Neuropathy is a microvascular complication of diabetes mellitus which leads to considerable morbidity and a decreased quality of life [
Neuropathic pain is difficult to treat, and standard analgesics are usually not effective enough [
An earlier meta-analysis of four randomized controlled trials (RCTs) on alpha lipoic acid (600 mg/day) in patients with diabetes and neuropathic pain concluded that three weeks of treatment with intravenous alpha lipoic acid (600 mg/day) led to a significant decrease in reported neuropathic pain [
In November 2010, three of the authors (GSM, AA, and NK) conducted a search for relevant publications in the electronic database MEDLINE, using the search engine
For study selection, the following inclusion criteria were used: (1) RCTs on alpha lipoic acid, (2) a study population consisting of patients with diabetes mellitus and peripheral neuropathic pain, and (3) use of the total symptom score (TSS) as the outcome measure. Language was not a restriction. GSM, AA, and NK independently identified studies to be included in the review by checking the titles and abstracts downloaded from the databases. A consensus meeting was then held to resolve any disagreements. The final decision to include or exclude any study was based on the article’s full text. The reference lists of the identified studies were reviewed to discover additional potentially eligible studies. Unpublished data and conference proceedings were excluded from this review.
The aforementioned authors proceeded to independently evaluate the quality of each study using the standardised evaluation form for RCTs and systematic reviews developed by the Dutch Cochrane Centre (
Methodological quality assessment of the included intervention studies.
Ziegler 1995 [ | Ruhnau 1999 [ | Ametov 2003 [ | Ziegler 2006 [ | ||
(1) | Randomisation? | yes | yes | yes | yes |
(2) | Concealment of allocation? | yes | yes | yes | yes |
(3) | Patients blinded? | yes | yes | yes | yes |
(4) | Doctors blinded? | yes | yes | yes | yes |
(5) | Investigators blinded? | NO | NO | NO | NO |
(6) | Groups comparable at baseline? | yes | yes | yes | yes |
(7) | Follow-up complete of >80% of patients? | yes | yes | yes | yes |
(8) | Intention-to-treat analysis? | yes | yes | yes | yes |
Level of evidence | 1b | 1b | 1b | 1b |
The primary outcome measure in this meta-analysis was the total symptom score (TSS). The TSS is a questionnaire in which the patient is asked to assess the intensity (absent, mild, moderate, severe) and the frequency (now and then, often, continuous) of four symptoms (pain, burning, paresthesia, numbness) resulting in a scaled score in which 0 means no symptoms and 14.64 means that all four symptoms are severe and more or less continuously present (Table
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 | Symptom intensity | |||
---|---|---|---|---|
Absent | Slight | 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 |
For the purpose of this meta-analysis, overall results based on TSS scores were combined for oral and intravenous administration of alpha lipoic acid and placebo. Meta-analysis was undertaken using RevMan5 software (The Nordic Cochrane Centre, The Cochrane Collaboration). The
We adhered to the QUOROM guidelines for the reporting of meta-analyses of randomised trials [
The search yielded 242 publications in Medline and 112 in Embase (Figure
Flow diagram.
A survey of the methodological quality assessment is shown in Table
Finally, four RCTs were included in our systematic review and meta-analysis. The study populations in the four selected RCTs were all made up of patients with peripheral diabetic neuropathy [
Overview of the included randomized, placebo-controlled studies with alpha lipoic acid in persons with symptomatic peripheral diabetic neuropathy.
Study | Research group | Length of study | Alpha lipoic acid dosage | Administration route | Primary outcome measure | Findings | Difference intervention versus control* (Significance) | level of evidence | ||
Patient type | Number of patients (Intervention/control) | Intervention | Control | |||||||
Ziegler 1995 ALADIN [ | DM2; 18–70 yr | 328 (65/63/66/66) | 3 weeks | (a) 100 mg daily | Intravenous | TSS | (a) 7.6 → 4.3 | 6.8 → 4.2 | −0.7 (ns) | 1b |
Ruhnau 1999 ORPIL [ | DM2; 18–70 yr | 24 (12/12) | 3 weeks | 3dd600 mg | Oral | TSS | 7.99 → 4.24 | 8.18 → 6.24 | −1.81 | 1b |
Ametov 2003 SYDNEY [ | DM1+ DM2; 18–74 yr | 120 (60/60) | 3 weeks | 600 mg daily for 14 days | Intravenous | TSS | −5.72 | −1.83 | −3.89 | 1b |
Ziegler 2006 SYDNEY 2 [ | DM1+ DM2; 18–74 yr | 181 (45/47/46 /43) | 5 weeks | (a) 600 mg daily | Oral | TSS | (a) 9.44 → 4.59 | 9.27 → 6.35 | −1.93 | 1b |
*Calculated differences between intervention and control groups: not controlled.
DM: diabetes mellitus.
ns: not significant.
TSS: Total Symptom Score.
A significant improvement in the TSS scores was reported in all studies. In these studies an average 50% reduction was seen in the TSS with the oral or intravenous administration of at least 600 mg per day. However, when compared to the subjects in the control groups, the reduction in TSS was actually less than the clinically relevant threshold of 30% [
Overall, the pooled standardized mean difference estimated from all trials revealed a reduction in TSS scores of −2.26 (CI: −3.12 to −1.41;
Standardized mean differences for the administration of orally and intravenously administered alpha-lipoic acid versus placebo in the treatment of neuropathic pain. Diamond denotes pooled estimate of overall effect. Weighing of individual studies is based on the inverse variance method. For subgroups, see Table
Standardized mean differences for the administration of intravenously administered alpha-lipoic acid versus placebo in the treatment of neuropathic pain. Diamond denotes pooled estimate of overall effect. Weighing of individual studies is based on the inverse variance method. For subgroups, see Table
Standardized mean differences for the administration of orally administered alpha-lipoic acid versus placebo in the treatment of neuropathic pain. Diamond denotes pooled estimate of overall effect. Weighing of individual studies is based on the inverse variance method. For subgroups, see Table
Based on the four level 1b randomized, placebo-controlled studies included here, there is evidence to support that alpha lipoic acid causes a significant and clinically relevant decrease in neuropathic pain when administered for a period of three weeks at a dosage of 600 mg per day (grade of recommendation A). However, the significant improvements seen after the oral administration of alpha lipoic acid over a period of 3–5 weeks at a dosage of ≥600 mg per day are probably not clinically relevant, because the reduction in TSS was actually less than the threshold of 30% considered to be clinically relevant. There are, at present, no publications in which the effects of long-term treatment with intravenous or oral lipoic acid are presented.
The RCTs are primarily performed by a single German research group. A number of these studies were multicenter studies which included German as well as Russian, Israeli, and Croatian patients. Presumably, there is no overlap between these patient populations. All studies were sponsored by a pharmaceutical company which manufactured alpha lipoic acid. A number of the authors received salaries from this company, besides which, the pharmaceutical company also had representatives sitting on the advisory body for several of these studies.
It is striking that clinically relevant effects on neuropathic pain are seen after only 3–5 weeks of alpha lipoic acid administration. This is unexpectedly rapid for an antioxidising diet supplement. This may be explained by the selective modulation of neuronal T-type calcium channels by alpha lipoic acid [
The included RCTs were not designed for neuropathic pain. Individual scores on each of the four symptoms of the TSS (pain, burning, paresthesia, numbness) were not available from the included studies.
Unfortunately, there are not yet any results published for its administration over a longer time period. The continued, long-term effectiveness of any treatment is of the utmost importance for chronic conditions such as diabetic neuropathy.
In The Netherlands, the cost of using alpha lipoic acid at a dosage of 600 mg per day varies between 17.15 and 75.00 euros per month, depending on the manufacturer [
Finally, a meta-analysis is likely to suffer from publication bias, methodological deficiencies, and heterogeneity. We kept the likelihood of bias to a minimum by developing a detailed protocol before starting this study, undertaking a meticulous search for published studies, and using explicit methods for study selection, data extraction, and data analysis. Also, we studied the totality of the randomized evidence by including all relevant properly randomized trials.
We conclude that intravenous administration of alpha lipoic acid leads to significant and clinically relevant improvements of symptomatic peripheral diabetic neuropathy in the short term. The results we present are encouraging enough to consider intravenous alpha lipoic acid for the treatment of diabetic neuropathy in patients, who do not respond to common therapy. It is unclear if the significant improvements seen with the oral administration of alpha lipoic acid are clinically relevant. Additional research of longer duration using an informative neuropathic pain scale will be necessary to investigate the effects of both routes.
G. S. Mijnhout developed the search strategy, performed database search and selection of studies and the methodological quality assessment, and wrote the manuscript; B. J. Kollen was responsible for the statistical methodology of study, performed statistical pooling, and edited the manuscript; A. Alkhalaf and N. Kleefstra performed database search, selection of studies, and methodological quality assessment and edited the manuscript; H. J. G. Bilo edited the manuscript and was responsible for critical appraisal and final approval of the manuscript. All authors read and approved the final manuscript.
The authors have no conflict of interest to disclose.
The authors thank A. Reznichenko, M.D., from the Kidney Centre, Department of Internal Medicine, University Medical Centre Groningen, The Netherlands, for her willingness to translate the Russian publication of Strokov et al. [