Treating painful diabetic polyneuropathy
Authors: Edward B Jude, Nicolaas Schaper
Journal: BMJ (2007)

The incidence of diabetes is expected to double over the next two decades, which will result in more people with complications of diabetes.1 Diabetic polyneuropathy is one of the most common, with a prevalence of around 30-50%. It can have a major impact on patients' quality of life, and treatment is usually needed for many years.2 3

Community based studies report the prevalence of painful diabetic polyneuropathy as around 16-26%,4 and in one study 80% of the patients had moderate or severe pain.5 Quality of life is reduced in patients with painful diabetic polyneuropathy, with restriction in daily and social activities, and the condition is associated with depression, sleep disturbances, and anxiety.3 6 7 In this week's BMJ Wong and colleagues report a systematic review of the effects of drug treatment in painful diabetic polyneuropathy.8

Many types of drugs have been studied for relief of pain in diabetic polyneuropathy,9 as little evidence exists that classic analgesics such as paracetamol or non-steroidal anti-inflammatory drugs are effective. Surveys show that there is substantial scope for improvement in clinical care. In one UK population based study almost 40% of people with painful neuropathy reported that they had never received any treatment, almost a third had been prescribed drugs with no known efficacy in neuropathic pain, and only a minority had been treated with tricyclic antidepressants or anticonvulsants.4 Similar findings of inadequate treatment was found in two more recent European and American studies.6 10

Wong and colleagues' review identified the randomised placebo controlled trials of topically applied and orally administered drugs.8 Clinical success was defined as a 50% reduction in pain; withdrawal due to adverse events was a secondary outcome. The review found that tricyclic antidepressants were most effective in reducing pain by 50% (odds ratio 31.73; 95% confidence interval 3.68 to 189.89), followed by traditional anticonvulsants (lamotrigine, sodium valproate, carbamazepine; odds ratio 7.59; 2.16 to 26.58), and the newer generation anticonvulsants (gabapentin, oxacarbazepine, pregabalin; odds ratio 3.25; 2.27 to 4.66). The newer generation anticonvulsants were most likely to cause withdrawals due to adverse events, followed by tricyclic antidepressants, and the traditional anticonvulsants (odds ratios 2.98, 2.32, 1.51 respectively). 

This review can help clinicians make evidence based choices in the management of painful diabetic polyneuropathy, and it also highlights some of the problems in the treatment regimens often prescribed for this condition. The efficacy of pharmacological treatment is limited: with of one of the most efficacious drugs in the meta-analysis, amitriptyline, three patients need to be treated to achieve a 50% reduction in pain score in one patient; in the other two patients the drug will have no effect or a limited effect. Adverse effects were not infrequent, and in the analysis of the effects of tramadol the odds ratio for withdrawal due to adverse events was higher than the odds ratio for 50% pain relief. It is difficult to compare the results of different trials in the review since the duration of treatment was highly variable (between 2 to 16 weeks) and could have influenced the number of withdrawals. Unfortunately all the trials in the review were relatively short; many included only a few patients), and for some drugs the confidence intervals were large. Clearly, robust studies with sufficient size and duration, preferably of at least one year, are needed.

Treatment of painful diabetic polyneuropathy is a clinical challenge and requires a treatment plan that should include psychosocial factors, glucose control, and, if necessary, pharmacological treatment. Listening to the patient and explaining the cause of the pain can help to reduce anxiety. Patients' beliefs and perceptions of the pain and its cause, coping strategies, mood changes, disturbed sleep, and anxiety all need to be addressed.

Several studies have looked at the impact of analgesic treatment on quality of life, sleep patterns, anxiety, and depression and most of them have shown an improvement in quality of life which might be directly related to improvement in pain score.11 Therefore, treating anxiety or depression first might also reduce the need for analgesics. A few observational studies have indicated that large variations in blood glucose can exacerbate the pain, so glycaemic control should be optimised.12 13

If, despite these measures, the pain persists and is so severe that pharmacological treatment is indicated tricyclic antidepressants seem the best first step, as suggested by Wong and colleagues' review. But contraindications include cardiac conduction disturbances and glaucoma, and side effects are not infrequent. The dilemma in treating painful diabetic polyneuropathy is what should be done with the many people who do not respond sufficiently to tricyclic antidepressants or in whom tricyclic antidepressants are contraindicated. Wong and colleagues suggest that the next step should be to use one of the older generation anticonvulsants. However, this advice is based on clustering a group of anticonvulsants with very different modes of action; if they are analysed separately, the number of studies for each drug is relatively small and the evidence for efficacy does not seem convincing. Therefore, we and others suggest pregabalin, duloxetine, or gabapentin as second line agents, as these drugs do not seem to differ much in efficacy or in the frequency and severity of side effects.9 Only one or two of these drugs should be included in the local treatment protocol, so that clinicians can develop sufficient experience with them. If this treatment fails, combination therapy or tramadol (or another opioid) can be considered.

Studies that evaluate the efficacy of the combination of two or more drugs to relieve pain are few. Only one study combined gabapentin and morphine in people with neuropathic pain; it showed that the combination gave better pain relief, required lower doses of both drugs, and fewer side effects than if the drugs were used singly.14

Although our knowledge of the treatment of painful diabetic polyneuropathy is growing, there is still no consensus on the most effective protocol. Therefore doctors treating people with diabetes must develop their own local screening and treatment protocols. They should include a treatment algorithm, indications and contraindications for drug treatment, potential adverse effects to look out for, and a simple technique to monitor the effectiveness of treatment.