Kim Farina-Graham, PhD

The American Diabetes Association defines diabetic peripheral neuropathy (DPN) as “the presence of symptoms and/or signs of peripheral nerve dysfunction in patients with diabetes after exclusion of other causes.” Approximately 16% of diabetic patients will experience painful diabetic neuropathy (PDN). PDN negatively affects overall quality of life and physical function. Through accurate diagnosis, early intervention, and effective management, primary care practitioners can play a significant role in improving the lives of their patients with PDN.

	The pathology underlying diabetic neuropathy is unknown. In some cases, PDN may be a sign of poor diabetic control. The Diabetes Control and Complications Trial provided the first evidence that stable blood glucose control reduces risk for development and progression of DPN.

	Achieving adequate blood glucose control may take months, however. While that should be a primary goal, symptom relief therapy should be initiated immediately. Due to the number of options for treating PDN, the potential safety issues related to these options, and the existence of conflicting guidelines, managing PDN might be daunting to some clinicians.

	Diagnosis of PDN requires careful clinical examination and medical history and, by definition, involves the exclusion of nondiabetic etiologies, such as metabolic and vascular conditions, arthritis, and vitamin deficiency. PDN is “one of the more common causes of extremity pain that may be confused with osteoarthritic or rheumatological conditions,” according to Christopher Gharibo, MD, medical director of pain medicine at NYU-Hospital for Joint Diseases. “Patients often have a combination of sensory, autonomic and, rarely, motor symptoms. Symptoms develop insidiously, wax and wane, and can be progressive, often in the setting of poor diabetes control. Many patients report numbness, tingling, dysesthesias of distal extremities, and constant pain with spontaneous jabs. The overall pain intensity is often worse at night and with humid or rainy weather.”

	The severity, frequency, and quality of pain should be assessed and documented, at initial presentation and at follow-up visits, using standardized pain measures. Clinicians are advised to document which of the patient’s activities are limited by their condition and try to improve the patient’s function with the analgesic plan.

	First and foremost, a program for stable and tight glucose control should be established. This is the only known method for changing the natural history of neuropathy in patients with type 1 diabetes. Pain relief may lag behind tight glucose control. There are, however, a variety of pharmacological and nonpharmacological options available for symptomatic relief.

	Treatment strategy should be tailored to the individual patient based on effectiveness, pain intensity, comorbidities and contraindications, potential drug interactions, tolerability, patient convenience, and cost. At the outset, realistic goals and expectations regarding time to and degree of pain relief need to be established. It will take 2—4 weeks for nonconventional analgesics to take effect due to their titration period. Little is known about which drug works best for particular types of pain; finding an effective treatment will likely involve trial and error. Most patients will experience only partial pain relief.

	Several modifiable risk factors for DPN have been identified, including poor glycemic control, obesity, dyslipidemia, hypertension, iatrogenic agents, vitamin B12 deficiency/elevated homocysteine, smoking, excessive alcohol consumption, and exposure to other toxic agents. To reduce risk, patient education should be provided and patients should be engaged in the development of treatment and behavior modification plans, as appropriate.

	In April 2011, the American Academy of Neurology (AAN), the American Association of Neuromuscular and Electrodiagnostic Medicine (ANNEM), and the American Academy of Physical Medicine and Rehabilitation (AAPMR) released evidence-based guidelines for the treatment of painful diabetic neuropathy.

	First-line monotherapy may involve anticonvulsants (ie, pregabalin, gabapentin) or the antidepressants amitryptiline, duloxetine, or venlafaxine. If the patient’s pain is severe, combination first-line therapy may be considered using a short-acting opioid such as tramadol. TCAs and gabapentin can be taken once a day, making them convenient for the patient and valuable if adherence is a concern. Duloxetine and pregabalin are the only agents formally approved by the US Food and Drug Administration for managing painful PDN.

	Other options include the topical agents capsaicin cream and isosorbide dinitrate spray. Percutaneous nerve stimulation, performed three to four times per week, is also effective in relieving PDN.

"Painful diabetic neuropathy is one of the more common causes of extremity pain that may be confused with osteoarthritic or rheumatological conditions."

—Christopher Gharibo, MD, Medical Director of Pain Medicine and Associate Professor of Anesthesiology and Orthopedics at NYU Langone-Hospital for Joint Diseases

	Anti-inflammatory agents are generally not useful for PDN. The AAN/ANNEM/AAPMR guidelines do not recommend oxcarbazepine, lamotrigine, lacosamide, clonidine, pentoxifylline, mexiletine, magnetic field treatment, low-intensity laser therapy, and Reiki therapy for treating PDN.

	Once treatment is initiated, follow-up should include regular monitoring and documentation of (1) pain severity, frequency, and characteristics; (2) satisfaction with treatment/impact on function & quality of life; (3) therapy adherence; and (4) side effects. When necessary, dosing should be optimized. A multimechanistic analgesic plan may be considered if pain continues. Opioid use is controversial in this setting, but may be an option if pain relief continues to be inadequate. Recommended opioids include tramadol, extended-release morphine sulphate, or fentanyl patch.

	Cases should be referred to a specialist when management is beyond the primary care physician’s comfort level or requires complex pharmacotherapy. All patients with DPN should be considered for podiatric referral and foot care education.

	1. Boulton A, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: A statement by the American Diabetes Association. 

	2. Daousi C, MacFarlane IA, Woodward A, et al. Chronic Painful peripheral neuropathy in an urban community: a controlled comparison of people with and without diabetes. 

	3. Bril V, England J, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. 

	4. Kuritzky, L. Managing diabetic peripheral neuropathic pain in primary care. 

Articles

The best setting for the treatment of painful diabetic neuropathy is primary care, where diabetes and its associated chronic pain can be managed as a single entity. The American Diabetes Association defines diabetic peripheral neuropathy (DPN) as "the presence of symptoms and/or signs of peripheral nerve dysfunction in patients with diabetes after exclusion of other causes." Approximately 16% of diabetic patients will experience painful diabetic neuropathy (PDN).