Treatment of DN should be targeted toward a number of different aspects: first, treatment of specific underlying pathogenic mechanisms; second, treatment of symptoms and improvement in quality of life; and third, prevention of progression and treatment of complications of neuropathy.
Glycemic and Metabolic Control Findings from numerous studies have shown a relationship between hyperglycemia and the development and severity of DN. The Diabetes Control and Complications Trial (DCCT) research group reported that clinical and electrophysiological evidence of neuropathy was reduced by 50% in subjects treated intensively with insulin. In the United Kingdom Prospective Diabetes Study (UKPDS), control of blood glucose levels was associated with improvement in vibration perception.[43,44] Investigators of the Steno trial, using multifactorial intervention, reported a reduction in the odds ratio to 0.32 for the development of autonomic neuropathy. Furthermore, results from the EURODIAB Prospective Complications study that included 3250 patients across Europe have shown that the incidence of neuropathy is also associated with potentially modifiable cardiovascular risk factors, including an elevated triglyceride level, a high body mass index, smoking, and hypertension. Treatment of neuropathy should, therefore, include measures to reduce macrovascular risk factors including hyperglycemia, blood pressure, and lipid control and lifestyle modifications including exercise and weight reduction, smoking cessation, a diet rich in omega-3 fatty acids, and avoidance of excess alcohol consumption. C-peptide replacement in animal models of type 1 diabetes mellitus has shown improvement of nerve function. Moreover, it is known to have stimulatory effects on endothelial nitric oxide synthase, thereby enhancing endoneurial blood flow. Results from previous studies of C-peptide in humans have shown significant improvement in sensory nerve conduction velocities, vibration perception, and autonomic nerve function.[49,50] In a recent exploratory, multicenter, randomized placebo-controlled study including 139 patients, 6 weeks of treatment demonstrated improvement in sensory nerve conduction velocities, vibration perception, and neurologic impairment scores.
Oxidative Stress Many studies have shown that hyperglycemia causes oxidative stress in tissues that are susceptible to complications of diabetes mellitus, including peripheral nerves. Fig. 4 presents our current understanding of the mechanisms and potential therapeutic pathways for oxidative stress-induced nerve damage. Studies show that hyperglycemia induces an increased presence of markers of oxidative stress, such as superoxide and peroxynitrite ions, and that antioxidant defense moieties are reduced in patients with diabetic peripheral neuropathy. Therapies known to reduce oxidative stress are therefore recommended. Therapies that are under investigation include aldose reductase inhibitors, α-lipoic acid, γ-linolenic acid, benfotiamine, and protein kinase C inhibitors.
Pathogenesis of diabetic neuropathies, modified from Vinik et al (5). AII indicates angiotensin II; AGE indicates advanced glycation end products; C' indicates complement; DAG indicates diacylglycerol; ET indicates endothelin; EDHF indicates endothelium-derived hyperpolarizing factor; IGF indicates insulinlike growth factor; INGAP indicates islet neogenesis-associated protein peptide; Na/K ATPase indicates sodium, potassium-adenosinetriphosphatase; NFκB indicates nuclear factor κB; NGF indicates nerve growth factor; NO indicates nitric oxide; NT3 indicates neurotropin 3; PKC indicates protein kinase C; PGI2 indicates prostaglandin I2; ROS indicates reactive oxygen species; VEGF indicates vascular endothelial growth factor.
Advanced glycation end products are the result of nonenzymatic addition of glucose or other saccharides to proteins, lipids, and nucleotides. In diabetes, excess glucose accelerates advanced glycation end product generation that leads to intracellular and extracellular protein cross-linking and protein aggregation. Activation of the advanced glycation end product receptor alters intracellular signaling and gene expression, releases proinflammatory molecules, and results in an increased production of reactive oxygen species that contribute to diabetic microvascular complications. Aminoguanidine, an inhibitor of advanced glycation end product formation, showed favorable results in animal studies, but human trials have been discontinued because of toxicity. Benfotiamine is a transketolase activator that reduces tissue advanced glycation end products. Several independent pilot studies have demonstrated its effectiveness in treating diabetic polyneuropathy. Findings from the Benfotiamine in the Treatment of Diabetic Polyneuropathy (BEDIP) 3-week study demonstrated subjective improvements in neuropathy score in the group that received 200 mg/d of benfotiamine tablets, with a pronounced decrease in reported pain levels. In a 12-week study, the use of benfotiamine plus pyridoxine hydrochloride (vitamin B6)/cyanocobalamin (vitamin B12) significantly improved nerve conduction velocity in the peroneal nerve along with appreciable improvements in vibratory perception. An alternate combination of benfotiamine (100 mg) and pyridoxine hydrochloride (100 mg) has been shown to improve diabetic polyneuropathy in a small number of diabetic patients. The use of benfotiamine in combination with other antioxidant therapies such as α-lipoic acid (see proceeding text) will soon be commercially available under the name Nutrinerve.
Aldose reductase inhibitors reduce the flux of glucose through the polyol pathway, inhibiting tissue accumulation of sorbitol and fructose. Newer aldose reductase inhibitors are currently being explored, and some trials with positive results have emerged with newer agents, but these may be insufficient per se, and combinations of treatments may be needed.
γ-Linolenic acid can cause significant improvement in results from clinical and electrophysiological tests for neuropathy.
α-Lipoic acid or thioctic acid has been used for its antioxidant properties and for its thiol-replenishing redox-modulating properties. Findings from many studies show its favorable influence on microcirculation and reversal of some symptoms of neuropathy.[59,60,61,62] A meta-analysis including 1258 patients from 4 randomized clinical trials concluded that 600 mg/d of intravenously administered α-lipoic acid significantly reduced symptoms of neuropathy and improved neuropathic deficits. The recently published Symptomatic Diabetic Neuropathy 2 (SYDNEY 2) trial showed significant improvement in neuropathic symptoms and neurologic deficits in 181 diabetic patients with 3 different dosages of α-lipoic acid compared with placebo over a 5-week period. The results of the Neurological Assessment of Thioctic Acid in Neuropathy (NATHAN) study, which examined the long-term effects of α-lipoic acid on electrophysiology and clinical assessments, will be presented at the 2007 American Diabetes Association meeting.
Protein kinase C activation is a critical step in the pathway to diabetic microvascular complications. It is activated by both hyperglycemia and disordered fatty-acid metabolism resulting in increased production of vasoconstrictive, angiogenic, and chemotactic cytokines including transforming growth factor-β, vascular endothelial growth factor, endothelin, and intercellular adhesion molecules. A multinational, randomized, phase-2, double-blind, placebo-controlled trial with ruboxistaurin (a protein kinase C-β inhibitor) failed to achieve the primary end points although significant changes were observed in many domains. Nevertheless, in a subgroup of patients with less severe DN (sural nerve action potential greater than 0.5 µV) at baseline and clinically significant symptoms, a statistically significant improvement in symptoms and vibratory detection thresholds was observed in the ruboxistaurin-treated groups as compared with the placebo-treated group. Results from a smaller, single center study recently published showed improvement in symptom scores, endothelium-dependent skin blood flow measurements, and quality of life scores in the ruboxistaurin-treated group. These studies and the NATHAN studies have pointed out the changing natural history of DN with the advent of therapeutic lifestyle change, statins, and angiotensin-converting enzyme inhibitors, which have slowed the progression of DN and drastically changed the requirements for placebo-controlled studies.
Growth Factors Increasing evidence suggests that there is a deficiency of nerve growth factor and the dependent neuropeptides substance P and calcitonin generelated peptide in patients with diabetes mellitus and that this contributes to the clinical perturbations in small-fiber function. Clinical trials with nerve growth factor have not been successful, but are subject to certain caveats with regard to design, and nerve growth factor still holds promise for treating sensory and autonomic neuropathies. The pathogenesis of DN includes loss of vasa nervorum, so it is probable that appropriate application of vascular endothelial growth factor would reverse the dysfunction. In diabetic animal models, introduction of the vascular endothelial growth factor gene into muscle improved nerve function. There are ongoing vascular endothelial growth factor gene studies with transfection of the gene into human muscle. Islet neogenesis-associated protein peptide comprises the core active sequence of islet neogenesis-associated protein, a pancreatic cytokine that can induce new islet formation and restore euglycemia in diabetic rodents. Maysinger et al reported significant improvement in thermal hypoalgesia in diabetic mice after 2-week treatment with islet neogenesis-associated protein peptide.
Immune Therapy Several different autoantibodies in human sera associated with DN have been reported that can react with epitopes in neuronal cells. In patients with diabetes mellitus, we have reported a 12% incidence of a predominantly motor form of neuropathy associated with monosialoganglioside antibodies. Perhaps the clearest link between autoimmunity and neuropathy has been the demonstration of an 11-fold increased likelihood of chronic inflammatory demyelinating polyneuropathy, multiple motor polyneuropathy, vasculitis, and monoclonal gammopathies in patients with diabetes. New data, however, support a predictive role of the presence of antineuronal antibodieswhich may not be innocent bystanders, but neurotoxinson the later development of neuropathy.[73,74] There may be select patients, particularly those with autonomic neuropathy, evidence of antineuronal autoimmunity, and chronic inflammatory demyelinating polyneuropathy who may benefit from intravenously administered immunoglobulin or large-dose steroids.
Pain control is one of the most difficult management issues in patients with DN. It often involves different classes of drugs and requires combination therapies. In any painful syndrome, special attention to the underlying condition is essential for the overall management and for differentiation from other conditions that may coexist in patients with diabetes (ie, claudication, Charcot's neuroarthropathy, fasciitis, osteoarthritis, radiculopathy, Morton's neuroma, tarsal tunnel syndrome). Small-nerve fiber neuropathy often presents with pain, but without objective signs or electrophysiologic evidence of nerve damage. Large-nerve fiber neuropathies produce numbness, ataxia, and incoordination. A careful history of the nature of pain, its exact location, and detailed examination of the lower limbs is mandatory to ascertain alternate causes of pain. Pain can be caused by dysfunction of different types of small-nerve fibers (A delta fiber versus C fiber) that are modulated by sympathetic input with spontaneous firing of different neurotransmitters to the dorsal root ganglia, spinal cord, and cerebral cortex. Fig. 5 describes the pathophysiological basis for the generation of neuropathic pain. Different types of pain respond to different types of therapies. Fig. 6 describes the different nerve fibers affected and possible targeted treatments.
Schematic representation of the generation of neuropathic pain. A, Central terminals of c-afferents project into the dorsal horn and make contact with secondary pain-signaling neurons. Mechanoreceptive A beta afferents project without synaptic transmission into the dorsal columns (not shown) and also contact secondary afferent dorsal horn neurons. B, Spontaneous activity in peripheral nociceptors (peripheral sensitization, black stars) induces changes in the central sensory processing, leading to spinal-cord hyperexcitability (central sensitization, blue star) that causes input from mechanoreceptive A beta fibers (light touch) and A delta fibers (punctuate stimuli) to be perceived as pain (allodynia). C, C-nociceptor degeneration and novel synaptic contacts of A beta fibers with "free" central nociceptive neurons, causing dynamic mechanical allodynia. D, Selective damage of cold-sensitive A delta fibers that leads to central disinhibition, resulting in cold hyperalgesia. Sympat indicates sympathetic nerve; NA indicates noradrenergic.
Mechanisms of pain and possible treatments. C fibers are modulated by sympathetic input with spontaneous firing of different neurotransmitters to the dorsal root ganglia, spinal cord, and cerebral cortex. Sympathetic blockers (eg, clonidine), and depletion of axonal substance P used by C fibers as their neurotransmitter (eg, capsaicin) may improve pain. In contrast, A delta fibers use sodium channels for their conduction, and agents that inhibit sodium exchange such as antiepileptic drugs, tricyclic antidepressants, and insulin may ameliorate this form of pain. Anticonvulsants (carbamazepine, gabapentin, pregabalin, topiramate) potentiate activity of γ-aminobutyric acid, inhibit sodium and calcium channels, and inhibit N-methyl-D-aspartate receptors and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors. Dextromethorphan blocks N-methyl-D-aspartate receptors in the spinal cord. Tricyclic antidepressants, selective serotonin reuptake inhibitors (eg, fluoxetine), and selective serotonin-norepinephrine reuptake inhibitors inhibit serotonin and norepinephrine reuptake, enhancing their effect in endogenous pain-inhibitory systems in the brain. Tramadol hydrochloride is a central opioid analgesic. 5-HT indicates serotonin; AMPA indicates α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid class of glutamate receptor; DRG indicates dorsal root ganglia; GABA indicates γ-aminobutyric acid; NMDA indicates N-methyl-D-aspartate class of glutamate receptor; SSNRI indicates selective serotonin-norepinephrine reuptake inhibitor; SSRI indicates selective serotonin reuptake inhibitor; TCA indicates tricyclic antidepressant.
C-Fiber Pain Small unmyelinated C-fiber damage gives rise to burning or lancinating pain often accompanied by hyperalgesia and dysesthesia. Peripheral sympathetic fibers are C fibers, too, and spontaneous firing or activation exacerbates the pain, which can be blocked with systemic administration of the α2-adrenergic agonist clonidine. These nerve fibers are peptidergic carrying substance P as the neurotransmitter. Depletion of substance P with local application of capsaicin abolishes transmission of painful stimuli to higher centers. Targeting higher levels of pain transmission also helps alleviate C-fiber pain.[77,78,79]
A Delta-Fiber Pain Pain from A delta fibers is deep-seated, dull, and aching. It responds to nerve blocks, tramadol hydrochloride or dextromethorphan hydrobromide, antidepressants, and tricyclic agents. Insulin infusion at a rate of 0.8 to 1.0 units/h without lowering blood glucose levels helps resolve pain in about 48 hours.N-methyl-D-aspartate receptor antagonists like dextromethorphan exert an analgesic effect in hyperalgesia and allodynia whereas centrally acting opioids such as tramadol achieve symptomatic relief.
Antidepressants in Neuropathy Antidepressants inhibit reuptake of norepinephrine and/or serotonin. Anticholinergic effects, orthostatic hypotension, and sexual side effects limit their use. They remain first-line agents in many centers, but consideration of their safety and tolerability is important in avoiding adverse effects, a common result of treating neuropathic pain. Dosages must be titrated on the basis of positive responses, treatment adherence, and adverse events. Among the norepinephrine reuptake inhibitors, desipramine hydrochloride, amitriptyline hydrochloride, and nortriptyline hydrochloride have been shown to be beneficial. Selective serotonin reuptake inhibitors that have been used to treat neuropathic pain are paroxetine hydrochloride, fluoxetine hydrochloride, sertraline hydrochloride, and citalopram hydrobromide. Recent interest has focused on antidepressants with dual selective inhibition of serotonin and norepinephrine, such as duloxetine hydrochloride and venlafaxine hydrochloride. Duloxetine hydrochloride has recently been approved to treat neuropathic pain in the United States. It is a selective, balanced and potent serotonin and norepinephrine reuptake inhibitor in the brain and spinal cord, and its use leads to increased neuronal activity in efferent inhibitory pathways. In a 12-week multicenter, double-blind clinical trial of 457 patients, Goldstein et al showed a 50% reduction in 24-h Average Pain Score (primary end point) in 49% of patients treated with 60 mg/d and in 52% of patients treated with 120 mg/d of duloxetine hydrochloride vs 26% of patients in the placebo group (P<.05). A second study by Raskin et al conducted with 449 patients for 6 months similarly demonstrated maintenance of pain relief through 28 weeks of treatment. Nonetheless, many adverse effects were reported including dizziness, somnolence, dry mouth, nausea, constipation, and reduced appetite. Physicians must be alert to suicidal ideation, exacerbation of autonomic symptoms, as well as aggravation of depression, and should stop the drug immediately if required. Venlafaxine hydrochloride in dosages of 150 and 225 mg/d significantly improved pain scores, although adverse effects included somnolence, nausea, and myalgias, and 7 of 244 treated patients (2.9%) developed significant electrocardiographic abnormalities.
Anticonvulsants in Diabetic Neuropathy Anticonvulsants have stood the test of time in treatment of DN. Principal mechanisms of action include sodium-channel blockade, potentiation of γ-aminobutyric acid activity, calcium-channel blockade, antagonism of glutamate at N-methyl-D-aspartate receptors or α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors.
Carbamazepine, 200 mg twice daily, is useful for patients with shooting or electric, shock-like pain, but is rapidly discontinued because of adverse events.
In a placebo-controlled trial, gabapentin-treated patients had significantly lower mean daily pain scores and improvement of all secondary efficacy parameters compared with subjects taking placebo. Gabapentin has the additional benefit of improving sleep, which is often compromised in patients with chronic pain. In the long-term, it is known to produce weight gain, which may complicate diabetes management, and it has not been successful in all trials.
Pregabalin produced significant improvements in pain scores within 1 week of treatment, which persisted for 6 to 12 weeks in 4 randomized controlled trials including 146 to 724 patients with diabetic neuropathy.[78,88,89,90] Adverse events included dose-related somnolence, ataxia and confusion, peripheral edema, and constipation. A recent Canadian study evaluated cost-effectiveness of pregabalin vs gabapentin for the treatment of painful DN, and the investigators concluded that pregabalin was more cost-effective when compared with gabapentin.
In trials of topiramate, a fructose analog, 50% of patients on topiramate vs 34% on placebo responded to treatment; treatment response was defined as greater than 30% reduction in pain score (P<.004). Topiramate also reduced pain intensity (P<.003) as well as sleep disruption scores (P<.02) when compared with placebo. This drug also lowers blood pressure, has a favorable impact on lipid levels, decreases insulin resistance, causes growth of intraepidermal nerve fibers, and improves quality of life.[40,92,93]
Lamotrigine, 200 to 400 mg/d, is an anticonvulsant with dual-action inhibition of neuronal hyperexcitability. Results from 2 randomized, placebo-controlled studies including 720 patients showed that the drug was inconsistently effective for the treatment of pain when compared with placebo, although it was generally safe and well tolerated.
Another approach in treating diabetic neuropathy is the use of combination treatments. In an outpatient study, Gilron et al showed that the use sustained-release morphine and gabapentin together is superior to either alone, although the combination was associated with an increased frequency of adverse effects.
As mentioned previously, pain symptoms in neuropathy significantly affect quality of life. Neuropathic pain therapy is challenging, and selection of pain medication and dosages must be individualized, with attention to potential adverse effects and drug interactions. An algorithm for the management of symptomatic diabetic neuropathy is described in Fig. 7.
Algorithm for managing symptomatic diabetic neuropathy, modified from Boulton et al. Nonpharmacologic, topical, or physical therapies can be useful at any time (eg, capsaicin, acupuncture). The only 2 drugs approved in the United States for the treatment of painful diabetic neuropathy are pregabalin and duloxetine. However, based on the number needed to treat, tricyclic antidepressants are the most cost-effective drugs.
Endocr Pract. 2007;13(5):550-566. © 2007 American Association of Clinical Endocrinologists