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13 Articles in Volume 11, Issue #6
A Diet for Patients With Chronic Pain
A Practical Approach to the Management Of Diabetic Neuropathy
Book Review: Handbook of Pain Assessment, Third Edition
Diagnosis of Neck and Upper Extremity Pain
Diet and Nutrition For Patients With Pain—The Time Is Here
Dislocated Shoulder: Approaches to Lessen The Pain of Reduction Techniques
Guide to Dietary Supplements Most Commonly Used in Pain Management
New Device Combines Acupuncture With Four Other Technologies to Alleviate Pain
PPM Editorial Board Outlines Nutritional Advice for Chronic Pain Patients
Prospective Study of a Lumbar Back Brace In an Interventional Pain Practice
Q&A: The Legal Implications Of Medical Marijuana
Smoking and Pain
The Skeptical Radiology Nurse

A Practical Approach to the Management Of Diabetic Neuropathy

Nerve damage may be present long before diagnosis. Early diagnosis and treatment is paramount to preventing long-term disability.

Diabetes mellitus is the leading cause of peripheral neuropathy. Diabetic peripheral neuropathy (DPN) affects up to 50% of people with diabetes. Diabetic neuropathies represent a heterogeneous group of disorders whose specific abnormalities can present with diverse clinical manifestations—from distal symmetric polyneuropathy (DSPN) to mononeuropathy, diabetic amyotrophy, autonomic dysfunction, cranial neuropathies, and entrapment neuropathies. Duration of diabetes, glycemic control, and preexisting cardiovascular risk factors independently correlate with the development and progression of DPN as well as cardiovascular autonomic neuropathy.

To this day, the pathogenesis of diabetic neuropathy remains unclear. Several factors have been implicated, among which are insulin resistance, oxidative stress, abnormal glucose metabolism, advanced glycation end products, and protein kinase C activation.

The presentation of DPN varies depending on the forms. Diabetic neuropathy usually has a long subclinical latency period whose identification and management are challenging. It is important to identify neuropathy in its earliest stages to prevent the extreme morbidity and healthcare costs associated with its progression. Treatment options include several pharmacologic agents, but only two are FDA-approved for painful neuropathy. Most importantly, strict glycemic control remains the only available treatment option to prevent the development of diabetic neuropathy.

This article focuses on the epidemiology and pathogenesis as well as clinical features, diagnosis, and management of DSPN, the most common form of diabetic neuropathy.

Defining Diabetic Neuropathy

The definition of diabetic neuropathy has remained elusive. In most cases, its detection is based on symptoms, but this complication of diabetes can be present and silent for a long time prior to diagnosis. Traditionally, diabetic neuropathy has been defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after excluding other causes.1 In 2009, preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the Eighth International Symposium on Diabetic Neuropathy in Toronto, a panel of experts convened to provide updates on classification, definitions, diagnostic criteria, and treatments of DPN (see Table 1).2

Table 1. New Definitions of Diabetic Peripheral Neuropathy (DPN)

Epidemiology

The epidemiology of diabetic neuropathy depends on the case definitions used. If presence of symptoms was used as a criterion, 10% to 15% of diabetic patients would have neuropathy. The prevalence increases to 50% when sensory testing and nerve conduction study criteria are included.3

The incidence and prevalence of diabetic neuropathy has been studied in several small- and large-scale trials in the United States, Canada, and Europe. The Rochester Diabetic Neuropathy Study was a longitudinal population-based study of 380 patients, of whom 102 had type 1 diabetes. The mean duration of diabetes was 14.5 years for type 1 and 8.1 years for type 2, respectively, and in this cohort the prevalence of polyneuropathy was 35.5% based on one abnormal nerve conduction test in two or more nerves. Only 14% of patients were symptomatic, however, and none had severe, disabling neuropathy.3

One of the landmark studies in the literature regarding diabetes complications is the DCCT (Diabetes Control and Complication) trial, which enrolled 1,441 patients with diabetes type 1 in 29 centers in the United States and Canada between 1983 and 1989. Patients with severe neuropathy were excluded. At the end of the study, 19% of all enrolled patients fulfilled criteria for definite clinical neuropathy (which at that time included abnormal findings in at least two categories from neuropathic symptoms, sensory deficits, or impaired reflexes attributable to distal symmetric polyneuropathy).4

Another large, prospective study conducted in Europe, EURODIAB (European Diabetes Prospective Complications) study, enrolled 3,250 patients with type 1 diabetes from 31 centers in Europe between 1989 and 1991. At baseline, 29% of patients had evidence of neuropathy. Subsequently, neuropathy developed in 276 of 1,172 patients after a mean follow-up of 7.3 years, bringing the cumulative incidence to 23.5%.5

Pathogenesis and Risk Factors

The exact pathogenesis of diabetic neuropathy remains unclear and may involve metabolic and vascular dysfunction. Proposed vascular etiologies include nerve dysfunction secondary to disease of vasa nervorum, the microvasculature to the nerves. Other proposed metabolic etiologies include insulin resistance, accumulation of sorbitol, oxidative stress, abnormal glucose metabolism, advanced glycation end products, and protein kinase C activation. In addition, cardiovascular risk factors (eg, hypertension, smoking, dyslipidemia, and male gender) are independent risk factors for the development of diabetic neuropathy, especially with the presence of overt cardiovascular disease at baseline.6

It is now known that multiple factors influence the development and progression of diabetic neuropathy. In the Rochester Diabetic Neuropathy Study, researchers concluded that the order of importance for the development and progression of diabetic neuropathy appeared to be microvascular disease, total hyperglycemic exposure, and type of diabetes.3 Similarly, the DCCT not only provided definitive proof of the association between chronic hyperglycemia and neuropathy, but also found that treatment significantly decreased the risk for developing diabetic neuropathy.4

The EURODIAB study found that diabetes duration, A1c values at baseline, and changes in A1c over time were risk factors for the development of neuropathy along with cardiovascular risk factors; risk for neuropathy increased with progressive worsening of hemoglobin A1c.5

Recent literature has shown that diabetic neuropathy may be a presenting symptom of diabetes, and that a small percentage of patients may have overt neuropathy at the time of diabetes diagnosis. The AusDiab (Australian Diabetes, Obesity and Lifestyles) study identified 1,154 patients with impaired glucose tolerance or impaired fasting glucose among 11,247 individuals aged 25 years and older in Australia.7 These patients were screened for neuropathy using modified neuropathy symptoms, disability, pressure perception scores, and postural hypotension.

An association was found between neuropathy scores and retinopathy; these findings confirm that neuropathy onset may precede the diagnosis of diabetes and that the mechanisms involved are at least partly related to microvascular complications of chronic hyperglycemia.7

Finally, most recently, a review of abstracts presented at the American Diabetes Association (ADA) scientific sessions in 2010 showed that 19% of patients with diabetes receiving metformin for 1 year had vitamin B12 levels lower than 250 ng/mL, and 23% had vitamin B12 levels of 250 to 400 ng/mL. Peripheral neuropathy was present in 77% and 23% of these patients, respectively, and also was found in 7% of those with normal B12 levels.8

Diagnosis and Clinical Presentation

As noted, diabetic neuropathy has a long subclinical latency period. The most common type of diabetic neuropathy is DSPN; it can be sensory or motor and may involve small and large fibers. In general, small-fiber disease precedes the onset of large-fiber disease, and sensory symptoms usually precede motor symptoms.1 To confirm a diagnosis, the presence of diabetic polyneuropathy must be established. In patients with findings consistent with neuropathy, causes other than diabetes, such as neurotoxic medications, heavy metal poisoning, alcohol abuse, vitamin B12 deficiency (especially in those taking metformin for prolonged periods of time),8 renal disease, chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis, should always be considered.9 Large-fiber neuropathy typically causes painless paresthesias with impairment of vibration and also proprioceptive dysfunction with altered touch, pressure sensation, and loss of ankle reflexes. The longest peripheral nerves are involved first; therefore, lower extremity involvement occurs first. Stocking/glove pattern is characteristic of the sensory impairment, which is seen both more commonly and earliest in the lower extremities, particularly in the feet. Severe neuropathy, defined as the inability to detect the 10-g Semmes-Weinstein monofilament, is associated with increased risk for foot ulcers and amputation.

Chronic neuropathy also manifests with pain, present in 13% to 26% of patients with diabetes.10 Neuropathic pain has a significant impact on quality of life, particularly because it causes considerable interference with sleep, mood, and daily activities. Manifestations of painful neuropathy include episodic or persistent pain, typically worse at night and improved by walking. Pain is described as burning/hot, electric, sharp, achy, and tingling sensation. The average pain is 5 out of 10 on a visual analog scale. In addition, allodynia (pain due to a stimulus that normally does not cause pain, eg, stroking) and hyperalgesia (severe pain due to a stimulus that normally causes slight pain, eg, a pinprick) may be present. These symptoms also may be accompanied by sensory loss, but patients with severe pain may have few clinical signs. The most frequent locations of pain include feet (96%), balls of feet (69%), toes (67%), dorsum of foot (54%), calves (37%), and heels (32%).11

Screening

The ADA’s 2011 Annual Standard of Care Guidelines recommend that patients with diabetes be screened annually for diabetic neuropathy using tests such as pinprick sensation, vibration perception (using a 128-Hz tuning fork), 10-g monofilament pressure sensation at the distal plantar aspect of both great toes and metatarsal joints, and assessment of ankle reflexes.12 The challenge of early diagnosis and detection of diabetic neuropathy is to identify the most sensitive and specific tests. Two tools have been shown to have excellent specificity and sensitivity in the physical examination of the patient with possible diabetic neuropathy: the 10-g Semmes-Weinstein monofilament examination (SWME) and the 128-Hz tuning fork.13,14

The 10-g SWME is a noninvasive, low-cost, simple, and accurate handheld calibrated nylon thread that buckles once it has delivered a force of 10 g. Applied to the skin surface, it provides a standardized measure of patients’ ability to sense a point of pressure. Based on the current literature, the optimal method is to use the 10-g monofilament to test the plantar aspects of the great toe, third, and fifth metatarsal heads. Patients are instructed to say “yes” each time they sense the monofilament on their foot. If patients fail to sense the monofilament after it bends, the test site is considered to be insensate.

In a recent systematic review of the literature, it was demonstrated that the SWME is an optimal tool for clinical testing of diabetic neuropathy. This meta-analysis reviewed all of the studies performed on the diagnostic properties of SWME throughout the world and was shown to achieve sensitivity of 90% or above. Therefore, the SWME can be an inexpensive, accurate, and painless way for primary and specialty care physicians to identify patients with DPN during a physical examination, especially because it allows the diagnosis of diabetic neuropathy before the appearance of obvious visual signs, such as foot deformities and calluses.13

The 128-Hz tuning fork has been used to assess peripheral neuropathy, usually by comparing how long the patient detects vibration in comparison with the examiner. It determines whether vibration sense is normal, impaired, or absent. The testing is performed by first activating the tuning fork (striking it against a hard object) and then applying it to a bony prominence where neuropathy is unlikely (eg, hand, elbow, wrist). Once the patient is familiar with the vibration, the vibrating fork is placed on the metatarsophalangeal joint. If vibration is felt by the patient, he or she will then indicate when it stops. As soon as the patient says that the vibration has stopped, the clinician should place the tuning fork on his or her wrist. If it is still vibrating, the patient has impaired vibration sense. If the patient feels no vibration, he or she has absent vibration sense and thus peripheral neuropathy. The 128-Hz tuning fork recently has been shown to provide superior predictive value for the detection of diabetic neuropathy.14

A more recent small study showed the accuracy of the clanging tuning fork as a test for diabetic neuropathy. Among patients with 8 seconds or less of vibration perception, results of monofilament testing were abnormal only in those whose vibration perception was less than or equal to 4 seconds. In the patients with vibration perception of 4 seconds or less, 50% had normal monofilament test scores, including 29% of those with absent vibratory sensation. This study showed that the 128-Hz tuning fork provides a quantitative assessment of DPN and can document severe neuropathy, even in the presence of a normal result with the SWME15

Treatment Strategies

Figure 1 is a screening/treatment algorithm that illustrates a practical approach to the patient with possible diabetes neuropathy. The primary strategy for the management of diabetic neuropathy is the prevention of neuropathy; we have definitive evidence from the DCCT study that the risk for diabetic neuropathy can be decreased by up to 69% with improved glycemic control.4

Figure 1. A practical approach to the patient with diabetes for the screening

In addition, because diabetic neuropathy has multifactorial pathogenesis, additional therapies should be aimed at controlling hypertension, normalizing dyslipidemia, smoking cessation, and weight reduction. However, despite the evidence in the literature and the multiple pharmacologic regimens available for diabetes treatment today, normoglycemia is not achieved in the majority of diabetic patients, and other therapies aimed at the pathogenetic mechanisms of diabetic neuropathy have been investigated.

Although not FDA-approved, antioxidant therapy with α-lipoic acid has been shown to have some success. The SYDNEY (Symptomatic Diabetic Neuropathy 2) trial showed that treatment with 600 mg daily of α-lipoic acid taken orally for 5 weeks reduced the chief symptoms of diabetic polyneuropathy, including pain, paresthesias, and numbness, to a clinical meaningful degree.16

In addition, a randomized placebo-controlled study, NATHAN 1, compared α-lipoic acid with placebo; after 4 years from randomization, the neuropathic deficit in the placebo group progressed, whereas the patients treated with α-lipoic acid improved and the drug was well tolerated throughout the trial.11

Most of the pharmacologic therapy, however, is aimed at symptomatic relief of pain. Control of symptoms constitutes a considerable management problem because the efficacy of a single therapeutic agent is not the rule, and simple analgesics are usually inadequate to control the pain. A reduction in symptoms of 30% to 50% is achievable in most patients with combination therapy.

There presently are several classes of agents used in the treatment of painful diabetic neuropathy: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), calcium channel modulators (α2δ ligands), sodium channel blockers, topical capsaicin, and opioids. To date, only two medications are formally approved by the FDA for treating painful diabetic neuropathy: duloxetine (Cymbalta), an SNRI, and pregabalin (Lyrica), a voltage-sensitive calcium channel modulator.

In multiple studies, pregabalin was shown to significantly reduce pain and sleep interference and achieve an improvement in quality of life at doses of 150, 300, and 600 mg daily, with greater benefit at higher doses. Median time of onset of pain relief was 4 days for the 600 mg per day group and 13 days for the 150 mg per day group. Dizziness, peripheral edema, and somnolence were the most frequent side effects and were dose-dependent. The discontinuation rate was higher at the 600-mg dose. Of note, pregabalin treatment resulted in weight gain, with a 7% increase from baseline to end point, especially with the 600 mg per day dose compared with placebo.17

The efficacy of the second FDA-approved drug for diabetic neuropathy, duloxetine, was analyzed in multiple randomized, double-blind, placebo-controlled, parallel-group trials pooled recently in a meta-analysis.18 All of these studies evaluated 60 mg of duloxetine daily or twice daily and showed beneficial effects compared with placebo starting in the first week of therapy. The most frequent side effects were nausea, fatigue, and somnolence at both doses.

Several other medications have been shown to have some efficacy in treating diabetic neuropathy. There is considerable experience with TCAs; however, there is a growing concern about a possible association of TCAs with sudden cardiac death; they also cause postural hypotension, which may be particularly problematic in patients with autonomic neuropathy. Venlafaxine, another SNRI, was shown to be efficacious, but clinically significant electrocardiographic changes were seen with high doses. Other antiepileptic medications, such as gabapentin, phenytoin, carbamazepine, oxcarbazepine, lamotrigine, topiramate, and valproic acid, have been shown to have some efficacy in treating painful diabetic neuropathy.19

Finally, topical capsaicin (Qutenza) and opioids, as well as second- and third-line drugs, have been used in the management of painful diabetic neuropathy. The most current recommendations can be found in the recently published 2011 evidence-based guideline from the American Academy of Neurology.20 The guideline is based on the results of a systematic review of the literature from 1960 to August 2008, with recommendations linked to the strength of the evidence. The basic question asked was: “What is the efficacy of a given treatment to reduce pain and improve physical function and quality of life (QoL) in patients with DPN?”

In the review, the recommendations are divided into levels A and B. Table 2 describes the list of drugs recommended for the management of PDN. In this guideline, pregabalin was found to be the most effective drug for the relief of painful diabetic neuropathy and was given a level A recommendation. Duloxetine, the other FDA-approved agent for painful diabetic neuropathy, was found to be “probably effective” and was given recommendation level B, together with several other compounds (eg, venlafaxine, amitriptyline, gabapentin, valproate) that have been used for the management of painful diabetic neuropathy.20

Table 2. Evidence-based Treatments of Painful Diabetic Neuropathy

Table 2. Evidence-based Treatments of Painful Diabetic Neuropathy

Conclusions

Diabetic peripheral neuropathy is a very common complication of diabetes with a long subclinical latency period that is present in up to 50% of patients. However, recent literature has shown that diabetic neuropathy may be a presenting symptom of diabetes (ie, in patients with impaired glucose tolerance), and a small percentage of patients may have overt neuropathy at the time of diabetes diagnosis. The exact pathogenesis remains unclear and may involve metabolic and vascular dysfunction. The diagnosis of DPN revolves around a careful history and physical examination aided by the use of diagnostic and screening tools, such as the 10-g SWME and the 128-Hz tuning fork. It is important to identify neuropathy in its earliest stages to prevent the extreme morbidity and healthcare costs associated with its progression.

The clinical presentation of DPN includes paresthesias, loss of ankle reflexes, and pain, which can significantly impact quality of life. Multiple studies have proven that intensive treatment of diabetes has benefits across all complications of diabetes mellitus, including diabetic neuropathy. Primary prevention of diabetic neuropathy remains optimal glycemic control, as well as control of hypertension and dyslipidemia. In addition, patient education has a very important role in preventing diabetic foot ulcer. Essential elements of patient education include daily foot checking, prompt calls for examination with new injury, never walking barefoot or on stocking feet, wearing only prescribed footwear, and breaking in new shoes slowly.

Therapeutic strategies are aimed mainly at symptomatic relief of pain, with two FDA-approved drugs, pregabalin and duloxetine, given alone or in combination with other therapeutic agents such as anticonvulsants, TCAs, opioids, and topical capsaicin. These therapies should be chosen carefully, with attention to the patient’s comorbidities and careful follow-up.

Editor's Comment
Practical Pain Management recognizes the prevalence and challenge in treating painful diabetic neuropathy. Consequently, we wish to publish thoughtful articles on this subject and salute the paper published here by Dr. Aleppo. We do not, however, endorse, sanction, or recommend the treatment guidelines recently published by the American Academy of Neurology. Painful diabetic neuropathy usually calls for multiple clinical trials to find an effective agent in a given patient and combination therapy, in severe cases, is usually the rule and not the exception. Physicians are advised to review the pain treatment guidelines published by any group but always prescribe treatments based on individual patient clinical response, financial means, and compliance.

Last updated on: September 21, 2011
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