Correspondence: Dr Hanan Khalil, School of Rural Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, PO Box 973, Vic 3825, Australia. Email: firstname.lastname@example.org
Diabetic neuropathy is the most common complication of diabetes as it affects a significant number of patients. The management of patients with diabetic neuropathy is complicated by several factors including the varied symptoms and response to the various treatments available. Strict blood glucose control remains the key to the management thus far nonetheless; it is associated with complications such as hypoglycaemia. In order to provide the most up-to-date evidence-based clinical recommendations pertinent to the management of diabetic neuropathy, several databases and clinical practice guidelines were searched for this evidence-based report. The main outcome measures are reduction in pain associated with diabetic neuropathy and the number of withdrawal rates due to adverse effects of the medications both of which are discussed in this report. Various pharmacological and non-pharmacological treatments are available with varying degrees of success in pain relief. The current evidence suggests that use of tricyclics antidepressants and conventional anticonvulsants for the short term of pain relief is beneficial. Combination therapy of opioids and anticonvulsants has also been found to be superior to monotherapy. Other treatment modalities such as the use of alpha-lipoic acid as an antioxidant and evening primrose oil through increased PGE1 synthesis have also been trialled with evidence of improvement in neuropathic pain. Evidence also supports non-pharmacological treatment such as the use of percutaneous electrical nerve stimulation. There is a scope for further improvement of the reporting of rating pain scales and including various outcomes measures such as quality of life and physical function when trialling new therapies for better evaluation of future treatments.
Diabetic neuropathy, which is caused by chronically raised blood sugar and diabetes, is the most common complication of diabetes. About 60% to 70% of all patients with diabetes will eventually develop peripheral neuropathy, although not all suffer pain. Symptoms of neuropathic pain associated with diabetic neuropathy include pain, paraesthesia, tingling and numbness. Neuropathies result in loss of sensation and balance, which result in a decrease in patients' quality of life. Furthermore, while the primary symptoms of neuropathy can be highly unpleasant, the secondary complications (e.g. falls and foot ulcers) are even more serious and can result in fractures, amputations and even death in patients with diabetes mellitus.[1, 2]
Management of diabetic neuropathy still remains problematic due to its various clinical presentations and the associated co-morbidities that patients may have. Other factors that contribute to the difficult management of these patients are the varied response to the different treatments available and that only 40% to 60% of patients obtain relief from their symptoms. Despite the evidence for the treatments available for patients with diabetic neuropathy, there is still lack of consensus about the best management options for those patients. In order to provide the most up-to-date evidence-based clinical recommendations pertinent to the management of diabetic neuropathy, several databases and clinical practice guidelines were searched for this evidence-based report. The main outcome measures are reduction in pain associated with diabetic neuropathy and the number of withdrawal rates due to adverse effects of the medications both of which are discussed in this report. However, there are some discrepancies in reporting the true benefits of some of the treatments because most published studies reported have used varying measures for quantifying pain reduction, which ranged from 30% to 50% reduction. This brief report summary presents the most up-to-date evidence-based recommendations available for diabetic neuropathy.
This evidence-based report is based on a comprehensive search of the literature and selected evidence-based healthcare databases. Databases such as Medline, Cochrane Central and grey literature were searched using search terms such as ‘diabetic neuropathy’, ‘pharmacological management’ and ‘non-pharmacological management’.
The cornerstone of managing painful diabetic neuropathy relies on achieving a strict control of blood glucose levels. Various studies have shown that patients with diabetes can reduce their risk of developing peripheral neuropathy by keeping their blood sugar levels as close to normal as possible.[2, 3] The diabetes control and complications trial examined 1441 patients with type 1 diabetes. The study showed that tight glycaemia control can significantly delay the onset and slow the progression of neuropathy, as measured by various tools including; clinical examination, autonomic testing and nerve conducting studies. As for type 2 diabetes, a recent Cochrane systematic review showed that enhanced glucose control reduces the incidence of clinical neuropathy, although this was not formally statistically significant (P = 0.06). The explanation for the reduction in neuropathy symptoms lie in the fact that enhanced glucose control does significantly reduce nerve conduction and vibration threshold abnormalities, which leads to symptomatic relief of painful diabetic neuropathy. Both pharmacological and non-pharmacological treatments have been used as additional options in managing diabetic neuropathic pain.
Pharmacological approaches thus far studied include the use of anticonvulsants, antidepressants, opioids, serotonin noradrenaline reuptake inhibitors, ion channel blockers and N-methyl-D-aspartate antagonists. A systematic review by Wong et al. examining the efficacy of various pharmacological approaches for the symptoms of diabetic neuropathy found that older generation anticonvulsants such as sodium valproate and carbamazepine and tricyclics antidepressants remain the most effective treatment for the short-term treatment of diabetic neuropathy symptoms. Studies on the long-term efficacy of these medications are lacking. The treatment period of short-term anticonvulsants ranged from 2 weeks to 3 months.
Furthermore, a meta-analysis of 10 randomised controlled studies reported on the efficacy of anticonvulsants with a total number of 1576 participants. The pooled odds ratio of treatment efficacy with traditional anticonvulsants was found to be 5.33 (95% CI, 1.77 to 16.02) compared with the odds ratio for the new anticonvulsants (e.g. pregabalin and oxcarbazepine) of 3.25 (95% CI, 2.27 to 4.66). Moreover, the pooled odds ratio for withdrawal due to adverse effects with the older generation of anticonvulsants was 3.25 (95% CI, 2.27 to 4.66) compared with the new generation of anticonvulsants of 2.98 (95% CI, 1.75 to 5.07). Thus it was concluded that conventional anticonvulsants seemed to be more efficacious than the newer generation type.
Antidepressants have long been preferred in the treatment of neuropathic pain because of their once daily administration regimen and their relatively low cost. Despite this widespread use only four studies examined the efficacy of antidepressants in patients with diabetic neuropathy with a total number of 94 participants. The drugs examined included desipramine, imipramine, amitriptyline and citalopram. The pooled odds ratio for treatment efficacy of the tricyclics antidepressants was found to be 22.24 (95% CI, 5.83 to 84.75) compared with citalopram odds ratio of 2.32 (95% CI, 0.3 to 38.2). The pooled odds ratio for withdrawal due to adverse events related to tricycle antidepressants was 2.32 (0.59 to 9.69) compared with citalopram of 5.6 (95% CI, 0.3 to 125.5).
In contrast, opioids have played a small role in the treatment of diabetic neuropathy due to their adverse effects and safety profile. Opioids efficacy was examined in three studies with a total of 329 patients. The drugs examined were oxycodone and tramadol. The odds ratio for the treatment efficacy of oxycodone was 4.25 (95% CI, 2.33 to 7.77). Withdrawal from opioids was relatively high with an odds ratio of 4.06 (1.16 to 14.21). Tramadol data could not be obtained as only one study examined its efficacy.
Other drugs such as duloxetine, a serotonin noradrenaline reuptake inhibitor; mexiletine, an ion channel blocker; and dextromethorphan, an N-methyl-D-aspartate antagonist were evaluated with modest results. Inconclusive results from these studies were due to the crossover design of the included studies; only four of the studies mentioned a washout out period hence the carry-over benefit of the first treatment could not be ignored. The only two drugs approved by the FDA for diabetic peripheral neuropathy are the antidepressant duloxetine and the anticonvulsant pregabalin.[11, 12]
Topical treatments such as isosorbide dinitrate spray and capsaicin cream were trialled with inconclusive results due to the small numbers of participants in the available studies and the lack of reporting of measurable data.[6, 7]
Combination therapy of medications was shown to be beneficial in a small study of 57 patients. The study showed that a combination of gabapentin and morphine produced superior pain relief and improvement in daily activities without increased side effects of each individual drug. The benefit of the combination therapy lies in the use of lower doses of each individual drug as a monotherapy for the treatment of diabetic neuropathy.[6-8]
Other promising modalities from small randomised controlled trials include the use of alpha-lipoic acid as an antioxidant and evening primrose oil through increased PGE1 synthesis. Both treatments improve nerve function and result in symptomatic improvement. The drawbacks for these treatments include chelation of metals such iron and copper with alpha-lipoic acid and inhibition of platelet aggregation with evening primrose oil. Close monitoring of patients on these treatments are advised.
Non-pharmacological treatments including percutaneous electrical nerve stimulation, electromagnetic field treatment and Reiki therapy were studied in small controlled studies. Percutaneous electrical nerve stimulation is the only non-pharmacological approach that is supported by enough evidence and could be considered for the treatment of diabetic neuropathy.[6, 7] A summary of the proposed treatment algorithm for diabetic neuropathy as discussed above is shown in Figure 1.
There are several limitations to the studies discussed above, which include the population characteristics, size, follow-up of treatment, doses of medications, methodological design and the various outcomes measured. Future studies examining the efficacy of those medications should apply more robust methodologies with specific outcomes measures in order to compare the various treatment options systematically. Several implications for research and practice should be considered such as devising a formalised process for rating pain scales and including various outcomes measures such as quality of life and physical function when trialling new therapies. Future studies should also include head to head comparisons of various combinations of medications at several doses and, as diabetic neuropathy is a chronic disease, long-term evaluations of therapies are essential.
In summary, despite advances in the understanding of the metabolic causes of neuropathy, treatments aimed at managing these pathological pathways have been limited. Accordingly, with the exception of tight glucose control, treatments aim at reducing pain and other associated symptoms. Concisely, evidence supports the use of tricyclics antidepressants and conventional anticonvulsants for the short-term pain relief of diabetic neuropathy. Combination therapy of opioids and anticonvulsants has also been found to be superior to monotherapy. Long-term therapies have not been studied as extensively as the short-term therapies. Another promising therapy with evidence to support its use is percutaneous electrical nerve stimulation. Its use may be worth considering in patients who are not responding to pharmacological treatments or who have specific contraindications to the treatments.