II. Epidemiology
- Occurs in Type I and Type II Diabetes Mellitus
- Occurs in 42% of Type II Diabetes Mellitus
- Onset within 10 years of disease
- Higher risk with higher Glycosylated Hemoglobin
- Partanen (1995) N Engl J Med 333:89-94 [PubMed]
III. Types
IV. Diagnosis
- See also Peripheral Neuropathy Testing
V. Differential Diagnosis
- See Leg Pain
- See Autonomic Neuropathy
- Peripheral Polyneuropathy
- Vitamin B12 Deficiency
- Especially when using Metformin
- Folic Acid Deficiency
- Iron Deficiency Anemia
- Hypothyroidism
- Uremia
- Chemical Toxin exposure (Heavy Metal Toxicity)
- Alcohol Abuse
- Sarcoidosis
- Leprosy
- Periarteritis nodosum
- Systemic Lupus Erythematosus
- Leukemia
- Vitamin B12 Deficiency
- Other important causes of Leg Pain
- Lumbar Disc Disease with radiculopathy
- Lumbar central spinal stenosis
- Claudication
- Night Cramps
- Restless Leg Syndrome
- Degenerative Joint Disease
VI. Complications (of distal symmetric Polyneuropathy)
VII. Management: Approach
- See dosing regimens in next section
- Background
- Combination therapy is more effective than monotherapy
- These steps are additive (except where Drug Interactions contraindicate the combinations)
- Tesfaye (2022) Lancet 400(10353): 680-90 [PubMed]
- Combination therapy is more effective than monotherapy
- Step 1
- See prevention below for diabetes care optimization including glycemic control
- Set realistic patient expectations (e.g. 30-50% symptom improvement with medications)
- Evaluate for other causes of Peripheral Neuropathy including B12 Deficiency (see differential diagnosis above)
- Reevaluate medication titrated to maximal dose at 3 month intervals
- Step 2
- Tricyclic Antidepressants (e.g. Amitriptyline, Nortriptyline, Desipramine): NNT 2-4
- Preferred in younger patients with decreased risk of falls, Hypotension
- Step 3
- Anticonvulsants (e.g. Gabapentin, Pregabalin): NNT 3-8
- Step 4
- Serotonin-Norepinephrine reuptake inhibitors (e.g. Duloxetine, Venlafaxine): NNT 4-11
- Step 5
- Reconsider differential diagnosis
- Consider SSRI (e.g. Escitalopram), although lack of adequate studies to support use
- Consider pain management referral
- Chronic Analgesics (Opioids, Tramadol) are not recommended due to adverse effects, abuse
- Adjuncts (add at any point)
- Topical Lidocaine (Lidoderm 5% patch) or the OTC, less expensive Lidocare 4% patch (but still expensive!)
- Capsaicin 0.075% cream (often intolerable due to burning)
- Transcutaneous electrical nerve stimulation (TENS)
- Isosorbide Dinitrate spray 30 mg applied to bottom of feet at bedtime
- Acupuncture (no large, high quality studies in Diabetic Neuropathy to support use)
VIII. Management: Medications for Painful Peripheral Neuropathy
-
Tricyclic Antidepressants
- May be more effective in burning, steady pain
- Avoid in the elderly due to strong Anticholinergic effects (see Beers List)
- Amitriptyline (Elavil) or Nortriptyline (Pamelor)
- Nortriptyline has less Anticholinergic effects than Amitriptyline, Imipramine
- Started at 10-30 mg at bedtime
- Increase to 50-75 mg (maximum 150 mg) at bedtime
- Desipramine (Norpramin) starting at 25 mg at bedtime
- Anticonvulsants
- May be more effective in sharp lancinating pain
- Gabapentin (Neurontin)
- Adjust for renal dysfunction
- Start at 100 mg at bedtime to 100 mg orally three time daily
- Advance to 300 orally three times daily (maximum 1200 mg three times daily)
- Pregabalin (Lyrica)
- Very similar to Gabapentin, but no generic yet available and expensive
- More convenient dosing (twice daily), and no Renal Dosing adjustment as contrasted with Gabapentin
- Start at 50 mg orally two to three times daily
- Titrate to 100 mg orally three times daily or 150 mg twice daily (maximum 300 mg twice daily)
- Other agents
- Other anticonvulsants (including Carbamazepine, Topiramate) do not have adequate evidence to support use
-
Serotonin-Norepinephrine Reuptake Inhibitors
- Duloxetine (Cymbalta)
- Start at 20 mg twice daily
- Advance to 60 mg daily (or divided 30 mg twice daily)
- Venlafaxine (Effexor)
- Extended release (preferred): Venlafaxine XR 37.5 mg daily (titrate to 225 mg daily)
- Regular (generic): Venlafaxine 37.5 mg twice daily (titrate to 225 mg divided twice daily)
- Duloxetine (Cymbalta)
- Topical pain management
- TENS Unit
- Lidocaine 5% patch (Lidoderm) up to 3 patches applied daily to affected area (applied for no more than 12 hours daily)
- Capsaicin 0.075% cream applied to affected area twice daily (start with small amount and slowly increase)
- Isosorbide Dinitrate spray 30 mg applied to bottom of feet at bedtime
-
Analgesics
- Acetaminophen may be used as needed
- NSAIDS are not typically recommended in Diabetes Mellitus
- Risk of renal, gastrointestinal and cardiovascular risks
- Opioids
- Other agents
- Vitamin B12 Supplementation as needed
- Alpha Lipoic Acid 600 to 1800 mg orally daily
- No compelling evidence as of 2022, but may be tried
- Discontinue after 1 month if ineffective
IX. Prevention
- See Diabetic Foot Care
- Optimize Glucose in Diabetes Mellitus management (Hemoglobin A1C <7-8%)
- Optimize Hypertension and Hyperlipidemia Management
X. References
- (2022) Presc Lett 29(3): 16-7
- (2017) Presc Lett 24(9): 50
- Aring (2005) Am Fam Physician 71:2123-30 [PubMed]
- Backonja (1998) JAMA 280:1831-36 [PubMed]
- Kochar (2004) QJM 97:33-8 [PubMed]
- Lindsay (2010) Am Fam Physician 82(2): 151-8 [PubMed]
- Lipnick (1996) Am Fam Physician 54(8):2478-84 [PubMed]
- McQuay (1996) Pain 68:217-27 [PubMed]
- Simmons (2000) Clinical Diabetes 18:116-7 [PubMed]
- Sindrup (1990) Pain 42:135-44 [PubMed]
- Snyder (2016) Am Fam Physician 94(3): 227-34 [PubMed]
- Veves (2008) Pain Med 9(6): 660-74 [PubMed]
- Wong (2007) BMJ 335(7610): 87 [PubMed]