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Highlights From the American Diabetes Association Compendium on Painful Diabetic Peripheral Neuropathy
Peripheral neuropathy is a significant and prevalent chronic complication of diabetes. Having peripheral neuropathy is an independent risk for foot ulceration and subsequent amputation.1,2 Recently, the American Diabetes Association (ADA) released a clinical compendium entitled “Diagnosis and Treatment of Painful Diabetic Peripheral Neuropathy” that summarizes key current ideas and guidelines.3 In this article, we present highlights of this compendium related to podiatric clinical practice.
Screening and Diagnosis of Diabetic Peripheral Neuropathy
Recommendations for frequency of assessment of DPN are annually starting at the time of diagnosis for type 2 diabetes, and five years after diagnosis for type 1 diabetes.3 Screening is also relevant for those with prediabetes and young people with signs or symptoms of DPN. DPN assessment in routine clinical care should include a detailed history, reflex testing, and at least two sensation tests, with at least one targeting each size of fiber (small and large).3 Symptoms associated with DPN relate to the fiber types affected (see table to left).
Large nerve fibers relay vibratory sensation, proprioception, and reflexive stimuli. One can evaluate proprioception by having the patient close their eyes, and the clinician moves the hallux into dorsiflexion or plantarflexion and has the patient respond with which position the toe is.4 A reflex hammer can test bilateral ankle reflexes, although reflexes may be lost early in DPN, in conjunction with intrinsic musculature. Clinicians can evaluate vibratory sensation with a 128-Hz tuning fork. Arguably, the 10-g monofilament is the most utilized screening tool for DPN in routine care5 and evaluates light-touch pressure sensation. In one study, the vibration perception threshold test at 25 volts (V) or a lack of perception at 4 or more sites using a 10-g monofilament had high sensitivity, and the specificity of these tests increased when combined.6 Although the vibration perception threshold test can be time-consuming, a traditional or electronic tuning fork can couple with a 10-g monofilament exam to efficiently and effectively screen for DPN.7
One should note that commercial monofilaments vary and can be imprecise and inaccurate after repetitive loading.8,9 In a mechanical study evaluating 10-g monofilaments after repetitive buckling, the investigators found that the accuracy of a single 10-g monofilament declined after 100 uses.10 This supports the notion of incorporating either multiple 10-g monofilaments or disposable ones to maintain accuracy in DPN screening. Despite in vitro variability, the 10-g monofilament remains a mainstay in the podiatric neurologic exam due to its clinical reproducibility, ease of administration, and low cost.5
Thermal discrimination and pinprick sensation can evaluate small nerve fibers, associated with protective sensation and nociception. A cool material, such as a metallic object can allow one to assess thermal discrimination.11 One can carefully evaluate pinprick sensation with a sharp object, including safety pins, which one should discard after every patient.12 Combining pinprick perception with vibratory perception and ankle reflexes can increase sensitivity for detecting polyneuropathies.13
It is important to note that some patients may present as seemingly asymptomatic or reluctant to report. In these situations, routine clinical examination can objectively pick up incidental findings of neuropathy. Therefore, heightened clinical suspicion for peripheral neuropathy in patients with diabetes is critical.
In addition to the clinical findings, there are several validated screening and diagnostic questionnaires for detecting DPN. These include the Toronto Clinical Neuropathy Score,14,15 the Utah Early Neuropathy Scale,16 the Neuropathy Disability Scale,17 and the Michigan Neuropathy Screening Instrument.18 Additionally, validated neuropathic pain scales can determine severity, including the McGill Pain Questionnaire19 and the Douleur Neuropathique en 4 Questions (DN4).20 Combining these questionnaires with clinical signs and symptoms can assist in diagnosis and monitoring of DPN and prevent unnecessary electrophysiologic testing, barring any high clinical suspicions of other differential diagnoses.6
Treatment Options for Painful Diabetic Peripheral Neuropathy
Approximately 30 percent of people with DPN experience painful symptoms requiring treatment.21 In a large study in the UK, people with type 2 diabetes had a higher prevalence of painful DPN.22 A small pilot study with continuous glucose monitoring confirmed that people with greater fluctuations in serum glucose and poor glycemic control more frequently experienced painful DPN than matched subjects with stable serum glucose levels and tight glycemic control.23 Therefore, an early and central component of managing painful DPN is to achieve stable, optimal glycemic control.24
When treating painful DPN, it is important to quantitatively measure pain to determine treatment and monitor effectiveness. These assessment scales can be simple (such as a visual analog scale (VAS) or DN4) or more detailed (such as the modified Toronto Clinical Neuropathy Score25 or the Neuropathy Total Symptom Score-6 instruments26).
The ADA compendium recommends a multi-pronged therapeutic approach, including pharmacological, topical, nonpharmacological, and nutraceutical therapies. Pharmacological treatments are limited because no current FDA-approved treatment mitigates progressive nerve fiber loss; however, a few target symptom relief. Currently, three pharmacologic therapies are FDA-approved to treat painful DPN: pregabalin, duloxetine, and tapentadol. Of these, tapentadol is an opioid and has limited clinical effectiveness.27 Other pharmacological therapies not FDA-approved include antiepileptic agents such as gabapentin and tricyclic antidepressant agents such as amitriptyline. Based on trial evidence, an expert panel recommends that the first-line therapy for painful DPN include tricyclic antidepressants, duloxetine, or anticonvulsants gabapentin or pregabalin.24 Recommendations aim to achieve 6 months of symptom relief with pharmacological therapy, followed by a gradual reduction of drug treatment. If symptoms reappear, a lower dose may be required for a few more months before re-evaluation.
Topical therapies are a viable option but may have limited clinical utility due to bilaterality and a relatively large surface area potentially affected by neuropathic pain. Nonetheless, an 8% long-acting capsaicin patch has received FDA approval for painful DPN with promising results.28,29
Nonpharmacological treatments include health behavior interventions (HBIs), passive modalities, and nerve stimulation treatments. HBIs such as exercise and dietary counseling may delay the onset of type 2 diabetes.30,31 Moreover, physical activity has been associated with a delay in onset and progression of DPN in patients with type 2 diabetes, even without improvement in weight loss or glycemic control.32 Passive modalities such as neurobiofeedback, static magnetic fields, and foot bath techniques may be helpful in the treatment of painful DPN, but further investigation is required. Currently, the effectiveness of energy or nerve stimulation treatments on delaying or preventing the onset of DPN symptoms remains unclear.33
Finally, the term “nutraceutical” describes the dual function of nutritional and pharmaceutical therapy.34,35 Although not formally defined by US law, nutraceuticals are often categorized as a dietary supplement, which requires intent for ingestion and sales as capsules, soft gels, gel caps, tablets, powers, or liquids.36 Due to the role of oxidative stress on the pathophysiology of diabetic neuropathy, antioxidants, such as ɑ-lipoic acid (ALA), diminish oxidative stress and positively affect DPN. Daily 600 mg doses of intravenous or oral ALA may reduce symptoms of DPN to a clinically significant degree and are recommended for treating DPN.37–39 Benfotiamine is a prodrug of thiamine (vitamin B1) that can reduce the formation of advanced glycation end-products (AGEs).40 Twice daily doses of 300 mg benfotiamine have improved neuropathy symptom scores in patients with DPN.40,41 Vitamin B12 deficiency can have neurologic consequences and is a possible risk associated with metformin treatment. In a 12-month RCT, vitamin B12 supplementation with 1000 µg/day in metformin-treated patients improved neurologic function.42 Therefore, the ADA recommends routine measurements of vitamin B12 levels with patients on metformin.43 There is also growing evidence of clinical utility in treating DPN with vitamin D, vitamin E, acetyl-L-carnitine, polyunsaturated fatty acids, and magnesium. In total, longer-term randomized controlled trials should clarify the value of using nutraceuticals in treating DPN.
Concluding Thoughts
The importance of prompt diagnosis and treatment of DPN cannot be understated. Annual DPN assessment should include a detailed history, reflex tests, and at least two sensation tests. A subset of patients with DPN may develop painful DPN, for which it is important to implement a multimodal approach, including pharmacologic, nonpharmacologic, topical, nutraceutical and health behavior interventions. It is also essential to consider the impact of social determinants of health when treating patients with diabetes and DPN.
Dr. Cheung is a first-year podiatric surgical resident at Yale-New Haven Hospital in New Haven, CT.
Dr. Wu is the Dean and Professor of Surgery at Dr. William M. Scholl College of Podiatric Medicine and Professor of Stem Cell and Regenerative Medicine at the School of Graduate Medical Sciences at Rosalind Franklin University of Medicine and Science in North Chicago, IL.
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