Pathophysiology

How Does Diabetes Mellitus Cause Nerve Damage?

Although the pathophysiology of diabetic neuropathy is unclear, most experts believe that hyperglycemia is the cause of the nerve damage in DPN.48 Hyperglycemia causes increased levels of intracellular glucose in nerves, leading to saturation of the normal glycolytic pathway.49 Nevertheless, different neuropathies may have different (and perhaps overlapping) mechanisms; for example, with focal or asymmetrical diabetic neuropathy syndromes, vascular injury or autoimmunity may play more important roles. Other factors thought to play a role include activation of the polyol pathway, advanced glycation end products, increases in oxidative stress, altered gene expression with altered cellular phenotypes, changes in cell physiology relating to endoskeletal structure or cellular transport, reduction in neurotropins, and nerve ischemia.

Managing Diabetic Neuropathy Requires Treating the Underlying Disease

Treatment of Neuropathic Pain in Type 2 Diabetes

Optimal management of diabetic neuropathies requires that clinicians understand that long-term control of blood sugars and reduction of cardiovascular risk factors is the cornerstone of treatment, both for diabetes and for diabetic neuropathy.3 Clinicians who properly treat the underlying diabetes have a better chance of reducing neuropathy and its accompanying symptoms, as opposed to regimens that simply address the neuropathy symptoms. Figure 2 presents the ADA and American Association of Clinical Endocrinologists/International Diabetes Federation–recommended goals for patients with type 2 diabetes who are at risk for diabetic neuropathy.4,50-52

Nonpharmacological Treatment Options

Lifestyle Modifications

Diet and exercise have been shown to promote cutaneous reinnervation and improve pain in diabetic neuropathy patients.23,53 Patients should be counseled on the benefits of weight loss, tobacco cessation, and the effects of alcohol on diabetic neuropathy.

The Importance of Foot Care

Once a patient has diabetic neuropathy, foot care becomes crucial for preventing ulceration, infection, and amputation.32 At each visit, the physician should examine the patient’s feet to detect evidence of neuropathy or early lesions, as well as skin breaks, red or callused areas, decreased pedal pulses, delayed capillary refilling, bony deformities, and protective sensation.17

Table 4 provides instructions clinicians should provide patients to foster effective foot care.5,17

Pharmacological Treatment Options

The classes of drugs with the best proven efficacy are antidepressants, anticonvulsants, and opioids.10 Duloxetine, a serotonin noradrenaline reuptake inhibitor (SNRI), and pregabalin are specifically approved by the U.S. Food and Drug Administration (FDA) for the treatment of painful DPN. All other agents must be considered “off-label,” although other considerations, including cost, intolerance of approved agents, comorbidities, and efficacy, may dictate their use.

Antidepressants

Duloxetine has been studied in 2 randomized, double-blind, placebo-controlled trials for relief of pain in patients with painful diabetic neuropathy,54,55 and is approved by the FDA at total dosages of 60 mg/day.56

The first study, published in 2005, was a 12-week, multicenter, double-blind study in which 457 patients experiencing pain due to polyneuropathy caused by type 1 or type 2 diabetes mellitus were randomly assigned to treatment with duloxetine 20 mg/day, 60 mg/day, or 60 mg BID or placebo.54 Duloxetine 60 and 120 mg/day demonstrated statistically significant greater improvement on the 24-hour average pain score compared to placebo. Duloxetine also proved more efficacious than placebo on almost all secondary measures (ie, worst pain severity and mood). Patients in the 120-mg/day treatment arm experienced a statistically significant improvement in Short Form-36 mental (P ≤ 0.01) and general health perception domains (P ≤ 0.001) as well.

All doses of duloxetine were well tolerated, with no significant changes in concentrations of A1C, LDL-C, HDL-C, or triglycerides.54 Adverse events included somnolence and constipation with the 60-mg/day dose, and nausea, somnolence, dizziness, constipation, dry mouth, sweating, decreased appetite, anorexia, and weakness with the 120-mg/day dose.

In another trial, patients with diabetic neuropathy were randomly assigned to receive either placebo (n = 116), duloxetine 60 mg/day (n = 116), or duloxetine 60 mg BID (n = 116).55 The patients treated with duloxetine 60 mg daily had marked improvements in 24-hour average pain score, 24-hour worst pain severity score, and night pain score (P < 0.001). Patients treated with duloxetine 60 mg BID also had improvements in 24-hour average pain score (P < 0.001), 24-hour worst pain severity score (P < 0.01), and night pain score (P < 0.001).

Another antidepressant, venlafaxine, has yielded efficacy in alleviating pain in diabetic neuropathy when used in higher doses (150-225 mg/day).57 In a randomized, placebo-controlled trial, venlafaxine extended-release (ER) at 2 doses (75 mg/day or 150-225 mg/day) was compared to placebo for the treatment of painful diabetic neuropathy. Rowbotham and colleagues concluded that the higher dose of venlafaxine ER significantly reduced pain intensity compared to placebo and venlafaxine ER 75 mg/day at week 6. The most common adverse events in the venlafaxine groups were nausea (> 10%) and somnolence (> 10%). Dyspepsia, insomnia, and sweating also occurred in 10% of the patients treated with venlafaxine ER 150-225 mg/day. Impotence was reported in 6% of the men receiving venlafaxine ER 75 mg/day and in 5% of the men receiving venlafaxine ER 150-225 mg/day.

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are widely used to treat neuropathic pain but are not FDA-approved for this purpose and have a significant adverse-effect profile.58 TCAs include amitriptyline, desipramine, clomipramine, and nortriptyline. TCAs have yielded significant pain relief in patients with DPN, although clinical trials of these agents have typically included small patient populations.59 Randomized, double-blind, crossover, placebo-controlled studies of amitriptyline and desipramine demonstrated that 67% of the patients receiving amitriptyline (P ≤ 0.001) experienced good to excellent pain relief, while 63% (P < 0.05) of the patients receiving desipramine experienced moderate or greater pain relief.

The side-effect profile of TCAs includes anticholinergic and muscarinic side effects, contraindicating all (especially amitriptyline) in the elderly and those with cardiovascular pathology.58 There is little efficacy difference between amitriptyline and desipramine (which has the lowest side-effect profile in this group), as Max and colleagues demonstrated in a small crossover study in 20 patients.60 The lower cost and demonstrated efficacy must be weighed against the significant side-effect profile including sudden cardiac death at higher doses.58

Anticonvulsants

Pregabalin is FDA-approved for painful diabetic neuropathy and postherpetic neuralgia.58 As an anticonvulsant, it is approved for the treatment of partial seizures. It is a Schedule V controlled substance with a mild potential for abuse.56

Studied in doses of 75, 150, 300, and 600 mg daily, pregabalin has yielded efficacy at the higher 2 doses in 3 randomized, double-blind, placebo-controlled studies.61-63 There may be a tendency for weight gain, especially at higher doses.61,63 Furthermore, a study conducted by Lesser et al reported significant incidences of dizziness, somnolence, and peripheral edema in both the 300- and 600-mg groups.61

The efficacy of gabapentin is comparable to amitriptyline at doses of 1565 mg/day compared to 59 mg/day.64

Lidocaine Patches

Lidocaine patches may be useful if the pain of diabetic neuropathy is very focal. One to 3 patches can be applied to intact skin over the painful area, 12 hours on and 12 hours off.65

Capsaicin Cream

Capsaicin cream depletes substance P, the major neurotransmitter used in conveying messages about pain into the central nervous system.66 This can be applied over the painful area 3-4 times daily.67 Gloves should be worn if this is used, and care taken to avoid contact with the eyes. Clinicians should note that many patients are unable to tolerate the intense increase in pain that occurs over the first few days that capsaicin cream is applied (until substance P is depleted).

Education and Effective Patient-Clinician Communication Is Critical for Treatment Success

Therapeutic patient education is a patient-centered approach directed toward patient needs, resources, and values.68 Education enables patients to improve their knowledge and skills with both their illness and treatment. It brings a better QOL, a greater therapeutic compliance, and a reduction in complications.

Patient education means more than conveying information about the patient’s disease.69 Education focuses on bolstering self-management, because patients who “take control” of their disease are not only better able to cope with the challenges of living with a chronic disease,69 but also to adhere to medication regimens and modify their lifestyles as necessary.68 Clinicians’ roles include providing information patients need to set priorities and solve problems, assisting and supporting the implementation of lifestyle changes by identifying reasonable modifications they can make, and providing emotional support and encouragement.68

One way clinicians can hone both their communication skills and be effective patient educators is by employing motivational interviewing.68 Optimal outcomes for diabetic neuropathy patients often depend on their willingness to modify longstanding behaviors and adhere to complex medication schedules. Many patients have difficulty accomplishing these tasks, which leads to poorer outcomes.

The purpose of motivational interviewing is to explore the reasons patients do not adhere to their treatment regimen in a nonjudgmental manner, and then have the patients consider another point of view and become actors in their own decision-making.70 This requires clinicians to hone their communication skills, not only their interviewing techniques, but also their ability to listen to patients. Golay and colleagues list the 4 requirements necessary to conduct effective motivational interviewing70:

• Ask open-ended questions instead of closed ones
• Validate patients’ efforts, personal efficacy, and self-esteem
• During therapeutic education, make use of reflective listening with empathic reformulations and paraphrasing, which reflect patients’ legitimate feelings
• Summarize the interview’s various stages to allow patients to follow the progress of the explanations of their ambivalence

Vég and colleagues demonstrated the therapeutic importance of using these techniques (especially asking open-ended questions) in a study of 183 patients with type 2 diabetes.69 The authors investigated whether they could determine patients’ diabetes self-management habits by asking 3 open-ended questions: “What is your role in your diabetes management?”; “What is your goal with your diabetes management?”; and “What kind of support do you need for your diabetes management?” The authors separated patients into 3 groups – Disease Manager, Compliant, and Disheartened – based on the patients’ answers to the 3 open-ended questions. Disease managers believed in taking a proactive role in their diabetes management and either had limited support needs or were happy with the support they received. Compliant patients tended to follow their clinicians’ treatment recommendations and expressed a greater need for support. Disheartened patients tended to explain why their treatments were not working and described a passive role for themselves in treating their disease. At the end of 24 months, Disease Manager patients reduced their A1C levels by -0.28. Compliant patients reduced their A1C by -0.18 after 6 months, but did not reduce their levels significantly after then. Disheartened patients did not reduce their A1C by statistically significant amounts.

Another approach clinicians can use with their patients is cognitive-behavioral techniques, which are focused on identifying the triggers that lead to negative behaviors.70 The key to cognitive-behavioral techniques is formulating a functional analysis (such as the one shown in Figure 3) that displays a hypothetical trigger, negative thoughts, emotions, behavior, and consequences of the behavior for a diabetic patient who does not adhere to proper dieting habits.

The functional analysis of this food binge described in Figure 3 enables clinicians to illustrate to patients how a trigger (in this case, frustration at work) leads to negative consequences.70 By analyzing the flow from trigger to consequence, patients can attain a better understanding of the underlying mechanisms responsible for their behaviors. Figure 4 displays how the “vicious cycle” can become a “virtuous circle” with a cognitive-behavioral approach.

Treatment Algorithm

Clinicians should formulate treatment regimens based on pathogenetic mechanisms,10 and strive to manage the pain symptoms associated with diabetic neuropathies while counseling patients to mitigate risk factors such as smoking, lack of physical activity, or a high-fat, high-calorie diet.23 Clinicians should also screen for the development and progression of diabetic neuropathy to reduce the risk of complications.10

Each type of diabetic neuropathy has its own prognosis, clinical course, and requirements for management. Clinicians should set realistic goals and reasonable expectations while developing a rapport with the patients, all of which are crucial in ensuring patient compliance with the therapeutic regimen.58 Developing a treatment plan for diabetic neuropathy includes discussion and negotiation between the patient and physician regarding the goals for therapy. Clinicians should explain that complete relief of pain may not be achieved.

Despite limitations in the available data concerning currently available agents that are effective in reducing pain due to diabetic neuropathy, a consensus panel has issued a treatment algorithm for neuropathic pain, as shown in Figure 5.23 The algorithm recommends initiating treatment with either an αalpha-2-deltaδ agonist (ie, pregabalin or gabapentin), a TCA, or an SNRI (ie, duloxetine). These options are evaluated on the basis of the contraindications and comorbidities of individual patients.

Clinicians should realize this algorithm in Figure 5 has the following limitations23:

• The underlying pain mechanisms in diabetic neuropathy have not been delineated
• Lack of direct head-to-head comparative trials
• Need for standardized study endpoints
• Need for further long-term efficacy and safety data
• Need for investigation of the efficacy and safety of different combination therapies

Conclusion

Diabetic neuropathy is a common and diverse complication that adversely affects the QOL and life expectancy of diabetes patients. Controlling hyperglycemia is crucial. Clinicians tasked with managing diabetic neuropathy patients must know how to properly diagnose the condition while considering differential diagnoses. Understanding current, rational, and evidence-based recommendations is necessary for treating DPN. Finally, in order to have a successful outcome, clinicians must counsel patients on various lifestyle modifications and forge partnerships with patients based on honest setting of goals and realistic expectations.

© Copyright 2009 Duke University School of Medicine, UNC Eshelman School of Pharmacy, and The Customer Link, Inc.

The views expressed in this publication are not necessarily those of Duke University School of Medicine, UNC Eshelman School of Pharmacy, The Customer Link, Inc., Pfizer Inc., UCB Inc., sanofi-aventis U.S. LLC., or the publisher.