Neuropathy

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
  • 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.

Introduction

Detectable sensorimotor polyneuropathy will develop within 10 years of the onset of diabetes in 40% to 50% of people with type 1 or type 2 diabetes (1). Furthermore, up to 50% of children with type 1 diabetes will have subclinical polyneuropathy (2). While clinical neuropathy is uncommon in people with type 1 diabetes within the first 5 years after the onset of diabetes, people with type 2 diabetes may have neuropathy at the time of diagnosis (3). Risk factors for neuropathy include elevated blood glucose levels, elevated triglycerides, high body mass index, smoking and hypertension (4). Foot ulceration, which depends on the degree of foot insensitivity (5), and amputation are important and costly sequelae of diabetic neuropathy (6). Although not all patients with neuropathy have motor or sensory symptoms, the neuropathic pain associated with symptomatic disease is frequently bothersome and often limits physical activity, quality of life and work productivity (7,8). Additionally, patients with neuropathy utilize more health resources than those without this complication (9). Both somatic and autonomic neuropathies may occur and may require referral to a specialist experienced in managing the affected body system. Mononeuropathy, particularly carpal tunnel syndrome, is common in people with diabetes and can be difficult to diagnose (10). The underdiagnosis of neuropathy is a fundamental problem in the primary care of people with diabetes and impedes the benefits of early identification, the management necessary to achieve improved glycemic control and the prevention of neuropathy-related sequelae (11).

Screening for Peripheral Neuropathy

Screening for neuropathy can be performed rapidly and reliably using the 10-g Semmes-Weinstein monofilament or the 128-Hz tuning fork (12–16). Methods for using the monofilament or tuning fork to detect diabetic neuropathy are explained in Appendix 8 (12,13,16). In individuals with significant early progressive symptoms of neuropathy or in whom a clinical suspicion of nondiabetic neuropathy exists, referral for additional neurological evaluation is indicated.

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.
  Suggested starting dose Suggested titration if tolerated Suggested maximal tolerated dose Estimated monthly cost for starting dose
Anticonvulsants        
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
Antidepressants        
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
Opioids        
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
Others        
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)

Management of Neuropathy

Intensive glycemic control is effective for the primary prevention and secondary intervention of neuropathy in people with type 1 diabetes (8,17,18). In fact, the benefits of intensive insulin treatment persist for over a decade for the primary prevention of neuropathy (19). In those with type 2 diabetes, lower blood glucose levels are associated with a reduced frequency of neuropathy (7,20). No other disease-modifying treatments are currently available. Multiple treatments are available for the management of neuropathic pain, and detailed evidence-based guidelines on the treatment of painful diabetic neuropathy (PDN) have been published (21). An important observation is that few patients have complete relief of painful symptoms with any treatment, and that a 30% to 50% reduction in baseline pain is considered to be a clinically meaningful response. There are insufficient comparative studies to recommend which oral medication should be used first, although most practitioners advise against the use of opioids for PDN due to the potential for dependency, tolerance, dose escalation and diversion (21). Anticonvulsants (22–30) and antidepressants (31–40) are most often used as first-line therapy. Details are listed in Table 1. Opioids are effective for PDN (41–45) and are used mostly when other treatments fail. Other effective therapeutic options include topical nitrate sprays (46,47), topical capsaicin (48–52) and transcutaneous electrical nerve stimulation (52,53). However, effective treatment with capsaicin involves short-term pain that limits its acceptability and generalizability in clinical practice. The surgical release of distal lower limb nerves is not recommended due to lack of evidence supporting efficacy (54) and the possible complications of foot and ankle surgery in patients with diabetes.

Although subclinical autonomic neuropathic manifestations are common, symptomatic involvement is infrequent. The diagnosis of symptomatic autonomic neuropathy is based on the exclusion of specific cardiovascular, gastrointestinal or genitourinary manifestations through assessment by a specialist in the affected system. The treatment of autonomic neuropathy is based primarily on expert opinion, but research in this field remains active.

Recommendations

  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 (13,16)].
  3. 3.People with diabetes should be treated with intensified glycemic control to prevent the onset and progression of neuropathy [Grade A, Level 1A (8,17), for type 1 diabetes; Grade B, Level 2 (20), 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 (24,29)], gabapentin, valproate [Grade B, Level 2 (23,27,28,55)])
    2. b.Antidepressants (amitriptyline, duloxetine, venlafaxine ) [Grade B, Level 2 (31,32,35,37,39)]
    3. c.Opioid analgesics (tapentadol ER, oxycodone ER, tramadol) [Grade B, Level 2 (41,43–45,55)]
    4. d.Topical nitrate spray [Grade B, Level 2 (46,47,51)]

Footnote:
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 (21).

References

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