I. Epidemiology

  1. 10% at dx of NIDDM, 50% after 25y
  2. Risk factors: male sex, age, HTN, poor glycemic control, hypercholesterolemia, smoking

II. Clinical features

  1. Usually a bilateral peripheral polyneuropathy
    1. Peripheral diabetic neuropathy typically causes hyperesthesias and pain in feet and ankles, worse at night
    2. Consider other causes of Peripheral Neuropathies when symptoms of neuropathy occur in a patient with diabetes
  2. Autonomic neuropathy can also occur, with any or all of the following:
    1. Erectile dysfunction
    2. Bladder dysfunction
    3. Orthostatic hypotension (often with tachycardia; can worsen with exercise)
    4. Diarrhea (often worse at night)
    5. Gastroparesis
    6. Hypoglycemia unawareness
    7. Dry hands and/or feet
    8. Gustatory sweating
  3. Tends to improve with better glucose control

III. Treatment

  1. Tricyclics--well-studied, effective
    1. Amitriptypline better than desipramine or fluoxetine (NEJM 326:1250, 1992; cited in NEJM rvw)
  2. Duloxetine
    1. In a study in 334 pts with diabetic neuropathy but no depression randomized to duloxetine 60mg QD, duloxetine 60mg BID, or placebo x 12wks.  Both duloxetine groups had sig. greater reductions in pain than placebo recipients; no sig. diff. between the duloxetine groups (Neurol. 67:1411, 2006--JW)
  3. Gapabentin
    1. 165 pts with DM (75% had type II) and neuropathy with HbA1c < 11 and normal renal function randomized to gabapentin (300-1200mg PO TID, titrated upward at weekly intervals until side f/x reached) vs. placebo. By 2 weeks and throughout the rest of the 8wk trial, there were sig. less sx in the gabapentin group. Note that it's renally excreted so dosage adjustments necessary in renal failure (JAMA 280:1831, 1998)
  4. Valproic acid
    1. In a study of 43 pts with painful diabetic neuropathy randomized to valproate 500mg QD vs. placebo (titrated to BID after 1wk if tolerated), after 3mos, mean pain scores had improved sig. more in the valproate group c/w the placebo group (QJM 97:33, 2004--AFP)
  5. Topiramate
    1. 323 pts with painful diabetic neuropathy randomized to topiramate (titrated upt o 400mg/d) vs. placebo; at 12wks, topiramate group had sig. greater reduction in mean pain scores; 36% of topiramate recipients vs. 21% of placebo recipients had a 50% or greater reduction in pain (Neurol. 63:865, 2004--JW)
    2. 1,259 pts with painful diabetic neuropathy randomized to topiramate at various doses (100-400mg/d) vs. placebo; at 22wks, no sig. diff. in pain intensity among the groups (Acta Neurol. Scand. 110:221, 2004--JW) 
  6. Mexiletine 150 BID-TID effective in an uncontrolled study of 35 DM with painful DM neuropathy; 50% had long-term (at least several months) improvement in pain (Study presented at Am. Ortho. Foot and Ankle Soc. 1998--AFP)
  7. Phenytoin and carbamazepine have been reported to be effective
  8. Nerve Growth Factor
    1. 250 pts with symptomatic diabetic neuropathy randomized to NGF SQ 3x/wk x 6mos vs. placebo; NGF pts had greater incidence of symptomatic improvement (75% vs. 49%) (Neurology 51:695, 1998--UW Pharm Letter)
  9. Capsaicin cream
  10. Lipoic acid
    1. In a study in 181 pts with symptomatic diabetic neuropathy randomized to lipoic acid vs. placebo, at 5wks the reduction in pain scors were sig. greater in the lipoic acid groups (there were 3, from 600-1800mg/d). Higher doses were associated with similar pain scores and more nausea than the 600mg/d dose ("SYDNEY 2" Trial; Diab. Care 29:2365, 2006--JW)
  11. Transcutaneous electrical nerve stimulation ("TENS")
    1. "H-wave" TENS was better than placebo in 31 pts w/painful DM neuropathy avg. 1.5y duration (Diab. Care 20:1702, 1997--JW)
    2. In a systematic review of use of TENS for diabetic neuropathy, 3 studies were found, none of them randomized controlled trials, but the trials did show a "modest reduction in pain" with TENS vs. a sham TENS application (Neurol. 74:173, 2010-AFP)
  12. Botulinum toxin
    1. In a study in 18 pts with painful diabetic neuropathy randomized to botulinum toxin type A vs. placebo, pain scores were sig. lower in botulinum toxin recipients at 1wk, 4wks, 8wks, and 12wks after injection (Neurology 72:1473, 2009-JW)
  13. Can treat diarrhea with tetracycline 200mg or 500mg x 1-2 at start of attack; unclear mechanism of action
  14. Can treat orthostatic hypotension with increased Na intake; elastic tights; fludrocortisone
  15. Transcutaneous electrical nerve stimulation (TENS)
(Sources include Core Content Review of Family Medicine, 2012)