Diabetic Peripheral Neuropathy

Background

• Diabetic peripheral neuropathies comprise a heterogeneous group of disorders resulting from damage to the peripheral nervous system, frequently manifesting as pain and/or impaired sensations in the extremities, affecting up to 50% of patients with diabetes.
• Prolonged hyperglycemia, oxidative and inflammatory stress, and dyslipidemia (in type 2 diabetes) are thought to be key factors in pathogenesis and disease progression.
• The most common type is distal symmetrical polyneuropathy (often synonymous with the term diabetic peripheral neuropathy); less common types include cardiovascular autonomic neuropathy, gastrointestinal autonomic neuropathy, urogenital autonomic neuropathy, sudomotor dysfunction, diabetic radiculoplexus neuropathy, thoracic radiculopathy, treatment-induced neuropathy, and mononeuropathies.

Evaluation

• Make a clinical diagnosis based on history and physical exam findings consistent with peripheral neuropathy in a patient with diabetes.
  • Ask about presenting symptoms including pain, paresthesia, or numbness in distal extremities, as well as balance problems. Note that up to 50% of patients may be asymptomatic.
  • Ask about autonomic symptoms such as light-headedness, early satiety, bladder dysfunction, erectile dysfunction, and bowel dysfunction.
  • Examine feet and hands for impaired sensations.
    • Consider evaluating temperature discrimination, pinprick sensation, vibration sensation (with a 128-hertz tuning fork), and light touch perception (with 10-gram monofilament testing) (Weak recommendation).
    • Examine ankle reflexes, which may be reduced or absent.
    • Evaluate gait, including Romberg sign for balance impairment.
    • Check for motor deficits or foot ulcers, which may indicate more advanced disease.
• If necessary, conduct diagnostic testing to exclude other causes of symptoms and signs or if diagnosis is uncertain, such as
  • complete blood count, metabolic panel, and other blood tests
  • electrophysiological testing, especially if atypical features such as rapid onset, asymmetrical presentation, or greater motor than sensory impairments
  • assessing heart rate variability during deep breathing, while rising from seated position, and with Valsalva maneuver
  • esophagogastroduodenoscopy, barium study of the stomach, scintigraphy of digestible solids, or 13C-octanoic acid breath test to assess for stomach obstruction and gastroparesis
  • magnetic resonance neurography or ultrasound to assess for mononeuropathy

Management

• Optimize glucose control to slow progression of diabetic peripheral neuropathy (Weak recommendation).
• Management of pain related to painful diabetic neuropathy
  • Assess potential adverse effects, comorbidities, cost, and patient preference when selecting a treatment (Strong recommendation).
  • Oral medications:
    • Medication classes effective for management of painful diabetic neuropathy include gabapentinoids, serotonin-norepinephrine reuptake inhibitors (SNRIs), sodium channel blockers, and tricyclic antidepressants.
    • First-line options include:
      • pregabalin starting dose (immediate release) 50 mg orally 3 times daily (150 mg/day), may increase to 100 mg orally 3 times daily (300 mg/day) within 1 week based on efficacy and tolerability (Strong recommendation)
      • gabapentin starting dose 100-300 mg orally 1-3 times daily, increase up to total dose of 900-3,600 mg/day (Strong recommendation)
      • duloxetine 60 mg orally once daily, lower starting dose may be considered for tolerability (Strong recommendation)
    • Other options include:
      • venlafaxine starting dose 37.5 mg orally once daily, increase up to total dose of 75-225 mg/day, as monotherapy
      • amitriptyline starting dose 10-25 mg orally once daily, increase up to total dose of 25-100 mg/day
      • sodium channel blocker such as oxcarbazepine 1,400-1,800 mg/day orally
    • Switch medication from different class if patient does not achieve pain improvement or experiences adverse effects with initial treatment choice (Strong recommendation).
    • Switch to or add medication from different class if patient achieves only partial improvement in pain with initial treatment (Strong recommendation).
    • Do not offer opioids or opioid/SNRI dual mechanism agents (tramadol and tapentadol) for management of painful diabetic neuropathy due to poor risk profile and lack of evidence for long-term efficacy (Strong recommendation).
    • Do not offer valproic acid for management of painful diabetic neuropathy
      • to any patients of childbearing potential due to potential teratogenicity (Strong recommendation)
      • to any other patients due to risk of serious adverse effects, unless multiple other medications are ineffective (Strong recommendation)
  • Consider other topical, nontraditional, or nonpharmacologic treatments based on patient preference (Weak recommendation); these include:
    • topical medications such as capsaicin 8% topical patch
    • nonpharmacologic interventions including cognitive behavioral therapy, exercise, Tai Chi, or mindfulness
  • Transcutaneous/percutaneous nerve stimulation and spinal cord stimulation have also been used for management of painful diabetic neuropathy, but evidence for efficacy is limited.
• Foot care
  • Assess feet at every visit in patients with diabetes and evidence of sensory loss or prior ulceration (Strong recommendation).
  • Offer specialized therapeutic footwear for high-risk patients including patients with severe neuropathy, foot deformities or ulcers, callous formation, poor peripheral circulation, and history of amputation (Strong recommendation).
• Management of diabetic autonomic neuropathy
  • Offer multifactorial diabetes management to reduce progression of cardiovascular autonomic neuropathy.
  • Offer nonpharmacologic and/or pharmacologic strategies for management of specific symptoms including orthostatic hypotension, diabetic gastroparesis, urinary dysfunction, sexual dysfunction, salivary and lacrimal dysfunction, and excessive sweating.