Treatments for fatigue in peripheral neuropathy

Review question

To assess the effects of treatments for fatigue in people with peripheral neuropathy.


Peripheral neuropathy is damage to the nerves outside the brain and spinal cord. Many people with peripheral neuropathy have feelings of severe tiredness (fatigue) that are not necessarily related to physical problems such as muscle weakness. Evidence in other long-term illnesses where fatigue is a problem suggests that medicines and other forms of treatment may help. The aim of this review was to assess the effect of drugs and other treatments, such as general or specific exercise, orthotics (devices such as braces), relaxation, counselling and cognitive, behavioural and educational strategies on feelings of fatigue in people with peripheral neuropathy.

Study characteristics

From a wide search, we identified three RCTs that met our selection criteria. The trials involved a total of 530 adults with peripheral neuropathy. Treatments were ascorbic acid (vitamin C) in people with Charcot-Marie-Tooth disease in two trials, and amantadine in Guillain-Barré syndrome in the third. Charcot-Marie-Tooth disease is an inherited nerve disease and Guillain-Barré syndrome is a condition where there is inflammation of the peripheral nerves. We chose measures of fatigue at four to 12 weeks as our preferred measure of the effects of treatment. The amantadine trial but not the ascorbic acid trials provided data at this time point; the ascorbic acid trials provided data more than 12 months after the start of the intervention.

Key results and quality of the evidence

There was insufficient evidence to determine the effects of amantadine when compared with an inactive treatment (placebo) for fatigue. and there were no major unwanted effects. We found evidence that ascorbic acid probably has little meaningful benefit for fatigue. No major unwanted effects were identified, but the trials were small. We assessed the quality of this evidence as moderate because the results were imprecise, which means they do not rule out the possibility that the drugs could have an effect. We found no evidence from RCTs on other medicines or treatments for fatigue in peripheral neuropathy.

There is insufficient evidence to determine the effect of amantadine for fatigue in GBS and ascorbic acid for fatigue in CMT1A. More high-quality studies are needed to provide evidence on which to base management of feelings of fatigue in peripheral neuropathy. The cost effectiveness of different interventions should also be considered in future RCTs.

The evidence in this review is current to November 2013.

Authors' conclusions: 

One small imprecise study in people with GBS showed uncertain effects of amantadine on fatigue. In two studies in people with CMT1A there is moderate-quality evidence that ascorbic acid has little meaningful benefit on fatigue. Information about adverse effects was limited, although both treatments appear to be well tolerated and safe in these conditions.

There was no evidence available from RCTs to evaluate the effect of other drugs or other interventions for fatigue in either GBS, CMT1A or other causes of peripheral neuropathy. The cost effectiveness of different interventions should also be considered in future randomised clinical trials.

Read the full abstract...

Persistent feelings of fatigue (or subjective fatigue), which may be experienced in the absence of physiological factors, affect many people with peripheral neuropathy. A variety of interventions for subjective fatigue are available, but little is known about their efficacy or the likelihood of any adverse effects for people with peripheral neuropathy.


To assess the effects of drugs and physical, psychological or behavioural interventions for fatigue in adults or children with peripheral neuropathy.

Search strategy: 

On 5 November 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, CINAHL Plus, LILACS and AMED. We also searched reference lists of all studies identified for inclusion and relevant reviews, and contacted the authors of included studies and known experts in the field to identify additional published or unpublished data. We also searched trials registries for ongoing studies.

Selection criteria: 

We considered for inclusion randomised controlled trials (RCTs) and quasi-RCTs comparing any form of intervention for fatigue management in adults with peripheral neuropathy with placebo, no intervention or an alternative form of intervention for fatigue. Interventions considered included drugs, pacing and grading of physical activity, general or specific exercise, compensatory strategies such as orthotics, relaxation, counselling, cognitive and educational strategies.

Data collection and analysis: 

Two review authors independently assessed risk of bias and extracted study data. We contacted study authors for additional information. We collected information on adverse events from the included trials.

Main results: 

The review includes three trials, which were all at low risk of bias, involving 530 people with peripheral neuropathy. The effects of amantadine from one randomised, double-blind, placebo-controlled, cross-over trial comparing amantadine with placebo for the treatment of fatigue in 80 people with Guillain-Barré syndrome (GBS) were uncertain for the proportion of people achieving a favourable outcome six weeks post-intervention (odds ratio (OR) 0.56 (95% confidence interval (CI) 0.22 to 1.35, N = 74, P = 0.16). We assessed the quality of this evidence as low. Two parallel-group randomised double-blind, placebo-controlled trials comparing the effects of two doses of ascorbic acid with placebo for reducing fatigue in adults with Charcot-Marie-Tooth disease type 1A (CMT1A) showed that the effects of ascorbic acid at either dose are probably small (standardised mean difference (SMD) -0.12 (95% CI -0.32 to 0.08, n = 404, P = 0.25)) for change in fatigue after 12 to 24 months (moderate quality evidence). Neither ascorbic acid study measured fatigue at four to 12 weeks, which was our primary outcome measure. No serious adverse events were reported with amantadine. Serious adverse events were reported in the trials of ascorbic acid. However,risk of serious adverse events was similar with ascorbic acid and placebo.