Diabetic Neuropathy

Aka: Diabetic Neuropathy, Diabetic Peripheral Neuropathy, Peripheral Neuropathy in Diabetes Mellitus

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II. Epidemiology

  1. Most common Diabetes Mellitus complication
  2. Occurs in Type I and Type II Diabetes Mellitus
  3. 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 (most common)
    1. Diabetic Distal Symmetric Polyneuropathy (stocking glove distribution)
  2. Diabetic Focal Neuropathy (Diabetic Mononeuropathy)
  3. Diabetic Autonomic Neuropathy
  4. Diabetic Amyotrophy (Symmetric Diabetic Proximal Motor Neuropathy)

IV. Diagnosis

  1. See Monofilament Foot Sensation Test
  2. Diabetic Neuropathy is a clinical diagnosis
    1. Monofilament Foot Sensation Test has poor Test Sensitivity (53%)
    2. Diagnosis is based on history and exam (e.g. foot neurovascular exam, skin exam)

V. Differential Diagnosis

  1. See Leg Pain
  2. See Autonomic Neuropathy
  3. Peripheral Polyneuropathy
    1. Vitamin B12 Deficiency (may be comorbid with Diabetic Neuropathy)
      1. Risks include Metformin, Bariatric Surgery, strict Vegetarian Diet, autoimmune disorders
    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. Management: Approach

  1. See dosing regimens in next section
  2. Background
    1. The only cure for Diabetic Neuropathy, is the prevention of its onset (esp. glycemic control)
      1. Prior nerve damage is not reversed by treatments for Diabetic Neuropathy
    2. Treatment goals are not curative
      1. Symptom management
      2. Slow Diabetic Neuropathy progression
      3. Protect the limbs (esp. feet) from injury
      4. Prevent complications (e.g. Diabetic Foot Wounds, amputations)
    3. 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. Zhang (2021) Front Med 8:756940 +PMID: 34901069 [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
    5. Encourage Exercise
      1. Exercise (aerobic, resistance, balance) may reduce pain and improve function, but evidence is poor
      2. Hernando-Garijo (2024) Physiother Theory Pract 21:1-14 +PMID: 37341684 [PubMed]
  4. Step 2
    1. Tricyclic Antidepressants (e.g. Amitriptyline, Nortriptyline, Desipramine): NNT 2-4
      1. Preferred in younger patients with decreased risk of falls, Hypotension
      2. May consider Duloxetine instead (for fewer adverse effects, e.g. Dry Mouth)
  5. Step 3
    1. Anticonvulsants (e.g. Gabapentin, Pregabalin): NNT 3-8
  6. Step 4
    1. Serotonin-Norepinephrine reuptake inhibitors (e.g. Duloxetine): 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. Isosorbide Dinitrate spray 30 mg applied to bottom of feet at bedtime
    4. Acupuncture
      1. No large, high quality studies in Diabetic Neuropathy to support use
      2. Yu (2021) J Clin Pharm Ther 46(3): 585-98 +PMID: 33511675 [PubMed]
    5. Neuromodulators
      1. Transcutaneous electrical nerve stimulation (TENS)

VII. 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)
      1. 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
      4. Advance to 1200 to 3200 mg/day
        1. Doses at least 1200 mg/day are needed for adequate effect
      5. Maximum 1200 mg orally three times daily (3600 mg/day)
      6. References
        1. Wiffen (2017) Cochrane Database Syst Rev 6(6):CD007938 PMID: 28597471 [PubMed]
    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
      5. Titrate to 300 mg orally twice daily as tolerated
        1. Higher doses (600 mg/day) are more effective than lower doses (300 mg/day)
      6. Maximum: 300 mg orally twice daily
      7. References
        1. Derry (2019) Cochrane Database Syst Rev (1): CD007076 +PMID: 30673120 [PubMed]
    4. Second-line anticonvulants in pain refractory to first line agents
      1. Precautions
        1. Low quality evidence compared with Gabapentinoids
        2. Greater adverse effects than Gabapentinoids
        3. Monitoring needed
      2. Carbamazepine
        1. Start 200 to 400 mg/day divided twice daily
        2. Advance to 600 to 1200 mg/day divided twice daily
        3. Wiffen (2014) Cochrane Database Syst Rev 2014(4):CD005451 +PMID: 24719027 [PubMed]
      3. Oxcarbazepine
        1. Start 300 to 600 mg/day divided twice daily
        2. Advance to 600 to 1800 mg/day divided twice daily
        3. Zhou (2017) Cochrane Database Syst Rev 12(12):CD007963 +PMID: 29199767 [PubMed]
    5. Other anticonvulsants NOT shown to be effective in Diabetic Neuropathy
      1. Topiramate
      2. Lacosamide
      3. Lamotrigine
      4. Valproic Acid
      5. Zonisamide
  3. Serotonin-Norepinephrine Reuptake Inhibitors
    1. Duloxetine (Cymbalta)
      1. Start at 20 mg orally twice daily (lower doses are ineffective)
      2. Advance to 60 mg daily (or divided 30 mg twice daily)
        1. Doses above 60 mg/day add no additional benefit
      3. Efficacy
        1. Similar efficacy to Amitriptyline and may be more effective than Pregabalin
      4. References
        1. Lunn (2014) Cochrane Database Syst Rev 2014(1):CD007115 +PMID: 24385423 [PubMed]
    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)
      3. Limited evidence compared with Duloxetine
  4. Topical pain management
    1. Lidocaine 4% cream/patch or 5% patch (Lidoderm)
      1. Apply up to 3 patches applied daily to affected area
      2. Apply for no more than 12 hours daily (12 hours on, 12 hours off)
    2. Capsaicin 0.075% cream
      1. Apply to affected area twice to three times daily
        1. Start with small amount and slowly increase
        2. Baron (2009) Curr Med Res Opin 25(7): 1663-76 [PubMed]
      2. Capsaicin is also available in a 8% patch (Qutenza) applied to painful area every 3 months
        1. Must be applied in medical provider's office (and costs in 2024 are $1000/patch)
        2. Derry (2013) Cochrane Database Syst Rev (2):CD007393 +PMID: 23450576 [PubMed]
    3. Isosorbide Dinitrate spray 30 mg
      1. Apply 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 (includes Tramadol)
      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
      1. Indicated in Vitamin B12 Deficiency
    2. Alpha Lipoic Acid (Thioctic acid)
      1. Natural Thiol Supplement with antioxidant and metal-chelating properties
      2. Dose: 600 to 1800 mg orally daily
      3. NOT recommended
        1. Lack of improvement compared with Placebo over 6-24 months (in Cochrane review)
        2. Low efficacy orally which is its primary use, better efficacy IV
        3. However, minimal to no adverse effects
        4. If prescribed despite poor evidence, discontinue after 1 month if ineffective
      4. References
        1. Abubaker (2022) Cureus 14(6):e25750 +PMID: 35812639 [PubMed]
        2. Baicus (2024) Cochrane Database Syst Rev 1(1):CD012967 +PMID: 38205823 [PubMed]
  7. Neuromodulators
    1. Transcutaneous electrical nerve stimulation (TENS)
      1. Has shown benefit in low quality studies
    2. Spinal Cord Stimulators
      1. Mixed efficacy in studies
      2. Adverse effects including surgical complications

VIII. Complications

  1. Charcot Foot
  2. Diabetic Foot Wound
  3. Diabetic Foot Osteomyelitis
  4. Peripheral Neuropathy Tremor

IX. Prevention

  1. See Diabetic Foot Care
  2. Prevention of Diabetic Neuropathy is critical, since treatments are symptomatic, not curative
  3. Optimize Glucose in Diabetes Mellitus management (A1C <7% in Type 1 and <8% in Type 2 Diabetes)
    1. Paradoxical increased neuropathic pain may be transiently present initially with Glucose optimization
    2. Symptomatic Neuropathy risk drops 60% with type 1 diabetes Hemoglobin A1C <7%
      1. Nathan (1993) N Engl J Med 329(14): 977-86 [PubMed]
  4. Optimize cardiovascular disease and other associated risks
    1. Optimize Hypertension Management, keeping systolic Blood Pressure at least <140 mmHg
    2. Optimize Hyperlipidemia Management, keeping LDL Cholesterol <100 mg/dl
    3. Tobacco Cessation
    4. Weight loss in Obesity (esp. BMI >35 kg/m2)
  5. Foot Care Specialty (e.g. Podiatry) Referral is Indicated for those at high risk of complications (e.g. amputation)
    1. Hemodialysis
    2. Charcot Foot
    3. Structural Foot Deformity (e.g. severe Hallux Valgus)
    4. History of Diabetic Foot Wounds
    5. Peripheral Arterial Disease

X. Resources

  1. Overall Neuropathy Limitations Scale (ONLS, MDcalc)
    1. https://www.mdcalc.com/calc/10242/overall-neuropathy-limitations-scale-onls

XI. 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. Bragg (2024) Am Fam Physician 109(3): 226-32 [PubMed]
  6. Kochar (2004) QJM 97:33-8 [PubMed]
  7. Lindsay (2010) Am Fam Physician 82(2): 151-8 [PubMed]
  8. Lipnick (1996) Am Fam Physician 54(8):2478-84 [PubMed]
  9. McQuay (1996) Pain 68:217-27 [PubMed]
  10. Simmons (2000) Clinical Diabetes 18:116-7 [PubMed]
  11. Sindrup (1990) Pain 42:135-44 [PubMed]
  12. Snyder (2016) Am Fam Physician 94(3): 227-34 [PubMed]
  13. Veves (2008) Pain Med 9(6): 660-74 [PubMed]
  14. Wong (2007) BMJ 335(7610): 87 [PubMed]

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Related Studies

Ontology: Diabetic Neuropathies (C0011882)

Definition (NCI) A chronic, pathological complication associated with diabetes mellitus, where nerve damages are incurred due to diabetic microvascular injury involving small blood vessels that supply these nerves, resulting in peripheral and/or autonomic nerve dysfunction.
Definition (MSH) Peripheral, autonomic, and cranial nerve disorders that are associated with DIABETES MELLITUS. These conditions usually result from diabetic microvascular injury involving small blood vessels that supply nerves (VASA NERVORUM). Relatively common conditions which may be associated with diabetic neuropathy include third nerve palsy (see OCULOMOTOR NERVE DISEASES); MONONEUROPATHY; mononeuropathy multiplex; diabetic amyotrophy; a painful POLYNEUROPATHY; autonomic neuropathy; and thoracoabdominal neuropathy. (From Adams et al., Principles of Neurology, 6th ed, p1325)
Definition (CSP) common complication of diabetes mellitus in which nerves are damaged as a result of hyperglycemia (high blood sugar levels).
Concepts Disease or Syndrome (T047)
MSH D003929
ICD9 250.6
SnomedCT 267472008, 154683002, 193182005, 866003, 190349003, 190353001, 230572002
English Neuropathies, Diabetic, Neuropathy, Diabetic, Diab.mell. with neuropathy, Diabetic Neuropathies [Disease/Finding], Neuropathy;diabetic, diabetic nerve damage, diabetic neuropathies, Neuropathy - diabetic, Diabetes + neuropathy, Diabetes mellitus with neurological manifestation, Diabetes mellitus NOS with neurological manifestation (disorder), Diabetes mellitus NOS with neurological manifestation, Diabetic neuropathies, Diabetic neuropathy, Diabetes mellitus with neuropathy, Diabetic neuropathy (disorder), neuropathy; diabetes (manifestation), Diabetic neuropathy (disorder) [Ambiguous], Diabetic Neuropathies, Diabetic Neuropathy, Diabetes with neurological manifestations, diabetic neuropathy
Italian Neuropatia diabetica, Neuropatie diabetiche
Swedish Diabetesneuropatier
Czech diabetické neuropatie, Diabetická neuropatie
Finnish Diabeettiset neuropatiat
Russian DIABETICHESKIE NEVROPATII, DIABETICHESKAIA POLINEVROPATIIA, DIABETICHESKAIA AMIOTROFIIA, DIABETICHESKAIA NEVRALGIIA, DIABETICHESKAIA NEVROPATIIA AVTONOMNAIA, ДИАБЕТИЧЕСКАЯ АМИОТРОФИЯ, ДИАБЕТИЧЕСКАЯ НЕВРАЛГИЯ, ДИАБЕТИЧЕСКАЯ НЕВРОПАТИЯ АВТОНОМНАЯ, ДИАБЕТИЧЕСКАЯ ПОЛИНЕВРОПАТИЯ, ДИАБЕТИЧЕСКИЕ НЕВРОПАТИИ
Japanese ﾄｳﾆｮｳﾋﾞｮｳｾｲﾆｭｰﾛﾊﾟﾁｰ, 糖尿病性ニューロパチー, 糖尿病性ニューロパシー, 糖尿病ニューロパシー, 糖尿病神経障害, 神経障害-糖尿病性, 糖尿病性神経障害
Croatian DIJABETIČNE NEUROPATIJE
Polish Neuropatie cukrzycowe
Hungarian Diabeteses neuropathia
Norwegian Nervesykdommer ved diabetes, Diabetiske nervesykdommer, Diabetesnevropatier, Diabetiske nevropatier
Spanish diabetes mellitus, SAI con manifestaciones neurológicas, diabetes mellitus, SAI con manifestaciones neurológicas (trastorno), Acropatía Diabética Úlcero-Mutilante, diabetes mellitus con neuropatía, diabetes sacarina con neuropatía, neuropatía diabética (concepto no activo), neuropatía diabética (trastorno), neuropatía diabética, Neuropatía diabética, Neuropatías Diabéticas
Portuguese Acropatia Diabética Ulceromutilante, Neuropatia diabética, Neuropatias Diabéticas
Dutch neuropathie; diabetes, diabetische neuropathie, Diabetische neuropathie, Neuropathie, diabetische
French Neuropathie diabétique, Neuropathies diabétiques
German Diabetische Neuropathie, Diabetische Neuropathien
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Diabetic peripheral neuropathy (C0740447)

Concepts Disease or Syndrome (T047)
SnomedCT 424736006
Dutch diabetische perifere neuropathie
French Neuropathie périphérique diabétique
German diabetische periphere Neuropathie
Italian Neuropatia periferica diabetica
Portuguese Neuropatia periférica diabética
Spanish Neuropatía periférica diabética, neuropatía periférica diabética, neuropatía periférica diabética (trastorno)
English Diabetic peripheral neuropathy (disorder), Diabetic peripheral neuropathy, diabetic peripheral neuropathy, diabetic peripheral neuropathy (diagnosis), peripheral diabetic neuropathy, diabetic neuropathy peripheral
Japanese ﾄｳﾆｮｳﾋﾞｮｳｾｲﾏｯｼｮｳｾｲﾆｭｰﾛﾊﾟﾁｰ, 糖尿病性末梢性ニューロパチー
Czech Diabetická periferní neuropatie
Hungarian Diabeteses peripheriás neuropathia
Derived from the NIH UMLS (Unified Medical Language System)

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