Effect of a-lipoic acid on symptoms

Clinical Report
Effect of a-lipoic acid on
symptoms and quality of
life in patients with painful
diabetic neuropathy

Evangelos Agathos, Anastasios Tentolouris ,
Ioanna Eleftheriadou, Panagiota Katsaouni,
Ioannis Nemtzas, Alexandra Petrou,
Christina Papanikolaou and
Nikolaos Tentolouris

Objective: To examine the effect of a-lipoic acid on neuropathic symptoms in patients with
diabetic neuropathy (DN).
Methods: Patients with painful DN were treated with 600 mg/day a-lipoic acid, orally,
for 40 days. Neuropathy Symptom Score (NSS), Subjective Peripheral Neuropathy Screen
Questionnaire (SPNSQ) and douleur neuropathique (DN)4 questionnaire scores were
assessed at baseline and day 40. Quality-of-life treatment effects were assessed by Brief
Pain Inventory (BPI), Neuropathic Pain Symptom Inventory (NPSI) and Sheehan Disability Scale
(SDS). Changes in body weight, arterial blood pressure, fasting serum glucose and lipids were also
Results: Out of 72 patients included, significant reductions in neuropathic symptoms were
shown by reduced NSS, SPNSQ and DN4 scores at day 40 versus baseline. BPI, NPSI, and
SDS in terms of work disability, social life disability, and family life disability scores were also
significantly reduced. Moreover, 50% of patients rated their health condition as ‘very much better’
or ‘much better’ following a-lipoic acid administration. Fasting triglyceride levels were reduced,

Diabetes Centre, First Department of Propaedeutic
Internal Medicine, Medical School, National and
Kapodistrian University of Athens, Laiko General
Hospital, Athens, Greece
Part of this work was orally presented at the 5th Hellenic
Congress of the Hellenic Association for the Study of the
Diabetic Foot (EMEDIP) on February 5–7, 2016, Athens,

Corresponding author:
Nikolaos Tentolouris, Diabetes Centre, First Department
of Propaedeutic Internal Medicine, Medical School,
National and Kapodistrian University of Athens, Laiko
General Hospital, 17 Agiou Thoma Street, 11527, Athens,
Email: ntentol@med.uoa.gr

Journal of International Medical Research
2018, Vol. 46(5) 1779–1790
! The Author(s) 2018
Reprints and permissions:
DOI: 10.1177/0300060518756540

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative
Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/)
which permits non-commercial use, reproduction and distribution of the work without further permission provided the original
work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).

but no difference was found in body weight, blood pressure, fasting glucose, or other lipids at day
40 versus baseline.
Conclusions: A-lipoic acid administration was associated with reduced neuropathic symptoms
and triglycerides, and improved quality of life.
A-lipoic acid, Diabetes mellitus, Diabetic neuropathy, Neuropathic symptoms, Painful diabetic
neuropathy, Quality of life
Date received: 26 November 2017; accepted: 9 January 2018

Diabetes mellitus is a major public health
problem, reaching epidemic proportions
globally. Approximately 9% of adults are

estimated to be affected by diabetes world-
wide, however, around half of the cases

remain undiagnosed.1 Peripheral neuropa-
thy is a common complication in patients

with diabetes, with population and clinic-
based studies suggesting prevalence rates of

5.3–47.6% for peripheral sensorimotor neu-
ropathy.2–6 Diabetic peripheral neuropathy

is associated with older age, long duration
of diabetes mellitus, poor glycemic control,

increased lipid levels and high blood pres-
sure.2 In addition to sensory loss and

motor deficits, diabetic neuropathy may be
associated with intractable neuropathic pain.
Significant improvements have been made in

therapeutic options that target mainly neu-
ropathic symptoms, but not in those that

target pathogenetic mechanisms.2 Despite
therapeutic advances, diabetic neuropathy
is still associated with substantial morbidity,
increased mortality, and impaired quality of
life (QoL) compared with patients who have
diabetes but no neuropathy.
Oxidative stress is thought to possess a

significant role in the pathogenesis of diabet-
ic neuropathy.7 A-lipoic acid, a very potent

antioxidative agent, has been shown to

improve nerve blood flow, reduce oxidative
stress and improve distal nerve conduction
in a rat model of diabetic neuropathy.8
Clinical studies investigating the effect of
a-lipoic acid on diabetic neuropathy have

revealed promising results in terms of neuro-
pathic symptoms.9–12 In addition, a recent

meta-analysis revealed that treatment with
300–600 mg/day a-lipoic acid, intravenously

(i.v.) for 2–4 weeks, was safe and significant-
ly improved nerve conduction velocity and

neuropathic symptoms.13
The aim of the current study was to
prospectively investigate the effect of
600 mg/day a-lipoic acid (Nevralip RetardVR
Medical Pharmaquality, Athens, Greece)

administered orally for 40 days, on symp-
toms, laboratory parameters, QoL, and over-
all health status of patients with painful

diabetic neuropathy.
Patients and methods
Study population and setting
This prospective, interventional study was
conducted at Laiko General Hospital,
Athens, Greece, between September 2015
and May 2016. Patients with type 1 or
type 2 diabetes mellitus, who were followed
at the outpatient Diabetes Clinic of Laiko
General Hospital and were eligible to
1780 Journal of International Medical Research 46(5)

participate, were consecutively enrolled into
the study. Inclusion criteria comprised the

following: (1) patient’s agreement to partic-
ipate; (2) aged 18–75 years; (3) diabetic

peripheral neuropathy diagnosis and
one typical painful neuropathic symptom

such as burning, shooting pain, paraesthe-
sia, muscle cramps or allodynia, in the feet,

for 6 months, that interfered with daily

life or sleep; and (4) if treated with medica-
tions for painful diabetic neuropathy, treat-
ment had to be stable for 3 months before

recruitment into the study. Exclusion crite-
ria comprised: (1) causes of neuropathy

other than diabetes (such as chronic alcohol

misuse, vitamin B12 deficiency, drug-
induced neuropathy), truncal neuropathy

or severe neurological diseases (such as
Parkinson’s disease and multiple sclerosis);
(2) severe renal disease defined as estimated
glomerular filtration rate (eGFR) < 30 ml/
min/1.73m2 using the Modification of Diet
in Renal Disease formula,14 or severe liver
disease; (3) recent treatment for cancer or
haematological malignancies; (4) presence
of foot ulcers; (5) peripheral arterial disease
defined as non-palpable pulses at the feet
arteries and/or intermittent claudication;
(6) use of agents in the previous 3 months
that could interfere with the interpretation

of results, such as opiates, vitamin B com-
pounds or antioxidants; and (7) pregnancy,

lactation, or childbearing age without use
of safe contraception.
Participants were prescribed 600 mg/day
a-lipoic acid (Nevralip RetardVR

), orally, for

40 days, and were advised not to discontin-
ue any medications for managing painful

diabetic neuropathy, antidiabetic drugs, or
medications used for managing arterial
hypertension or dyslipidaemia during the
The study was approved by the Ethics
Committee of Laiko General Hospital,
and was conducted in accordance with the
Declaration of Helsinki (1964). Written

informed consent was obtained from all
Definition of neuropathy
Diabetic peripheral neuropathy was defined
as the presence of signs and/or symptoms of
peripheral nerve dysfunction in patients
with diabetes after the exclusion of other
causes.2 In the current study, assessment
of diabetic peripheral neuropathy included
examination of symptoms and signs, and
quantitative sensory testing. Symptoms of
somatic neuropathy were assessed using
the Neuropathy Symptom Score (NSS), as
described previously,2 and the Neuropathy
Disability Score (NDS) was used, as
described previously,15 to quantify signs of
diabetic peripheral neuropathy. The criteria

for diagnosing diabetic peripheral neuropa-
thy were NDS 6 irrespective of the NSS

values, or NDS 1⁄4 3–5 with NSS 5.2
Data collection and patient follow-up

Two visits were scheduled for data collec-
tion, physical examination and laboratory

testing of participating patients: the first

prior to initiation of a-lipoic acid adminis-
tration (baseline visit) and the second at day

40 following initiation of a-lipoic acid

(2nd visit). The following data were collect-
ed from participants’ medical records and

through personal interviews by one trained
healthcare professional (E.A.): age, gender,
type of diabetes mellitus, history of other
underling diseases, diabetes medications,

other medications, and alcohol consump-
tion. Height and weight were measured in

light clothing and body mass index (BMI)
was calculated. Systolic and diastolic blood
pressure was measured twice, 2 min apart,
with the patient in a sitting position and
the mean of the two measurements was
recorded. All measurements were performed
at the baseline visit (by E.A.) and at the end
of the study (2nd visit at day 40 [by C.P.]).
Agathos et al. 1781

Assessment of neuropathic symptoms and
QoL measures

Data regarding patients’ neuropathy symp-
toms, QoL, and patients’ perception of

overall health status were collected by one
trained healthcare professional (E.A)
during the baseline (E.A.) and 2nd visit
(C.P.) using specific questionnaires. All
questionnaires were administered via face

to face interview with the healthcare profes-
sional and without any time limit.

Neuropathy symptom scores were calcu-
lated for both visits using the following

1. Neuropathy Symptoms Score (NSS),16

comprising five questions about neuropa-
thy symptoms, with a score ranging from

‘0’ (no neuropathic symptoms) to ‘10’ (the
most severe neuropathic symptoms).
2. Subjective Peripheral Neuropathy Screen
Questionnaire (SPNSQ),17 comprising 15
‘yes/no’ questions regarding symptoms
of neuropathy, with the score calculated

by summing the ‘yes’ answers, and rang-
ing from ‘0’ (no neuropathic symptoms)

to ‘15’ (the most severe neuropathic
3. Douleur neuropathique (DN)4
Questionnaire,18 comprising 10 ‘yes/no’
items regarding neuropathic pain, with
the score calculated by summing the
‘yes’ answers, and ranging from ‘0’ (no
neuropathic pain) to ‘10’ (the most
severe neuropathic pain).

Quality of life was assessed using the fol-
lowing questionnaires.

1. Brief Pain Inventory (BPI)-modified
short form (SF),19 comprising 11 items
(the first four concerned the severity of
patients’ pain, and the remaining seven

concerned the degree to which pain inter-
feres with the common dimensions of

feeling and function). The answers to

all items ranged from ‘0’ (‘no pain’ in the
case of the first four and ‘no interference’
in the case of the other seven) to ‘10’ (‘pain
as bad as you can imagine’ in the case of
the first four and ‘interferes completely’ in
the case of the other seven). Two scores
were calculated: the BPI severity score
(mean number of correct answers to the
first four items) and the BPI interference
score (mean number of the correct answers
to the last seven items).
2. Neuropathic Pain Symptom Inventory
(NPSI),20 comprising six scores: Total
Intensity Score, ranging from ‘0’ (none)
to ‘100’ (worst imaginable); and five
scores corresponding to dimensions of

pain, namely, burning (superficial) spon-
taneous pain, pressing (deep) spontane-
ous pain, paroxysmal pain, evoked pain,

and paraesthesia/dysesthesia (all ranging
from ‘0’ [none] to ‘10’ [worst imaginable]).
3. Sheehan Disability Scale (SDS),21 which

included three self-rated items that mea-
sured functional impairment, and generat-
ed three scores: work-disability score, social

life-disability score, and family-life disabili-
ty score, ranging from ‘0’ (no disability) to

‘10’ (worst imaginable disability).
Patient Global Impression-Improvement
(PGI-I) was also estimated during the 2nd
visit. In particular, the patient described
his/her condition, compared with how it
was before the initiation of treatment with

a-lipoic acid, using the following descrip-
tors: ‘very much better’, ‘much better’,

‘a little better’, ‘no change’, ‘a little worse’,
‘much worse’, or ‘very much worse’. The

physician who administered the question-
naires at the 2nd visit (C.P.) was not

aware of the baseline visit responses.
Laboratory assays
Blood samples (approximately 15 ml per
sample) were collected following a 12-h
overnight fast, via venepuncture of the
1782 Journal of International Medical Research 46(5)

forearm vein. Blood samples were left for

10 min at room temperature to allow clot-
ting and then centrifuged at 4042 g for 15

min at 4C. Measurements were performed
immediately following centrifugation.
Fasting serum glucose, creatinine and lipids
were measured using an automated

Technicon RA-XT clinical chemistry analy-
ser and reagents (Technicon Instruments,

Tarrytown, NY, USA) according to the
manufacturer’s instructions. The
Friedewald formula22 was used to calculate

low-density lipoprotein cholesterol (LDL-
C). Glycosylated haemoglobin (HbA1c) was

measured using high-performance liquid
chromatography, and eGFR was calculated
using the Modification of Diet in Renal
Disease formula. All measurements were
performed at the baseline and 2nd visit,

except for serum creatinine which was mea-
sured only at baseline.

Statistical analyses
Data were analysed using SPSS software,
version 22.0 (IBM, Armonk, NY, USA)

for Windows. Continuous variables are pre-
sented as mean SD, or median, minimum

and maximum values. Nominal variables

are presented as n (%) prevalence or fre-
quencies. A 95% confidence interval (CI)

was calculated to assess the difference in
mean NSS between the baseline and 2nd
Visit. Student’s t-test was used to compare
total scores/measurements between the
baseline and 2nd visit. McNemar’s test
was used to compare the percentage of
‘yes’ responses for the DN4 questionnaire
and SPNSQ between the baseline and 2nd
visit. Multivariate linear regression was

used to investigated any statistical associa-
tions between changes in NSS, DN4 ques-
tionnaire and SPNSQ scores from the

baseline and 2nd visit (dependent variables)
and the following parameters (independent
variables): age, sex, BMI, comorbidities,
arterial blood pressure and heart rate. All

tests were two sided with a 1⁄4 0.05. A P val-
ue < 0.05 was considered statistically

Sample size
The sample size was determined by the
number of patients with diabetes that could
be recruited within one year. The sample size
of 72 patients gave a very high precision
regarding the CI estimation of the difference
in NSS between the baseline and 2nd visit.
Specifically, the precision was 0.5 units and
the corresponding CI for the NSS difference
(improvement) was 2.6 0.5 (95% CI 2.1,
During the study period 96 patients with
neuropathy were invited to participate; 10
patients failed to meet the study inclusion
criteria and 14 patients were not eligible due
to exclusion criteria. Of these, 72 patients
were eligible and all completed the study
successfully. Baseline characteristics and
medications are shown in Tables 1 and 2,

Statistically significant reductions in neu-
ropathic symptoms were noted by patients

following the 40-day administration of
a-lipoic acid, indicated by changes in NSS,
SPNSQ and DN4 scores. Mean NSS score
was 7.9 (range, 4–10) at the baseline visit
compared with 5.3 (range, 2–10) at day 40
of treatment (P < 0.001). Results of the

SPNSQ by visit revealed a statistically sig-
nificant decrease in 14 out of the 15 ques-
tions for neuropathy symptoms at day 40

compared with baseline (Table 3), while
mean SPNSQ score decreased from
8.8 (range, 3–15) at baseline to 4.4 (range,

0–14) at the end of a-lipoic acid administra-
tion at day 40 (P < 0.001). Statistically

significant reductions were also noted for
the DN4 questionnaire scores, in all 10
questions regarding pain characteristics
Agathos et al. 1783

(Table 4). In addition, patients’ mean DN4
questionnaire score was also significantly
reduced from baseline (mean score, 5.7
[range, 1–9]) compared with day 40 (mean
score, 2.8 [range, 0–8]; P < 0.001).
Regarding patients’ QoL, BPI scores
revealed a significant reduction in pain
severity (mean score, 4.3 [range, 0–9] at
baseline versus 2.3 [range, 0–9] at day 40;
P < 0.001) and pain interference (mean

score, 5.2 [range, 0–10] at baseline versus
3.2 [range, 0–9.7] at day 40; P < 0.001).
Similarly, a significant reduction in NPSI
score was noted in terms of NPSI Total
Intensity Score (mean score, 40.1 [range,
8–88] at baseline versus 20.3 [range: 0–86]
at day 40; P < 0.001), burning (superficial)
spontaneous pain (mean score, 5.6 [range,
0–10] at baseline versus 2.9 [range, 0–10] at

day 40; P < 0.001), pressing (deep) sponta-
neous pain (mean score, 3.5 [range, 0–10] at

baseline versus 1.8 [range, 0–9.5] at day 40;
P < 0.001), paroxysmal pain (mean score,
4.3 [range, 0–9.5] at baseline versus 2.0
[range, 0–9.5] at day 40; P < 0.001),
evoked pain (mean score, 2.3 [range, 0–
8.7] at baseline versus 1.5 [range, 0–6.3] at

Table 1. Baseline demographic and clinical char-
acteristics in 72 adult patients with painful diabetic

neuropathy scheduled to receive 600 mg/day
a-lipoic acid, orally, for 40 days.
Characteristic Value
Age, years 65.2 8.4
Sex, male 28 (38.9)
Body mass index, kg/m2 31.3 5.4
Type 1 diabetes mellitus 11 (15.3)
Type 2 diabetes mellitus 61 (84.7)
Duration of diabetes, years 12.7 8.8
Systolic blood pressure, mmHg 134.2 13.9
Diastolic blood pressure, mmHg 75.8 9.6
Heart rate, beats/min 73.8 10.3
Glycosylated haemoglobin HbA1c, % 7.8 1.9
Estimated glomerular
filtration rate, ml/min/1.73 m2

75.3 21.2

Location of
neuropathic symptoms*
Foot 67 (93.1)
Calves 17 (23.6)
Thigh 8 (11.1)
Medical history*
Coronary artery disease 12 (16.7)
Stroke 6 (8.3)
Peripheral vascular disease 33 (45.8)
Diabetic nephropathy 13 (18.1)
Retinopathy 14 (19.4)
Fasting glucose, mg/dl 141.4 53.7
Total cholesterol, mg/dl 190.4 24.7
Triglycerides, mg/dl 146.8 73.4
High density lipoprotein
cholesterol, mg/dl

49.7 9.6

Low density lipoprotein
cholesterol, mg/dl

110.6 17.4
Data presented as mean SD or n (%) patient prevalence. *
More than one answer is possible in these items.

Table 2. Baseline medications of 72 adult patients
with painful diabetic neuropathy scheduled to
receive 600 mg/day a-lipoic acid, orally, for 40 days.
Treatment type Prevalence
Diabetes treatment*
Insulin 56 (77.8)
Biguanide 46 (63.9)
Dipeptidyl peptidase

22 (30.6)
Sulfonylurea 11 (15.3)
Glinide 1 (1.4)
Glucagon-like protein-1
receptor agonist

4 (5.6)
Pioglitazone 3 (4.2)
co-transporter 2 inhibitors

1 (1.4)

Other treatment*
Statin 50 (69.4)
Fibrate 8 (11.1)
Antihypertensive 60 (83.3)
Antiplatelet therapy 45 (62.5)
Medication for painful
Pregabalin 18 (25.0)
Gabapentin 8 (11.1)
Paracetamol 3 (4.2)
Duloxetine 2 (2.8)
Data presented as n (%) patient prevalence. *
Patients may receive more than one medication.
1784 Journal of International Medical Research 46(5)

day 40; P < 0.001), and paraesthesia/dyses-
thesia (mean score, 5.9 [range, 0–10] at

baseline versus 3.0 [range, 0–10] at day 40;

P < 0.001). Statistically significant reduc-
tions were also evident in the SDS score

between the baseline and day 40 visit, in
terms of work disability score, social life
disability score, and family life disability
score (P < 0.001; Figure 1).

Lastly, PGI-I at the day 40 visit revealed
that 36 patients (50%) rated their health
condition as ‘very much better’ or ‘much
better’. No change was reported by 14
patients (19.4%), and none of the patients
reported worsening of symptoms.
In terms of laboratory parameters,

mean fasting triglyceride levels were signif-
icantly reduced during the a-lipoid acid

Table 3. Baseline and end-of-treatment Subjective Peripheral Neuropathy Screen
Questionnaire responses of 72 adult patients with painful diabetic neuropathy treated with 600
mg/day a-lipoic acid, orally, for 40 days.

Positive response rate

significancea Neuropathic symptom Baseline End of treatment
Do you ever have legs and/or feet that
feel numb?

63 (87.5) 30 (41.7) P <0.001

Do you ever have any burning pain in
your legs and/or feet?

60 (83.3) 28 (38.9) P <0.001
Are your feet too sensitive to touch? 26 (36.1) 16 (22.2) P 1⁄4 0.013
Do you get muscle cramps in your legs
and/or feet?

53 (73.6) 20 (27.8) P <0.001

Do you ever have any prickling or tin-
gling feelings in your legs or feet?

56 (77.8) 20 (27.8) P <0.001

Does it hurt at night or when the
covers touch your skin?

26 (36.1) 10 (13.9) P <0.001

When you get into the tub or shower,
are you unable to tell the hot water
from the cold water with your feet?

22 (30.6) 17 (23.6) NS

Do you ever have any sharp, stabbing,
shooting pain in your feet or legs?

47 (65.3) 17 (23.6) P <0.001

Have you experienced an asleep feeling
or loss of sensation in your legs or

18 (25.0) 5 (6.9) P <0.001
Do you feel weak when you walk? 51 (70.8) 34 (47.2) P <0.001
Are your symptoms worse at night? 48 (66.7) 27 (37.5) P <0.001
Do your legs and/or feet hurt when you

46 (63.9) 26 (36.1) P <0.001

Are you unable to sense your feet when
you walk?

39 (54.2) 24 (33.3) P <0.001

Is the skin on your feet so dry that it
cracks open?

37 (51.4) 27 (37.5) P 1⁄4 0.002

Have you ever had electric shock-like
pain in your feet or legs?

44 (61.1) 17 (23.6) P <0.001

Data presented as n (%) positive response. a
Statistically significant differences at P < 0.05 (McNemar’s test).
NS, no statistically significant between group difference (P > 0.05; McNemar’s test).
Agathos et al. 1785

administration (146.8 mg/dl [range, 49–
390 mg/dl] at baseline versus 135.5 mg/dl
[range, 56–337 mg/dl] at day 40;

P 1⁄4 0.004). No statistically significant dif-
ference was found in terms of fasting glu-
cose, total cholesterol, LDL-C, high-density

lipoprotein cholesterol, HbA1c, BMI, arte-
rial blood pressure or heart rate between

the baseline and day 40 visits (data not
A-lipoic acid was well tolerated, no patient
discontinued treatment, and no adverse

events were noted during the 40-day treat-
ment period.

The aim of the current study was to
prospectively investigate the effects of

a-lipoic acid on neuropathic symptoms, lab-
oratory parameters and overall quality of

life in patients with diabetic neuropathy.
Treatment with 600 mg/day a-lipoic acid,
orally for 40 days was found to be

Table 4. Baseline and end-of-treatment douleur neuropathique (DN)4 ques-
tionnaire responses of 72 adult patients with painful diabetic neuropathy treated

with 600 mg/day a-lipoic acid, orally, for 40 days.
Positive response rate [see


characteristic Baseline

End of

Burning 57 (79.2) 24 (33.3) P <0.001
Painful cold 22 (30.6) 13 (18.1) P 1⁄4 0.012
Electric shock 43 (59.7) 17 (23.6) P <0.001
Tingling 61 (84.7) 33 (45.8) P <0.001
Pins and needles 62 (86.1) 26 (36.1) P <0.001
Numbness 62 (86.1) 31 (43.1) P <0.001
Itching 22 (30.6) 12 (16.7) P 1⁄4 0.006
Hypoesthesia to touch 31 (43.1) 19 (26.4) P 1⁄4 0.002
Hypoesthesia to prick 29 (40.3) 15 (20.8) P <0.001
The pain is caused or
increased by brushing

22 (30.6) 10 (13.9) P <0.001

Data presented as n (%) positive response. a
Statistically significant differences (P < 0.05; McNemar’s test).

Figure 1. Sheehan Disability Scale scores of 72
adult patients with painful diabetic neuropathy
treated with 600 mg/day a-lipoic acid, orally, for 40
days; Data presented as mean SD; P < 0.001

between baseline and day 40 visit for all compari-
sons (Student’s t-test).

1786 Journal of International Medical Research 46(5)

associated with a clinically significant and
prompt reduction in neuropathy symptoms
and an overall improvement in patients’
quality of life. Indeed, treated patients

noted significant improvements in neuro-
pathic symptoms, indicated by reduced

NSS, SPNSQ, and DN4 questionnaire
scores following 40 days of treatment with
a-lipoic acid compared with baseline scores.
Importantly, the patients noted an overall
improvement in quality of life, which was
reflected by the reduction in pain severity
and pain interference in terms of BPI
scores; total score, burning spontaneous
pain, pressing spontaneous pain, paroxysmal

pain, evoked pain, and paraesthesia/dyses-
thesia in NPSI scores; and work disability

score, social life disability score, and family
life disability score in the SDS. In addition,
fasting triglyceride levels were significantly

reduced during the 40-day period. The over-
all treatment demonstrated an excellent

safety profile. It remains to be determined
if the improvement of neuropathy symptoms

could be further enhanced by treatment pro-
longation beyond 40 days and more impor-
tantly if this will have an impact on the long-
term course of diabetic neuropathy per se.

A-lipoic acid, an essential co-enzyme for

energy production in mitochondria, demon-
strates substantial antioxidant properties

and an effect on whole-body physiology.23
A-lipoic acid is found in very low quantities
in almost all foods, and is used as a dietary
supplement and a pharmaceutical agent.24
A-lipoic acid is well absorbed, diffuses

efficiently in both extra-cellular and intra-
cellular spaces, and penetrates the blood-
brain barrier.25 It has been used in several

oxidative-stress models such as diabetes,
ischemia-reperfusion injury, cataract, and
neurodegenerative disorders, as well as in
mushroom and heavy metal poisoning.
Adverse events of a-lipoic acid may include
nausea, vomiting and mild skin reactions.25
A meta-analysis of four clinical trials
comprising 1 258 patients with diabetic

neuropathy (a-lipoic acid-treated group,
716 patients; placebo group, 542 patients)
showed a favourable effect for 600 mg/day
a-lipoic acid, administered i.v., for three

weeks.26 In particular, the relative differ-
ence between baseline and the end of the

three-week treatment was 24.1% for Total
Symptom Score (a composite score of all
neuropathic symptoms), and 16.0% for

Neuropathy Impairment Score.26 In addi-
tion, the responder rates were 52.7%

( 50% improvement in Total Symptom
Score) in the a-lipoic acid-treated group
compared with 36.9% in the placebo
group (P < 0.05).26 This meta-analysis
showed a clear reduction in pain, burning,
paraesthesia, and numbness in the a-lipoic
acid-treated group,26 and no difference in
terms of adverse events and overall safety
was noted between the two groups.

Moreover, another meta-analysis of 15 ran-
domized controlled trials involving patients

with diabetic peripheral neuropathy showed
that treatment with 300–600 mg/day a-lipoic

acid, i.v. for 2–4 weeks was statistically supe-
rior to the control group for increasing

median and peroneal motor nerve conduc-
tion velocity and median and peroneal sen-
sory nerve conduction velocity.13

The pathogenesis of diabetic neuropathy
remains largely unknown. Metabolic and
vascular defects, under increased oxidative
stress, are both implicated in nerve injury in
patients with diabetes.7,13 The rationale for
improvement in neuropathic symptoms in
patients with diabetes, following treatment
with a-lipoic acid, most probably relies on
its antioxidant action. A-lipoic acid, and its
reduced form, dihydrolipoic acid, act as
antioxidants through neutralization of a
variety of reactive oxygen species, inhibition
of reactive-oxygen generators, and repair of
damage caused by other oxidants.23,24 The
antioxidant action of a-lipoic acid may also

contribute to the clinically-significant subsi-
dence of neuropathic symptoms through

improvement in nerve blood flow.27
Agathos et al. 1787

Moreover, a-lipoic acid may interact with
other antioxidants or contribute additively
to the antioxidant effect through different
parameters.25 A recent study compared the
effects of 300 mg/day a-lipoic acid for
90 days with two other antioxidants,
namely omega 3 fatty acids and vitamin E,
in patients with type 2 diabetes mellitus.28 In
this study, significant improvements were
found in all treatment groups in parameters
of oxidative stress, insulin resistance, BMI,
waist circumference, and total cholesterol
Evidence-based clinical indications for
administration of a-lipoic acid include

migraine and chronic pain. In patients suf-
fering from migraines, 600 mg/day a-lipoic

acid, administered orally for three months,
showed a statistically significant reduction
in the number, duration and severity of
migraine crises per month, and an overall
response rate of 30%, while these outcomes
remained unchanged in the placebo

group.29 In patients with peripheral neuro-
pathic sciatic pain caused by herniated disc,

600 mg/day a-lipoic acid for 60 days signif-
icantly improved signs and symptoms and

electromyography findings compared with
1180 mg/day acetyl-L-carnitine. In addition,
more patients receiving a-lipoic acid than
acetyl-L-carnitine reported a reduced need
for analgesics (71% versus 45.5%;
P 1⁄4 0.05).30 Similar results have been noted
with 600 mg/day a-lipoic acid in patients
with lower back pain and chronic cervical
pain, and with 300 mg/day a-lipoic acid in
patients with carpal tunnel syndrome.31–33
Clear advantages of the current study
include its prospective design and the very
high precision with the specific sample size.
Moreover, the study was a conducted in a
single centre, thus limiting the possibility of
between-centre variability, as noted by
others.26 This was an open-label study,
however, without a placebo treatment arm,
and as such has inherent limitations, since

both the study participants and the health-
care providers were aware of the treatment

provided. Thus, imagined or random effects
of the agent cannot be ruled out.
Furthermore, it is unclear if and at what
extent the recorded benefits in the present
study group would subside after a-lipoic
In conclusion, the current study suggests
that 600 mg/day a-lipoic acid, administered
orally for 40 days, to patients with painful

diabetic neuropathy, has a clinically signif-
icant impact on controlling neuropathy

symptoms, fasting triglycerides, and quality
of life. Moreover, half of the treated
patients rated their health status as ‘much
better’ or ‘very much better’ following 40

days of treatment. The current findings sug-
gest that a-lipoic acid is beneficial and thus

should be considered for routine adminis-
tration in patients with diabetes and periph-
eral neuropathy. Whether the recorded

improvements could be augmented further

by prolongation of a-lipoic acid administra-
tion beyond 40 days, or if a-lipoic acid

could decelerate the course of neuropathy
in the long-term, remains to be determined.
Nevralip RetardVR

tablets were kindly provided
by Medical Pharmaquality, Athens, Greece.
Declaration of conflicting interests
The authors declare that there is no conflict of
This research received no specific grant from any
funding agency in the public, commercial, or
not-for-profit sectors.
Anastasios Tentolouris http://orcid.org/0000-

1788 Journal of International Medical Research 46(5)

1. International Diabetes Federation. IDF
Diabetes Atlas, 7th Edition. Brussels,
Belgium: International Diabetes Federation.
http://www.diabetesatlas.org (2015, accessed
November 2017).
2. Boulton AJ, Vinik AI, Arezzo JC, et al.
Diabetic neuropathies: a statement by the
American Diabetes Association. Diabetes
Care 2005; 28: 956–962.
3. Partanen J, Niskanen L, Lehtinen J, et al.
Natural history of peripheral neuropathy in
patients with non-insulin-dependent diabetes
mellitus. N Engl J Med 1995; 333: 89–94.
4. Dyck PJ, Kratz KM, Karnes JL, et al. The
prevalence by staged severity of various
types of diabetic neuropathy, retinopathy,
and nephropathy in a population-based
cohort: the Rochester Diabetic Neuropathy
Study. Neurology 1993; 43: 817–824.
5. D’ Souza M, Kulkarni V, Bhaskaran U,
et al. Diabetic peripheral neuropathy and
its determinants among patients attending
a tertiary health care centre in Mangalore,
India. J Public Health Res 2015; 4: 450.

6. Veglio M and Sivieri R. Prevalence of neu-
ropathy in IDDM patients in Piemonte,

Italy. The Neuropathy Study Group of the
Italian Society for the Study of Diabetes,
Piemonte Affiliate. Diabetes Care 1993; 16:
7. Brownlee M. The pathobiology of diabetic
complications: a unifying mechanism.
Diabetes 2005; 54: 1615–1625.
8. Nagamatsu M, Nickander KK, Schmelzer
JD, et al. Lipoic acid improves nerve blood
flow, reduces oxidative stress and improves

distal nerve conduction in experimental dia-
betic neuropathy. Diabetes Care 1995; 18:

9. Ziegler D, Low PA, Litchy WJ, et al.
Efficacy and safety of antioxidant treatment
with a-lipoic acid over 4 years in diabetic
polyneuropathy: the NATHAN 1 trial.
Diabetes Care 2011; 34: 2054–2060.
10. Ziegler D. Management of painful diabetic
neuropathy: what is new or in the pipeline
for 2007? Curr Diab Rep 2007; 7: 409–415.
11. Jiang DQ, Li MX, Ma YJ, et al. Efficacy
and safety of prostaglandin E1 plus lipoic

acid combination therapy versus monother-
apy for patients with diabetic peripheral

neuropathy. J Clin Neurosci 2016; 27: 8–16.
12. Ametov AS, Barinov A, Dyck PJ, et al. The

sensory symptoms of diabetic polyneurop-
athy are improved with alpha-lipoic acid:

the SYDNEY trial. Diabetes Care 2003; 26:
13. Han T, Bai J, Liu W, et al. A systematic
review and meta-analysis of a-lipoic acid in

the treatment of diabetic peripheral neurop-
athy. Eur J Endocrinol 2012; 167: 465–471.

14. Levey AS, Bosch JP, Lewis JB, et al. A more

accurate method to estimate glomerular fil-
tration rate from serum creatinine: a new

prediction equation. Modification of Diet
in Renal Disease Study Group. Ann Intern
Med 1999; 130: 461–470.
15. Young MJ, Boulton AJ, MacLeod AF, et al.

A multicentre study of the prevalence of dia-
betic peripheral neuropathy in the United

Kingdom hospital clinic population.
Diabetologia 1993; 36: 150–154.
16. Meijer JW, Smit AJ, Sonderen EV, et al.
Symptom scoring systems to diagnose distal
polyneuropathy in diabetes: the Diabetic
Neuropathy Symptom score. Diabet Med
2002; 19: 962–965.
17. Venkataramana AB, Skolasky RL,
Creighton JA, et al. Diagnostic utility of
the subjective peripheral neuropathy screen

in HIV-infected persons with peripheral sen-
sory polyneuropathy. AIDS Read 2005; 15:

18. Spallone V, Morganti R, D’Amato C, et al.
Validation of DN4 as a screening tool for

neuropathic pain in painful diabetic poly-
neuropathy. Diabet Med 2012; 29: 578–585.

19. Zelman DC, Gore M, Dukes E, et al.
Validation of a modified version of the
brief pain inventory for painful diabetic
peripheral neuropathy. J Pain Symptom
Manage 2005; 29: 401–410.
20. Bouhassira D, Attal N, Fermanian J, et al.
Development and validation of the
Neuropathic Pain Symptom Inventory.
Pain 2004; 108: 248–257.
21. Sheehan DV, Harnett-Sheehan K and Raj
BA. The measurement of disability. Int
Clin Psychopharmacol 1996; 11: 89–95.
Agathos et al. 1789

22. Friedewald WT, Levy RI and Fredrickson
DS. Estimation of the concentration of
low-density lipoprotein cholesterol in

plasma, without use of the preparative ultra-
centrifuge. Clin Chem 1972; 18: 499–502.

23. Evans JL and Goldfine ID. Alpha-lipoic
acid: a multifunctional antioxidant that
improves insulin sensitivity in patients with
type 2 diabetes. Diabetes Technol Ther 2000;
2: 401–413.

24. Papanas N and Ziegler D. Efficacy of alpha-
lipoic acid in diabetic neuropathy. Expert

Opin Pharmacother 2014; 15: 2721–2731.
25. Packer L, Witt EH and Tritschler HJ.
Alpha-lipoic acid as biological antioxidant.
Free Radic Biol Med 1995; 19: 227–250.
26. Ziegler D, Nowak H, Kempler P, et al.

Treatment of symptomatic diabetic poly-
neuropathy with the antioxidant alpha-
lipoic acid: a meta-analysis. Diabet Med

2004; 21: 114–121.
27. Haak E, Usadel KH, Kusterer K, et al.

Effects of alpha-lipoic acid on microcircula-
tion in patients with peripheral diabetic neu-
ropathy. Exp Clin Endocrinol Diabetes 2000;

108: 168–174.
28. Udupa AS, Nahar PS, Shah SH, et al. Study
of comparative effects of antioxidants on

insulin sensitivity in type 2 diabetes mellitus.
J Clin Diagn Res 2012; 6: 1469–1473.
29. Magis D, Ambrosini A, Sandor P, et al. A
randomized double-blind placebo-controlled
trial of thioctic acid in migraine prophylaxis.
Headache 2007; 47: 52–57.
30. Memeo A and Loiero M. Thioctic acid and
acetyl-L-carnitine in the treatment of sciatic

pain caused by a herniated disc: a random-
ized, double-blind, comparative study. Clin

Drug Investig 2008; 28: 495–500.
31. Ranieri M, Sciuscio M, Cortese AM, et al.
The use of alpha-lipoic acid (ALA), gamma
linolenic acid (GLA) and rehabilitation in
the treatment of back pain: effect on
health-related quality of life. Int J
Immunopathol Pharmacol 2009; 22: 45–50.
32. Letizia Mauro G, Cataldo P, Barbera G,
et al. A-lipoic acid and superoxide dismutase
in the management of chronic neck pain: a
prospective randomized study. Drugs R D
2014; 14: 1–7.
33. Di Geronimo G, Caccese AF, Caruso L,
et al. Treatment of carpal tunnel syndrome
with alpha-lipoic acid. Eur Rev Med
Pharmacol Sci 2009; 13: 133–139.

Leave a reply