Recent advances in the management of diabetic distal symmetrical polyneuropathy

Abstract

There is now little doubt that poor blood glucose control is an important risk factor for the development of diabetic peripheral neuropathy (DPN). Furthermore, traditional cardiovascular risk factors for macrovascular disease appear to be associated with an increased risk of DPN. The recently established International Expert Group on Diabetic Neuropathy has recommended new criteria for the diagnosis of DPN in the context of clinical and research settings. Studies in experimental diabetes examining the pathogenesis of DPN have identified a number of metabolic abnormalities including polyol pathway hyperactivity, increased advanced glycation end-point formation, alterations in the protein kinase C beta pathway through diacylglycerol and oxidative stress. There is now strong evidence implicating nerve ischemia as the cause of DPN. Studies in human and animal models have shown reduced nerve perfusion and endoneurial hypoxia. These endoneurial microvascular changes strongly correlate with clinical severity and the degree of nerve-fiber pathology. Unfortunately, many compounds that have been effective in animal models of neuropathy have not been successful in human diabetic neuropathy. The only compounds found to be efficacious in human diabetic neuropathy, and are in clinical use, are the anti-oxidant, α-lipoic acid and the aldose reductase inhibitor, epalrestat. Overall, the evidence emphasizes the importance of vascular dysfunction, driven by metabolic change, in the etiology of DPN, and highlights potential therapeutic approaches. Epidemiological data on diabetic painful neuropathic pain (DPNP) are limited. In one population-based study, the prevalence of DPNP, as assessed by a structured questionnaire and examination, was estimated at 16%. It was notable that, of these patients, 12.5% had never reported symptoms to their doctor and 39% had never received treatment for their pain. Thus, despite being common, DPNP continues to be underdiagnosed and undertreated. Pharmacological treatment of DPNP include tricyclic compounds, serotonin noradrenalin reuptake inhibitors, the anti-oxidant α-lipoic acid, anticonvulsants, opiates, membrane stabilizers, topical capsaicin and so on. Management of the patient with DPNP must be tailored to individual requirements and will depend on the presence of other comorbidities. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00083.x).

Keywords: Diabetic neuropathy; Diabetic peripheral neuropathy; Painful diabetic neuropathy.

Figure 1

Classification of diabetic polyneuropathy. Adapted from Reference 3.

Figure 2

Risk factors for incident neuropathy. The EURODIAB Prospective Complications Study showing odds ratios for the various risk factors for distal symmetrical polyneuropathy in a cohort of 1101 type 1 diabetes mellitus patients followed for 7.3 ± 0.6 years. Adapted from Reference 16. BMI, body mass index; CVD, cardiovascular disease.

Figure 3

The efficacy of duloxetine in improving 24‐h average pain scores. Reproduced from Reference 38 with permission of the International Association for the Study of Pain (IASP).

Figure 4

Proportion of patients meeting ≥50% and ≥30% improvement using pregabalin in seven clinical trials. Copyright 2008 American Diabetes Association from Diabetes Care 2008; 31: 1448–1454 (Reference 44). Reprinted with permission from the American Diabetes Association.

Figure 5

Treatment algorithm for diabetic peripheral neuropathic pain. Reprinted from Reference 33. SNRI, serotonin noradrenalin re‐uptake inhibitor; TCA, tricyclic antidepressant.

Figure 6

Current thinking with regard to the pathogenesis of diabetic peripheral neuropathies. Deficits in neurotrophic factors and autoimmunity might also play a part. AGE, advanced glycation end‐point; AGE‐RAGE, advanced glycation end‐point receptor for AGE; BMI, body mass index; BP, blood pressure; DAG, diacylglycerol; DM, diabetes mellitus; NO, nitric oxide; PKC, protein kinase C; RBC, red blood cell.

Figure 7

Compounds that have undergone trials for the treatment of diabetic peripheral neuropathies (adapted from Reference 64). Copyright 2008 American Diabetes Association from Diabetes Care 2008; 31: S255–S261. Reprinted with permission from the American Diabetes Association. ACE, angiotensin‐converting enzyme; BDNF, brain‐derived neurotrophic factor.