Diabetic Neuropathy

Aka: Diabetic Neuropathy, Peripheral Neuropathy in Diabetes Mellitus

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II. Epidemiology

  1. Occurs in Type I and Type II Diabetes Mellitus
  2. Occurs in 42% of Type II Diabetes Mellitus
    1. Onset within 10 years of disease
    2. Higher risk with higher Glycosylated Hemoglobin
    3. Partanen (1995) N Engl J Med 333:89-94 [PubMed]

III. Types

  1. Bilateral Peripheral Polyneuropathy in Diabetes (Diabetic Distal Symmetric Polyneuropathy)
  2. Diabetic Focal Neuropathy (Diabetic Mononeuropathy)
  3. Diabetic Autonomic Neuropathy
  4. Diabetic Amyotrophy (Symmetric Diabetic Proximal Motor Neuropathy)

IV. Diagnosis

  1. See also Peripheral Neuropathy Testing

V. Differential Diagnosis

  1. See Leg Pain
  2. See Autonomic Neuropathy
  3. Peripheral Polyneuropathy
    1. Vitamin B12 Deficiency
      1. Especially when using Metformin
    2. Folic Acid Deficiency
    3. Iron Deficiency Anemia
    4. Hypothyroidism
    5. Uremia
    6. Chemical Toxin exposure (Heavy Metal Toxicity)
    7. Alcohol Abuse
    8. Sarcoidosis
    9. Leprosy
    10. Periarteritis nodosum
    11. Systemic Lupus Erythematosus
    12. Leukemia
  4. Other important causes of Leg Pain
    1. Lumbar Disc Disease with radiculopathy
    2. Lumbar central spinal stenosis
    3. Claudication
    4. Night Cramps
    5. Restless Leg Syndrome
    6. Degenerative Joint Disease
      1. Hip Osteoarthritis
      2. Knee Osteoarthritis
      3. Ankle Osteoarthritis

VI. Complications (of distal symmetric Polyneuropathy)

  1. See Charcot Foot
  2. See Foot Wound
  3. See Suspected Osteomyelitis in Diabetes Mellitus
  4. See Peripheral Neuropathy Tremor

VII. Management: Approach

  1. See dosing regimens in next section
  2. Background
    1. Combination therapy is more effective than monotherapy
      1. These steps are additive (except where Drug Interactions contraindicate the combinations)
      2. Tesfaye (2022) Lancet 400(10353): 680-90 [PubMed]
  3. Step 1
    1. See prevention below for diabetes care optimization including glycemic control
    2. Set realistic patient expectations (e.g. 30-50% symptom improvement with medications)
    3. Evaluate for other causes of Peripheral Neuropathy including B12 Deficiency (see differential diagnosis above)
    4. Reevaluate medication titrated to maximal dose at 3 month intervals
  4. Step 2
    1. Tricyclic Antidepressants (e.g. Amitriptyline, Nortriptyline, Desipramine): NNT 2-4
    2. Preferred in younger patients with decreased risk of falls, Hypotension
  5. Step 3
    1. Anticonvulsants (e.g. Gabapentin, Pregabalin): NNT 3-8
  6. Step 4
    1. Serotonin-Norepinephrine reuptake inhibitors (e.g. Duloxetine, Venlafaxine): NNT 4-11
  7. Step 5
    1. Reconsider differential diagnosis
    2. Consider SSRI (e.g. Escitalopram), although lack of adequate studies to support use
    3. Consider pain management referral
    4. Chronic Analgesics (Opioids, Tramadol) are not recommended due to adverse effects, abuse
  8. Adjuncts (add at any point)
    1. Topical Lidocaine (Lidoderm 5% patch) or the OTC, less expensive Lidocare 4% patch (but still expensive!)
    2. Capsaicin 0.075% cream (often intolerable due to burning)
    3. Transcutaneous electrical nerve stimulation (TENS)
    4. Isosorbide Dinitrate spray 30 mg applied to bottom of feet at bedtime
    5. Acupuncture (no large, high quality studies in Diabetic Neuropathy to support use)

VIII. Management: Medications for Painful Peripheral Neuropathy

  1. Tricyclic Antidepressants
    1. May be more effective in burning, steady pain
    2. Avoid in the elderly due to strong Anticholinergic effects (see Beers List)
    3. Amitriptyline (Elavil) or Nortriptyline (Pamelor)
      1. Nortriptyline has less Anticholinergic effects than Amitriptyline, Imipramine
      2. Started at 10-30 mg at bedtime
      3. Increase to 50-75 mg (maximum 150 mg) at bedtime
    4. Desipramine (Norpramin) starting at 25 mg at bedtime
  2. Anticonvulsants
    1. May be more effective in sharp lancinating pain
    2. Gabapentin (Neurontin)
      1. Adjust for renal dysfunction
      2. Start at 100 mg at bedtime to 100 mg orally three time daily
      3. Advance to 300 orally three times daily (maximum 1200 mg three times daily)
    3. Pregabalin (Lyrica)
      1. Very similar to Gabapentin, but no generic yet available and expensive
      2. More convenient dosing (twice daily), and no Renal Dosing adjustment as contrasted with Gabapentin
      3. Start at 50 mg orally two to three times daily
      4. Titrate to 100 mg orally three times daily or 150 mg twice daily (maximum 300 mg twice daily)
    4. Other agents
      1. Other anticonvulsants (including Carbamazepine, Topiramate) do not have adequate evidence to support use
  3. Serotonin-Norepinephrine Reuptake Inhibitors
    1. Duloxetine (Cymbalta)
      1. Start at 20 mg twice daily
      2. Advance to 60 mg daily (or divided 30 mg twice daily)
    2. Venlafaxine (Effexor)
      1. Extended release (preferred): Venlafaxine XR 37.5 mg daily (titrate to 225 mg daily)
      2. Regular (generic): Venlafaxine 37.5 mg twice daily (titrate to 225 mg divided twice daily)
  4. Topical pain management
    1. TENS Unit
    2. Lidocaine 5% patch (Lidoderm) up to 3 patches applied daily to affected area (applied for no more than 12 hours daily)
    3. Capsaicin 0.075% cream applied to affected area twice daily (start with small amount and slowly increase)
    4. Isosorbide Dinitrate spray 30 mg applied to bottom of feet at bedtime
  5. Analgesics
    1. Acetaminophen may be used as needed
    2. NSAIDS are not typically recommended in Diabetes Mellitus
      1. Risk of renal, gastrointestinal and cardiovascular risks
    3. Opioids
      1. Not recommended due to adverse effects, abuse
      2. Tramadol (Ultram)
        1. See Tramadol for precautions (lower efficacy with adverse effect risk)
      3. Other Opioids
        1. Avoid unless no other option available
  6. Other agents
    1. Vitamin B12 Supplementation as needed
    2. Alpha Lipoic Acid 600 to 1800 mg orally daily
      1. No compelling evidence as of 2022, but may be tried
      2. Discontinue after 1 month if ineffective

IX. Prevention

  1. See Diabetic Foot Care
  2. Optimize Glucose in Diabetes Mellitus management (Hemoglobin A1C <7-8%)
  3. Optimize Hypertension and Hyperlipidemia Management

X. References

  1. (2022) Presc Lett 29(3): 16-7
  2. (2017) Presc Lett 24(9): 50
  3. Aring (2005) Am Fam Physician 71:2123-30 [PubMed]
  4. Backonja (1998) JAMA 280:1831-36 [PubMed]
  5. Kochar (2004) QJM 97:33-8 [PubMed]
  6. Lindsay (2010) Am Fam Physician 82(2): 151-8 [PubMed]
  7. Lipnick (1996) Am Fam Physician 54(8):2478-84 [PubMed]
  8. McQuay (1996) Pain 68:217-27 [PubMed]
  9. Simmons (2000) Clinical Diabetes 18:116-7 [PubMed]
  10. Sindrup (1990) Pain 42:135-44 [PubMed]
  11. Snyder (2016) Am Fam Physician 94(3): 227-34 [PubMed]
  12. Veves (2008) Pain Med 9(6): 660-74 [PubMed]
  13. Wong (2007) BMJ 335(7610): 87 [PubMed]

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