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Examining -lipoic acid for use in Diabetic Neuropathy as

an Effective Alternative to Current Therapy

Resident Pharmacotherapy RoundsKristle 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 pain2.

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

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Figure 1. Mechanisms of Tissue Injury by Hyperglycemia12

c.

The polyol pathway (Figure 2)

i.

Implicated in metabolic changes that occurii.

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

Hyperglycemia

Glycationpathway

Glycatedproteins (i.e.

A1C)

Alteredfunction or

turnover

AGE

Receptormediated

cytokineeffects

Sorbitolpathway

Sorbitol andfructose

Osmoticeffects

Oxidativeeffects

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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.

Diagnosis5,11,13

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 examinationb.

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

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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 neuropathy5

Method Advantage Disadvantage

Clinical/neurological examination Simple, easy to use Not sensitive or reproducible

Electrophysiology Sensitive, objective Assesses only large fibers, requires special

equipment

Quantitative sensory tests (QST) Evaluates both large and small nerve fibers Subjective, low reproducibility, requires

special equipment

Sympathetic skin response (SSR) Simple, fast, objective Semi quantitative, low sensitivity

Quantitative sudomotor axon reflex test

(QSART)

Sensitive, objective, reproducible Requires special equipment , time consuming

Autonomic testing Objective, quantitative Moderate sensitivity, requires special

equipment

Nerve/skin biopsy Quantitative, sensitive Invasive, problems with wound healing,

specialist histological technique to quantify

intraepidermal nerve fiber

Corneal confocal microscopy/Corneal

aesthesiometry

Rapid, noninvasive, reiterative, quantitative Requires special equipment and expertise

Table 2. Description of the Stages of Severity10

Grade 0 No abnormality of NC

Grade 1a Abnormality of NC

Grade 1b NC abnormally of stage 1a plus neurologic signs typical of DSPN but without neuropathy symptoms

Grade 2a NC abnormality of stage 1a plus neurologic signs typical of DSPN but without neuropathy symptoms

Grade 2b NC abnormality of stage 1a, a moderate degree of weakness of ankle dorsiflexion with or without

neuropathy symptoms

Table 3. Definitions of minimal criteria for typical DPN10

Possible

DSPN

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

Probably

DSPN

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

Confirmed

DPSN

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

V.

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 opioidsg.

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 ratioefficacy Odds ratiowithdrawal

(secondary to AE)

NNT NNH

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

anticonvulsants5.3 (1.816.0) 1.5 (0.37.0) 2.13.2 2.73.0

New generation

anticonvulsants3.3 (2.34.7) 3.0 (1.755.1) 2.94.3 26.1

Opioids 4.3 (2.37.8) 4.1 (1.214.2) 2.63.9 9.0

VI.

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

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); 1040-

1043

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 diseaseso 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 groupsSignificantly improved TSS pain and burning subscores

Change from baseline to Day 19

Placebo Thioctic Acid (ALA) P-value

TSS in feet -1.94 + 1.50 (-24%) -3.75 + 1.88 (-47%) P = 0.021*

HPAL -0.96 + 1.32 (-29%) -2.20 + 1.65 (-60%) P = 0.072

NDS +0.18 + 0.4 -0.27 + 0.47 P = 0.025*

*statistically significant

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Authors

Conclusion

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

Comments Strengths

Randomized, double-blind, placebo

controlled trial

Exclusion of patients currently or previouslytaking antioxidants one month before the

study

Weaknesses

Small sample size, only 22 patients

completed the trial

Short duration of treatmentNever defined the severe concomitant

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 Care2006;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 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 last3 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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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

Results 181 diabetic patients in Russia and Israel randomized, only 166 completed the trial

All groups were comparable in age, gender, disease state, blood pressure, polyneuropathystage

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

Change from baseline after 5 weeks on treatment

ALA600 ALA1200 ALA1800 Placebo

Mean TSS -4.9 (51%)* -4.5 (48%)* -4.7 (52%)* -2.9 (32%)

Response rate 62% 50% 56% 26%

Stabbing Pain -1.40* -1.56* -1.46* -0.83Burning Pain -1.32* -1.09* -1.15* -0.50

Parethesiae -1.16 -0.85 -1.12 -0.80

Numbness -0.97 -0.99 -0.98 -0.79

Changes from initial screening levels after 5 weeks

ALA600 ALA1200 ALA1800 Placebo

NSC number -2.8* -2.8* -2.7 -1.7

NSC severity -7.4* -7.2* -7.6* -4.9

NSC change +8.6* +8.5* +9.5* +5.4

NIS -3.80 -3.85 -3.85* -2.38

NIS-LL -3.75 -2.63 -2.70 -2.08

NIS-LL sensoryfunction

-2.25* -1.73 -1.55 -1.05

*statistically significant

Authors

Conclusions

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

Comments Strengths

Randomized, double-blind placebo-

controlled

Safety analysis and adverse effects were

reported

Weaknesses

Relatively small study

Short duration of treatment

Self-report of symptom improvement

Randomization method was not describedInclusion 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

o NIS-LL and seven nerve conduction test score > 97.5th

percentile

o NIS-LL > 2 points

o One of two abnormalities:

Abnormal nerve conduction attributable in two separate nerves > 99th

percentile for distal latency or < 1 percentile for nerve conduction velocity

or amplitude

Abnormal heart rate during deep breathing (HRDB) < 1

st

percentile or TSS inthe 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

patientsability to participate in the trialo 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

admissiono 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 4-

week 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 testsSecondary outcomes:

o NIS, NIS-LL

Results 460 diabetic patients randomized

Improved NIS (P=0.028), NIS-LL (P=0.05), and NIS-LL muscle weakness subscore (P=0.045)

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

Compositescore

NIS-LL+7(nds)

-0.40 + 4.92 0.19 + 4.74 -0.37 + 5.59 0.29 + 5.37

Authors

Conclusion

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

Comments Strengths

Randomized double blind placebo

controlled

Appropriate time length

Assessed nerve conductionLarge study population

Weaknesses

Extensive exclusion criteria may have

influenced the patient population

Inclusion of T1DM patients

Stable insulin regimen was never defined

VIII.

Summary

Study Patient

type

Primary

outcome

Secondary

outcome

ALA dosage Length of

Study

Difference in

intervention vs.

control for primary

outcome

ORPIL T2DM TSS HPAL, NDS a)600 mg TID 3 weeks -1.81 (P= 0.021)

SYDNEY 2T1DM +

T2DMTSS NCS, NIS

a)600 mg

dailyb)1200 mg

daily

c)1800 mg

daily

5 weeks

-1.93 (P

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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, occurredmost 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 DSPNc.

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

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

Drug and dose Subjects (N) Duration(wk) Mean age (y) Measured

outcome

NNT (95%

CI)

NNH (95% CI)

Various tricyclic

antidepressants

and doses

177 3-12 50Overall

effectiveness1.3 (1.2-1.5)

Treatmentcessation: 28

(17.6-68.9)

Minor adverse

effects: 6(4.2-

10.7)

Duloxetine

60mg/d 120

mg/d

655

65512 N/A

50% pain

reduction

6.0 (5-10)

6.0 (5-10)

Treatment

cessation: 17 (12-

50)

Pregablin 600mg/d 1425 5-13 59 50% painreduction 5 (4-6.6)

Somnolence: 8.8

(7-12)*

Dizziness: 2.8

(2.5-3.2)

Treatment

cessation: 8.8

(6.8-12)

Gabapentin

1200-3600

mg/d

829 4-12 5850% pain

reduction5.8 (4.3-9.0)

Any adverse

effect: 6.6 (5.3-

9.0)

Treatment

cessation: 32 (19-

100)

Oxycodone 20-

80 mg/d36 4 63

Moderate painrelief (defined as

a score of 3 on a

6-point scale)

2.6 (N/A)

Nausea: 4(2-219)

Constipation: 4(2-19)

Treatment

cessation: 7 (4-

87)

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

Absent Symptom

Slight

Intensity

Moderate

Severe

Occasional 0 1.00 2.00 3.00

Frequent 0 1.33 2.33 3.33

(Almost)

continuous

0 1.66 2.66 3.66

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Appendix C4

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Appendix D15-18

Trial Patient

Type

ALA dosage Length

of study

Authors Conclusion

ALADIN I T2DM

a)100 mg IV

b)600 mg IV

c)1200 mg IV

3 weeksSignificant improvement in TSS (pain,

numbness, and parathesias)

ALADIN IIT1DM

T2DM

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

2 yearsSignificant improvement in peripheral

NC

ALADIN

IIIT2DM

LA 600 mg/day IV x 3 weeks

followed by LA 600 mg PO TID x 6

months

7 months

Trend towards improved neuropathy

but no statistically significant

improvement

SYDNEY IT1DM

T2DM

600 mg IV daily 5 days per week

for 14 treatments3 weeks

Rapid, significant and clinical

improvement in TSS (positive

neuropathic sensory systems)

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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 studyObjective 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

Responders

(n)

Non-Responders

(n)

Rate of Side

Effects

Frequency of

outpatient visits

(per 3 months)

ALA

(n= 443)333 110 3% 3.8

Gabapentin

(n = 293)132 (45%) 161 (55%) 68% 7.9

Non

treatment

(n =150)

- 110 (73%) - -

Authors

Conclusion

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

Comments Strengths

Large study population

Study length was appropriate

Compared ALA to pharmacologic

treatment

Weaknesses

Observational study

No inclusion or exclusion criteria listed

ALA was compared to gabapentin

however gabapentin is not a first line

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Appendix F

Abbreviations

ADA- American Diabetes Association

ALA- alpha lipoic acid

DSPN- diabetic sensorimotor polyneuropathy

HPAL- Hamburg Pain Adjective List

QOL-quality of life

NISneuropathy 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

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

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