Canadian Diabetes Association Clinical Practice Guidelines Expert Committee

Vera Bril MD, FRCPC Bruce Perkins MD, MPH, FRCPC Cory Toth MD, FRCPC

  • Key Messages
  • Recommendations
  • Figures
  • Highlights
  • Full Text
  • References

Key Messages

  • Elevated blood glucose levels, elevated triglycerides, high body mass index, smoking and hypertension are risk factors for neuropathy.
  • Intensive glycemic control is effective for the primary prevention or secondary intervention of neuropathy in people with type 1 diabetes.
  • In people with type 2 diabetes, lower blood glucose levels are associated with a reduced frequency of neuropathy.
  • Simple physical examination screening tests, such as the monofilament and vibration perception tests for neuropathy, perform reasonably well for the identification of neuropathy and prediction of its future onset.

Highlights of Revisions

  • The grading of the evidence of the various agents for relief of painful peripheral neuropathy (Table 1) has been updated.
Table 1
Treatment options for the management of painful diabetic peripheral neuropathy
bid, 2 times a day; OD, once daily; qhs, every bedtime; qid, 4 times a day.
Dose ranges are for adults and are taken from published trials; smaller starting doses and slower titration schedules may be indicated. Optimal doses are the lowest doses required for maximum efficacy without significant side effects. Although required for some agents, dose adjustments for renal and hepatic dysfunction are not shown here. Physicians should refer to the most current edition of the Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association, Ottawa, Ontario, Canada) for product monographs and complete prescribing information.
Denotes that this drug is not currently approved by Health Canada for the management of neuropathic pain associated with diabetic peripheral neuropathy.
Gabapentin (23,55) 300 mg bid May titrate slowly up to 600 mg po qid 3,600 mg/day $36.55
Pregabalin (24–26,30) 75 mg bid May titrate slowly up to 300 mg po bid 600 mg/day $101.84
Valproate (27,28) 250 mg bid May titrate slowly up to 500 mg po bid 1500 mg/day $12.37
Amitriptyline (31,32) 10 mg qhs May titrate slowly up to 100 mg po qhs 150 mg/day $19.92
Duloxetine (35,40) 30 mg OD May titrate to 60 mg po OD 120 mg/day $138.81
Venlafaxine (37) 37.5 mg bid May titrate slowly up to 150 mg po bid 300 mg/day $8.16
Dextromethorphan (41) 100 mg qid May titrate slowly up to 200 mg po qid 960 mg/day $4.08
Morphine sustained release (55) 15 mg bid May titrate slowly up to 60 mg po bid 180 mg/day $62.05
Oxycodone ER (43) 10 mg bid May titrate slowly up to 40 mg po bid 160 mg/day $56.90
Tapentadol ER 100 mg bid May titrate slowly up to 250 mg po bid 500 mg/day  
Tramadol (44) 50 mg qid May titrate slowly up to 50 mg po qid 400 mg/day $132.30
Topical nitrate sprays (46,47,51) 30 mg spray to legs qhs May titrate slowly up to 30 mg spray to legs bid 60 mg/day $1.36
Capsaicin cream (48,49) 0.075% cream applied 3–4 times per day May titrate to 5–6 times per day 5–6 applications per day $14.14
Transcutaneous electrical nerve stimulation (53,56)
  Suggested starting dose Suggested titration if tolerated Suggested maximal tolerated dose Estimated monthly cost for starting dose


  1. 1.In people with type 2 diabetes, screening for peripheral neuropathy should begin at diagnosis of diabetes and occur annually thereafter. In people with type 1 diabetes, annual screening should commence after 5 years' postpubertal duration of diabetes [Grade D, Consensus].
  2. 2.Screening for peripheral neuropathy should be conducted by assessing loss of sensitivity to the 10-g monofilament or loss of sensitivity to vibration at the dorsum of the great toe [Grade A, Level 1 (1,2)].
  3. 3.People with diabetes should be treated with intensified glycemic control to prevent the onset and progression of neuropathy [Grade A, Level 1A (3,4), for type 1 diabetes; Grade B, Level 2 (5), for type 2 diabetes].
  4. 4.The following agents may be used alone or in combination for relief of painful peripheral neuropathy:
    1. a.Anticonvulsants (pregabalin [Grade A, Level 1 (6,7)], gabapentin, valproate [Grade B, Level 2 (8-11)])
    2. b.Antidepressants (amitriptyline, duloxetine, venlafaxine ) [Grade B, Level 2 (12-16)]
    3. c.Opioid analgesics (tapentadol ER, oxycodone ER, tramadol) [Grade B, Level 2 (9,17–20)]
    4. d.Topical nitrate spray [Grade B, Level 2 (21-23)]

Denotes that this drug is not currently approved by Health Canada for the management of neuropathic pain associated with diabetic peripheral neuropathy.

Most studies failed to achieve Grade A, Level 1, due to a <80% completion rate (24).


  1. Perkins BA, Olaleye D, Zinman B, et al. Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care 2001;24:250-6.
  2. Perkins BA, Orszag A, Ngo M, et al. Prediction of incident diabetic neuropathy using the monofilament examination: a 4-year prospective study. Diabetes Care 2010;33:1549-54.
  3. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86.>
  4. Reichard P, Berglund B, Britz A, et al. Intensified conventional insulin treatment retards the microvascular complications of insulin-dependent diabetes mellitus (IDDM): the Stockholm Diabetes Intervention Study (SDIS) after 5 years. J Intern Med 1991;230:101-8.
  5. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352: 837-53.
  6. Richter RW, Portenoy R, Sharma U, et al. Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain 2005;6:253-60.
  7. Guan Y, Ding X, Cheng Y, et al. Efficacy of pregabalin for peripheral neuropathic pain: results of an 8-week, flexible-dose, double-blind, placebo-controlled study conducted in China. Clin Ther 2011;33:159-66.
  8. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998;280:1831-6.
  9. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005;352:1324-34.
  10. Kochar DK, Jain N, Agarwal RP, et al. Sodium valproate in the management of painful neuropathy in type 2 diabetes: a randomized placebo controlled study. Acta Neurol Scand 2002;106:248-52.
  11. Kochar DK, Rawat N, Agrawal RP, et al. Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study. QJM 2004; 97:33-8.
  12. Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 1987;37: 589-96.
  13. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992;326:1250-6.
  14. Raskin J, Wang F, Pritchett YL, et al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neruopathic pain. Pain Med 2005;6:346-56.
  15. Rowbotham MC, Goli V, Kunz NR, et al. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain 2004;110:697-706.
  16. Kaur H, Hota D, Bhansali A, et al. A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy, a randomized, double-blind, crossover clinical trial. Diabetes Care 2011;34:818-22.
  17. Sang CN, Booher S, Gilron I, et al. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiology 2002;96:1053-61.
  18. Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. CMRO 2011;27:151-62.
  19. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998;50: 1842-6.
  20. Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003;60: 927-34.
  21. Yuen KC, Baker NR, Rayman G. Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray: a double-blind placebo-controlled crossover study. Diabetes Care 2002;25:1699-703.
  22. Agrawal RP, Choudhary R, Sharma P, et al. Glyceryltrinitrate spray in the management of painful diabetic neuropathy: a randomized double blind placebo controlled cross-over study. Diabetes Res Clin Pract 2007;77: 161-7.
  23. Agrawal RP, Goswami J, Jain S, et al. Management of diabetic neuropathy by sodium valproate and glyceryltrinitrate spray: a prospective double-blind randomized placebo-controlled study. Diabetes Res Clin Pract 2009;83: 371-8.
  24. Bril V, England J, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011;3:345e52. 352.e1-21.


Reproduced with permission from Canadian Journal of Diabetes © 2013 Canadian Diabetes Association. To cite this article, please refer to For citation.

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