle weakness subscore (P=0.045)

Results

Changes in clinical neuropathy scores and nerve function test from baseline to 2 and 4
years
2 Years
4 Years
ALA
Placebo
ALA
Placebo
N
214
207
215
207
Composite
score
-0.40 + 4.92
0.19 + 4.74
-0.37 + 5.59
0.29 + 5.37
NIS-LL+7(nds)
Four year treatment with ALA in mild-moderate DSPN resulted in clinically meaningful
improvement and prevention of progression of neuropathic impairments
ALA is well tolerated
ALA did not influence a change in the composite score NIS-LL+7
No statistically significant improvement in NC
Strengths
Weaknesses
Randomized double blind placebo
Extensive exclusion criteria may have
controlled
influenced the patient population
Appropriate time length
Inclusion of T1DM patients
Assessed nerve conduction
Stable insulin regimen was never defined
Large study population

Authors
Conclusion

Comments

VIII.

Summary

Study

Patient
type

Primary
outcome

Secondary
outcome

ALA dosage

Length of
Study

ORPIL

T2DM

TSS

HPAL, NDS

3 weeks

SYDNEY 2

T1DM +
T2DM

TSS

NCS, NIS

a)600 mg TID
a)600 mg
daily
b)1200 mg
daily
c)1800 mg
daily

NATHAN
I

T1DM
+T2DM

NIS-LL + 7
neurophysiologic
tests

TSS

Green

a)600 mg
daily

Difference in
intervention vs.
control for primary
outcome
-1.81 (P= 0.021)

5 weeks

-1.93 (P<0.05)
-1.58 (P<0.05)
-1.78 (P<0.05)

4 years

0.1+0.02 (P=0.105)

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IX.

Safety and Toxicity27

a. Currently no established upper limit for ALA consumption in humans
b. ALADIN I, II, and III and the SYDNEY I clinical trials reported no adverse effects when ALA was
used at doses up to 2400mg/day
c. Tang et al. reported that adverse events including nausea, vomiting, and vertigo, occurred
most frequently at dose of 1200-1800 mg/day
d. Due to ALA improving glucose utilization there is an increased risk of hypoglycemia in
patients using insulin or anti-diabetic agents

X.

Conclusions
a. It is still unclear whether oral administration of ALA leads to significant improvement of
symptomatic peripheral diabetic neuropathy
b. Although promising, further studies are needed to assess long-term treatment of ALA given
orally in an outpatient setting to assess its potential as a viable treatment option for
patients with DSPN
c. Studies comparing ALA with current treatment therapies are necessary to assess superiority
and/or non-inferiority
d. Studies assessing long term safety and toxicity are necessary

XI.

Other potential therapeutic uses for ALA26,27

a. Endothelial dysfunction and Anti-inflammatory
i. The ISLAND trial conducted by Sola et al. showed ALA significantly increased nitric
oxide synthesis in human aortic endothelial cells leading to improved vasodilation
and a 15% reduction in serum interleukin-6 levels following 4 weeks of
supplementation with ALA 300 mg/day
b. Hypotensive Agent
i. Research by Takokah et al. suggests that ALA inhibits renal and vascular
overproduction of endothelin-1, a vasoconstrictor secreted by the endothelium

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Appendix A13

Drug and dose

Various tricyclic
antidepressants
and doses

Duloxetine
60mg/d 120
mg/d

Pregablin 600
mg/d

Gabapentin
1200-3600
mg/d

Oxycodone 2080 mg/d

Meta-analysis of drug therapy vs. placebo for diabetic neuropathic pain

Subjects (N)
Duration(wk)
Mean age (y)
Measured
NNT (95%
outcome
CI)

177

3-12

50

Treatment
cessation: 28
(17.6-68.9)

Overall
effectiveness

1.3 (1.2-1.5)

655
655

12

N/A

50% pain
reduction

6.0 (5-10)
6.0 (5-10)

1425

5-13

59

50% pain
reduction

5 (4-6.6)

829

4-12

36

58

63

NNH (95% CI)

Minor adverse
effects: 6(4.210.7)
Treatment
cessation: 17 (1250)
Somnolence: 8.8
(7-12)*
Dizziness: 2.8
(2.5-3.2)
Treatment
cessation: 8.8
(6.8-12)
Any adverse
effect: 6.6 (5.39.0)

50% pain
reduction

5.8 (4.3-9.0)
Treatment
cessation: 32 (19100)
Nausea: 4(2-219)

Moderate pain
relief (defined as
a score of 3 on a
6-point scale)

2.6 (N/A)

Constipation: 4(219)
Treatment
cessation: 7 (487)

NNH: number needed to harm; NNT: number needed to treat

Appendix B4
Total Symptom Score (TSS): scoring system for neuropathic symptoms (pain, burning, paresthesia, and
numbness). The score can range from 0 (no symptoms) to maximally 14.64 (all symptoms present, severe,
continuous)
Symptom
frequency
Occasional
Frequent
(Almost)
continuous

Green

Absent
0
0
0

Symptom
Slight
1.00
1.33
1.66

Intensity
Moderate
2.00
2.33
2.66

Severe
3.00
3.33
3.66

Page 13

Appendix C4

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Page 14

Appendix D15-18
Trial

Patient
Type

ALA dosage

Length
of study

Authors Conclusion

a)100 mg IV
ALADIN I

ALADIN II

T2DM

T1DM
T2DM

ALADIN
III

T2DM

SYDNEY I

T1DM
T2DM

Green

b)600 mg IV

3 weeks

Significant improvement in TSS (pain,

numbness, and parathesias)

2 years

Significant improvement in peripheral

NC

c)1200 mg IV
a)600 mg IV x 5 days followed by
oral LA for 2 years
b)1200 mg IV x 5 days followed by
oral LA for 2 years
LA 600 mg/day IV x 3 weeks
followed by LA 600 mg PO TID x 6
months
600 mg IV daily 5 days per week
for 14 treatments

7 months

3 weeks

Trend towards improved neuropathy

but no statistically significant
improvement
Rapid, significant and clinical
improvement in TSS (positive
neuropathic sensory systems)

Page 15

Appendix E20
Switching from pathogenetic treatment with alpha-lipoic acid to gabapentin and other analgesics in painful
diabetic neuropathy: a real-world study in outpatients. Ruessmann H.J., Journal of Diabetes and Its
Complications (2009). 23:174-177
Design
Observational study
Objective
To evaluate whether switching from the pathogenetic treatment option alpha lipoic acid to drugs
for symptomatic treatment of neuropathic pain such as gabapentin would be associated with
changes in efficacy, safety, and cost-effectiveness.
Population
Cohort of diabetic patients with painful neuropathy from large private practices
Methods
Participants were treated with alpha lipoic acid oral daily dose of 600mg for a mean period
of 5 years
After stopping treatment the patients were immediately switched to either:
o gabapentin 600-2400 mg/day (n= 293 )
o no treatment due to no acute symptoms (n = 150)
Responders to gabapentin defined as those who had least moderate pain relief or pain free
no later than 6 months after starting the treatment and non responders reported either no
pain relief or slight pain relief at doses up 2400 mg/day
Responders to ALA defined as those who had symptom relief and showed improved in
neuropathic deficits and non responders had no symptom relief after 3 weeks of treatment
Neuropathic symptoms and deficits were assessed using the NSS and NDS
Results
In the untreated group 110 (73%) of patients developed neuropathic symptoms as soon as 2
weeks after the end of treatment with ALA
In the gabapentin group:
o 131 (45%) stopped taking the drug due to intolerable side effects
o 132 (45%) responded to an average dose of 1200 mg/day
o 161(55%) were non responders at doses up to 2400 mg/day
Required further treatment consisting of pregabalin, carbamazepine,
amitriptyline, tramadol, or morphine in monotherapy or in combination
Daily cost of ALA was considerably lower than those for gabapentin or drugs used in
combination

ALA
(n= 443)
Gabapentin
(n = 293)
Non
treatment
(n =150)
Authors
Conclusion
Comments

Green

Responders
(n)

Non-Responders
(n)

Rate of Side
Effects

Frequency of
outpatient visits
(per 3 months)

333

110

3%

3.8

132 (45%)

161 (55%)

68%

7.9

110 (73%)

Switching from long-term treatment with alpha lipoic acid to central analgesic drugs such as
gabapentin is associated with increased side effects, frequencies of outpatient visits, and
daily cost of treatment
Strengths
Weaknesses
Large study population
Observational study
Study length was appropriate
No inclusion or exclusion criteria listed
Compared ALA to pharmacologic
ALA was compared to gabapentin
treatment
however gabapentin is not a first line

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treatment in any of the guidelines for

diabetic neuropathy
Gabapentin was not titrated to as high as
3600 mg/day which was the target dosed
reached in the only available larger trial
with gabapentin

Appendix F
Abbreviations
ADA- American Diabetes Association
ALA- alpha lipoic acid
DSPN- diabetic sensorimotor polyneuropathy
HPAL- Hamburg Pain Adjective List
QOL-quality of life
NIS neuropathy impairment score
NCS- neuropathic symptoms and change score
NC- nerve conduction
NCT-nerve conduction test
NDS- neuropathy disability score
QSART- quantitative sudomotor axon reflex test
ROS- reactive oxygen species
SFN- small fiber neuropathy
TSS- total symptom score

Green

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