By: Tamara Yunusova, Senior Staff Editor

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Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, burdening almost 50% of the diabetic population.¹ While diabetic neuropathy is a broad term that may refer to a spectrum of autonomic, focal, proximal and peripheral neuropathies, it is generally characterized by poor gait and abnormal cold/heat sensations. As numerous studies have shown neuropathy to be closely tied to hyperglycemia, strict glycemic control is imperative to prevent the progression of the disease.² Although pharmacological therapy has yet to target the underlying mechanisms of neuropathy, current treatments are well equipped to address neuropathic pain, which is present in 10 – 20% of cases of DPN.³ Tricyclic antidepressants and anticonvulsants are commonly used to treat DPN-associated pain.

DPN is defined as the presence of signs or symptoms of peripheral nerve dysfunction in a patient with diabetes after ruling out other causes.⁴ It is caused by the degeneration of small, unmyelinated C fibers or thinly myelinated Aβ sensory fibers that mediate pain and temperature sensation.^2,5 Damage to the C fibers results in small fiber neuropathy which is characterized by allodynia, non-painful stimuli that are perceived as painful, and hyperesthesia, which is when normally painful stimuli become excruciatingly painful.⁶ Symptoms of DPN include numbness, tingling, burning, aching, and an abnormal sensational response to pain and temperature.^2,6 More specifically, peripheral neuropathy can be characterized by negative and positive symptoms or may be asymptomatic. Negative symptoms include loss of sensation and strength, while positive symptoms include pricking and pain.⁷ Over time, symptoms may progress from the toes to the foot and eventually up the leg. Furthermore, symptoms are not restricted to the lower limbs and may occur in the hands and fingers as well.^2,5 Relative to various neuropathies, peripheral neuropathy is the most common in diabetics.

The results of the Diabetes Control and Complications Trial (DCCT), a clinical study conducted between 1983 and 1989, support the theory that diabetic peripheral neuropathy develops as a result of hyperglycemia.⁸ This study assessed the development and progression of DPN in 1,441 patients with type 1 diabetes mellitus who were assigned to receive conventional or intensive therapy. Conventional therapy consisted of one to two daily injections of insulin, daily monitoring of urine or blood glucose (BG), and education about diet and exercise. Intensive therapy consisted of three or more injections of insulin or administration via an external pump. The goal of conventional therapy was to attain a preprandial BG between 70 and 120 ^mg/_dL, postprandial BG < 180 ^mg/_dL, a weekly 3 am measurement > 65 ^mg/_dL, and a monthly hemoglobin A1C < 6%. Study results indicated a 60% reduction in neuropathy in patients who had received intensive therapy. This was confirmed by a follow-up study, which showed lower incidence of DPN in the intensive therapy group at years 13 and 14.⁸

From a biochemical standpoint, the polyol pathway illustrates the correlation between hyperglycemia and peripheral neuropathy. The underlying principle of the pathway is that under hyperglycemic conditions, the body metabolizes glucose differently. As a consequence of the impaired metabolism, nerve conduction is delayed.^1-2 More specifically, in a non-hyperglycemic state, glucose is metabolized by glycolysis, the citric acid cycle, and oxidative phosphorylation.² However, when glucose levels are elevated, glucose bypasses these processes and, instead, is reduced to sorbitol by aldose reductase, and then further oxidized to fructose by sorbitol dehydrogenase.^1-2 Excess levels of sorbitol and fructose byproducts decrease the expression and uptake of myo-inositol in rats with streptozocin-induced diabetes leading to the slowing of nerve conduction.²

Moreover, as the conversion of glucose to sorbitol and fructose is an NADPH-depleting process, the resulting oxidative stress is another factor that may contribute to the development of DPN. This cofactor is necessary for the recycling of GSSH to GSH or glutathione, an enzyme that prevents the formation of superoxide radicals and thereby reduces oxidative stress.^1-2 A recent study conducted by Ho et al.² showed that deletion of aldose reductase prevented GSH depletion and superoxide formation. By inducing alterations in metabolism and increasing oxidative stress, hyperglycemia poses as DPN risk factor.

Based upon the findings of the DCCT study and biochemical studies which demonstrate the role of hyperglycemia in the development of DPN, it can be concluded that strict control of blood glucose levels can delay progression of this condition. By educating patients about the importance of keeping blood glucose levels under control with routine self-monitoring and proper BG meter use, pharmacists can delay the progression of neuropathy and, ultimately, improve the quality of life in patients with DPN. In addition to BG control, proper foot care constitutes another facet of effective DPN management. Pharmacists can educate patients about foot care and the importance of routine foot examinations. Patients are recommended to inspect their feet daily for open sores, blisters and changes in shape or color of the skin. It is also recommended that patients wash their feet daily with warm water and soap and dry them thoroughly. Patients should be advised to wear comfortable shoes and socks and avoid walking barefoot.^8.

While studies such as the DCCT underline the contribution of hyperglycemia to the development and progression of DPN, the findings of more recent studies diverge from the notion of the glucocentric model. In addition to hyperglycemia, many factors including neuronal insulin resistance and dyslipidemia may play a role in the pathogenesis of DPN. Relative to the etiological factors, however, the contribution of glucose is currently most understood.

Tricyclic antidepressants (TCAs) serve as the first line treatment for neuropathic pain. TCAs modulate pain transmission by inhibiting the reuptake of norepinephrine and serotonin. The American Diabetes Association recommends amitriptyline as the first choice among tricyclic antidepressants.⁹ However, due to anticholinergic adverse effects, dose titration to higher doses is restricted with this agent.^9,10 Duloxetine, a selective serotonin norepinephrine reuptake inhibitor, is the only TCA that is FDA approved for neuropathic pain.⁹ Studies indicate that duloxetine 60 mg and 120 mg daily are efficacious for treating pain.¹¹ Common side effects of duloxetine include nausea, somnolence, dizziness, decreased appetite, and constipation. Because nausea is common, patients are encouraged to take the drug on a full stomach. Duloxetine should not be used in conjunction with other serotonin or norepinephrine reuptake inhibitors, but can be combined with anticonvulsants.⁵

In the presence of contraindications or ineffective treatment outcomes, anticonvulsants (e.g. gabapentin or pregabalin) may be used in place of TCAs. The starting dose for gabapentin is 300 to 600 mg three times daily. The drug can be titrated slowly up to a maximum of 900 mg four times daily. The major side effects of gabapentin are somnolence, dizziness, and ataxia. Pregabalin is initiated at 50 mg twice a day and slowly increased to 150 mg two times a day. The maximum dose approved by the FDA for the treatment of DPN is 300 ^mg/_day. Common side effects of pregabalin include dizziness, vertigo, incoordination, ataxia, blurred vision, sedation, and confusion. It is classified as a Schedule V drug and thus, may be habit forming.⁵ In comparison to gabapentin, pregabalin is more readily absorbed (1 hour vs. 3-4 hours) and has greater bioavailability.² Gabapentin and pregabalin modulate neurotransmitter release and regulate neuronal hyperexcitability by binding to the α2-δ subunit of voltage-gated calcium channels and decreasing calcium influx at nerve terminals.¹² While both compounds are structurally related to GABA, it is important to note that neither is metabolically converted to GABA nor inhibits GABA uptake or degradation.¹³ Currently, duloxetine and pregabalin are the only treatments approved by the FDA for peripheral neuropathy-associated pain.

An alternative to the aforementioned therapies is the use of topical lidocaine or capsaicin patches. Therapeutic advantages include lack of drug interactions, minimal side effects, and no need for dose titration.⁶ Lidocaine 5% patches are FDA-approved and have shown to be effective in the management of neuropathic pain. Relative to other treatments, lidocaine patches have fewer and less severe side effects, which include burning sensation, elevated aspartate aminotransferase levels and blood pressure, headache, muscle spasms, and tingling sensation. Capsaicin, which is available as 0.075% cream or an 8% patch, is another option for the management of neuropathic pain. Although it is an efficacious pain treatment, daily use of capsaicin can result in the degeneration of epidermal and dermal nerve fibers. The nerve fibers regenerate upon discontinuation of the agent. Cautious use of this agent is recommended as its effects are more pronounced in DPN patients.⁶

As close monitoring of blood glucose levels and preventive measures constitute the most effective treatment for DPN, pharmacists are integral in educating patients about proper glucose control and the importance of preventive measures such as routine foot examinations and exercise.

SOURCES:

1. Cheng T, Edwards JL, Feldman EL, et al. Diabetic neuropathy: mechanism to management. Pharmacological Therapy. 2008;120:1.
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6. Gibbons CH, Hovaguimian A. Clinical approach to the treatment of painful diabetic neuropathy. Therapeutic Advances in Endocrinology and Metabolism. 2011;2:27.
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8. Pisano M. Diabetic peripheral neuropathy. U.S. Pharmacist. 2014;39:35-38.
9. Kaur H, Hota D, Bhansali A, et al. A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy: a randomized, double-blind, cross-over clinical trial. Diabetes Care 2011;34:818.
10. Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 1987;37:589.
11. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev 2014;1:CD007115.
12. Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses. Diabetes Care. 2008; 31:1448.
13. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998;280:1831.

[pubmed_related keyword1=”diabetes” keyword2=”peripheral” keyword3=”neuropathy”]

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