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Diabetic neuropathy

Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions usually result from diabetic microvascular injury involving small blood vessels that supply nerves (vasa nervorum). Relatively common conditions which may be associated with diabetic neuropathy include third nerve palsy; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy; a painful polyneuropathy; autonomic neuropathy; and thoracoabdominal neuropathy. more...

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Diabetes is the leading cause of neuropathy in developed countries, and neuropathy is the most common complication and greatest source of morbidity and mortality in diabetes patients. It is estimated that the prevalence of neuropathy in diabetes patients is approximately 20%. Diabetic neuropathy is implicated in 50-75% of nontraumatic amputations.

The main risk factor for diabetic neuropathy is hyperglycemia. In the DCCT (Diabetes Control and Complications Trial, 1995) study, the annual incidence of neuropathy was 2% per year, but dropped to 0.56% with intensive treatment of Type 1 diabetics. The progression of neuropathy is dependent on the degree of glycemic control in both Type 1 and Type 2 diabetes. Duration of diabetes, age, cigarette smoking, hypertension, height and hyperlipidemia are also risk factors for diabetic neuropathy.

Pathology and pathogenesis

There are four factor involved in the development of diabetic neuropathy:

  1. Microvascular disease,
  2. Advanced glycated end products,
  3. Protein kinase C, and the
  4. Polyol pathway.

Microvascular disease

Vascular and neural diseases are closely related and intertwined. Blood vessels depend on normal nerve function, and nerves depend on adequate blood flow. The first pathological change in the microvasculature is vasoconstriction. As the disease progresses, neuronal dysfunction correlates closely with the development of vascular abnormalities, such as capillary basement membrane thickening and endothelial hyperplasia, which contribute to diminished oxygen tension and hypoxia. Neuronal ischemia is a well-established characteristic of diabetic neuropathy. Vasodilator agents (e.g., angiotensin-converting-enzyme inhibitors, α1-antagonists) can lead to substantial improvements in neuronal blood flow, with corresponding improvements in nerve conduction velocities. Thus, microvascular dysfunction occurs early in diabetes, parallels the progression of neural dysfunction, and may be sufficient to support the severity of structural, functional, and clinical changes observed in diabetic neuropathy.

Advanced glycated end products

Elevated intracellular levels of glucose cause a non-enzymatic covalent bonding with proteins, which alters their structure and destroys their function. Certain of these glycated proteins are implicated in the pathology of diabetic neuropathy and other long term complications of diabetes.

Protein kinase C (PKC)

PKC is implicated in the pathology of diabetic neuropathy. Increased levels of glucose cause an increase in intracellular diacylglycerol, which activates PKC. PKC inhibitors in animal models will increase nerve conduction velocity by increasing neuronal blood flow.


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What is the best treatment for diabetic neuropathy?
From Journal of Family Practice, 5/1/04


Tricyclic antidepressants, anticonvulsants, and capsaicin reduce the pain of diabetic neuropathy; limited data suggests that lidocaine patches may also be efficacious. Both tricyclic antidepressants and anticonvulsants are superior to placebo in relieving painful diabetic neuropathy. Compared with placebo, patients taking tricyclic antidepressants report reduced pain (number needed to treat [NNT] for at least 50% reduction= 3.5) (strength of recommendation [SOR]: A). Similarly, patients taking anticonvulsants report reduced pain (NNT for at least 50% reduction in pain=2.7) (SOR: A).

Limited evidence suggests that selective serotonin reuptake inhibitors (SSRIs) are no more efficacious than placebo (SOR: C). Both antidepressants and anticonvulsants have a high rate of minor adverse effects (number needed to harm [NNH]=2.7 for both). Tricyclic antidepressants have an NNH of 17 for side effects severe enough that patients withdrew from the study.

Compared with placebo, topical capsaicin also reduces pain (NNT=4) (SOR: A); however, there are no systematically collected data on side effects for capsaicin. A single case series demonstrates that lidocaine patches are efficacious for neuropathic pain, though expensive (SOR: B). Almost no trims comparing different classes of treatments have been performed.


A recent well-done meta-analysis (1) summarized available randomized placebo-controlled trims of antidepressants (including tricyclics and SSRIs) and anticonvulsants (including phenytoin, carbamazepine, and gabapentin). Almost all trims compare individual agents against placebo, and there have been no head-to-head trials that address functional outcomes, quality of life, patient satisfaction, or cost. Most trials do not describe diagnostic criteria, consider causes of pain other than diabetes or address diabetic control, which is known to predict frequency of neuropathy. Finally, very few trials include typical primary care patients in a primary care setting or control for important confounding variables such as over-the-counter medications or comorbid illnesses.

Within the constraints of this literature, placebos have a substantial impact, with an aggregate 32% of patients receiving placebo reporting at least 50% reduction in pain. A total of 16 trials have addressed the efficacy of antidepressants for diabetic neuropathy. Compared with placebo, tricyclic antidepressants have an aggregate NNT of 3.5 (95% confidence interval [CI], 2.6-4.7) for patients reporting at least 50% reduction of pain, along with an NNH of 2.7 (95% CI, 2.1-3.9) for minor adverse effects (typically the muscarinic effects of dry mouth, constipation, and blurred vision) and 17 (95% CI, 10-43) for side effects severe enough to cause withdrawal from a trial. Dosages were in the low to middle range of those used to treat depression; there was no significant difference in efficacy between trials less than 3 weeks and those greater than 3 weeks. No evidence supports differences among different tricyclic agents, and limited evidence suggests that SSRIs are no more efficacious than placebo.

A total of 4 randomized placebo-controlled trials (1 each for phenytoin [Dilantin], carbamazepine [Tegretol], gabapentin [Neuronfin], and valproate [Depakote]) have extractable data about the efficacy of anticonvulsants for the pain of diabetic neuropathy. As a class, the NNT for patients reporting at least a 50% reduction in pain was 2.7 (95% CI, 2.2-3.8); the NNH for minor adverse effects (typically transient central nervous system effect such as dizziness, somnolence, or disturbance in gait) was 2.7 (95% CI, 2.2-3.4).

These summary estimates do not include the valproate trial, (2) which was reported after the meta-analysis was completed; the report did not allow calculation of NNT, but the findings were consistent with these results. Phenytoin dosage was 300 mg/d; carbamazepine dosage was titrated to 200-600 mg/d, gabapentin from 300-3600 mg/d, and valproate 1200 mg/d. Patients taking anticonvulsants did not have a higher rate of withdrawal compared to those taking placebo. Limited evidence suggests no significant differences among anticonvulsants; there is insufficient evidence to determine optimal dosage of any of these agents.

Studies involving topical agents are also limited. According to an information summary, (3) a total of 4 trials have addressed the efficacy of topical capsaicin for neuropathic pain. Compared with placebo, capsaicin reduces pain (NNT=4; 95% CI, 2.9-6.7), but no pooled information is available on side effects or rate of study withdrawal. Finally, 1 case series has suggested that lidocaine patches are efficacious for diabetic neuropathy. (4)

A variety of other interventions have been reported for diabetic neuropathy, including nonsteroidal anti-inflammatory drugs, transcutaneous electrical nerve stimulation (TENS), angiotensin-converting enzyme inhibitors, and Tramadol, but there have been no published systematic evaluations of them.

The Table characterizes the agents, the number of trials that address each, the NNT, NNH, typical effective dose, and approximate retail cost per month with the average effective dose.


American Diabetes Association practice guidelines do not address neuropathy; UptoDate emphasizes prevention through glycemic control, with initial treatment using amitriptyline or nortriptyline, followed by capsaicin and anticonvulsants. (5)


(1.) Collins SL, Moore RA, McQuayHJ, Wiffen P. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage 2000; 20:449-458.

(2.) Kochar DK, Jain N, Agarwal RP, Srivastava T, Agarwal P, Gupta S. Sodium valproate in the management of painful neuropathy in type 2 diabetes--a randomized placebo controlled study. Acta Neurol Scand 2002; 106:248-252.

(3.) Zhang WY, Li Wan Po A. The effectiveness of topically applied capsaicin. A meta-analysis. Eur J Clin Pharmacol 1994; 46:517-522.

(4.) Devers A, Galer BS. Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study. Clin J Pain 2000; 16:205-208.

(5.) Feldman, EL, McColluch, DK. Treatment of diabetic neuropathy. UpToDate. Last updated May 8, 2003. Available at: Accessed on September 8, 2003.

RELATED ARTICLE: Clinical commentary.

Anticonvulsants and antidepressants effective at reducing perception of pain

The management of patients with chronic pain requires a combination of artistry and skill. As each individual's perceptions, expectations and response to therapy differ, dynamic treatment approaches are required. The relative dearth of evidence supporting effective treatments for chronic pain compounds the problem. This evidence review helps to lessen some of the guesswork for patients with diabetic neuropathy. Anticonvulsants and antidepressants are impressively effective at reducing patients' perceptions of pain at a favorable benefit to significant harm ratio, NNT of 2-4 vs. NNH of 18. Several things however, aren't clear from the literature: as these were all placebo comparisons, which drug is more effective? As well, were reductions in functional limitation and disability measures or improvements in quality of life scores demonstrated? Will other newer agents prove to be superior? Despite these unanswered questions, for patients with diabetic neuropathy good evidence now supports what has likely been many clinicians' preference for the treatment of most chronic pain conditions; any alternative to narcotics.

Charissa Fotinos, MD, Seattle-King County Public Health, Seattle, Wash

Warren P. Newton, MD, MPH, Department of Family Medicine, University of North Carolina at Chapel Hill; Linda Collins, MSLS, Health Sciences Library, University of North Carolina at Chapel Hill

COPYRIGHT 2004 Dowden Health Media, Inc.
COPYRIGHT 2004 Gale Group

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