Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus (DM). It affects up to 50% of patients, and up to 50% of those affected experience painful neuropathy. DPN has been defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes.1 Once diagnosed, this disease presents a unique challenge to patient management. Painful diabetic neuropathy (PDN) is associated with significant morbidity and costly sequelae including ulcer formation and amputation. Treatment reduces painful symptoms and improves quality of life.
PDN is primarily a clinical diagnosis (Table 1). The first step includes a detailed history. The pain is often manifested in a symmetrical “glove and stocking” distribution, affecting the lower extremities first.2 The physical exam should include assessment of pressure, vibration and superficial pain sensation. All three have similar efficacy in detecting neuropathy; however, monofilament testing has a positive likelihood ratio of 15 for the prediction of foot ulcers and amputation.1,3,4
As DPN is a diagnosis of exclusion, rule out other forms of neuropathy (Table 1). Investigations should be directed by the patient’s medical history and clinical findings and can include serum B12, TSH and testing of renal function. For the complex patient with multiple co-morbidities, or in those with unusual features not consistent with DPN, such as a short history of DM, features of other syndromes, or a neuropathy that’s not in keeping with a symmetrical glove and stocking distribution, consider referral to a specialist or other tests such as electromyography (EMG), nerve conduction studies or a nerve biopsy.
The management of PDN involves three main elements — foot care/education, glycemic control and pharmacological intervention. Tight glycemic control is one of the greatest primary prevention measures for diabetic neuropathy and also has some effect on secondary prevention.5-7 This was demonstrated in the Diabetes Control and Complications Trial (DCCT) where intensive glucose control in insulin-dependent diabetics markedly reduced the risk for developing DPN by 21-78%.5,6 For type 2 DM, tight glycemic control also reduces the frequency of DPN.7
Managing pain can be accomplished systematically. Prior to treatment, establish an understanding with your patient that complete pain relief is an unrealistic goal, as people with PDN achieve no more than 30-50% pain reduction.1,2
The major drug classes used to treat PDN include antidepressants — tricyclic antidepressants (TCAs) and serotonin norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, opioids and topical agents. The Canadian Diabetes Association (CDA) states that there’s “insufficient comparative studies to justify a recommendation on which oral medication should be attempted first”4; however, antidepressants, anticonvulsants and opioids had level 1A evidence for initial treatment of PDN.4 A number of publications have outlined an algorithm for initiating treatment based on current available evidence (Figure 1).2,8,9 Table 2 provides the dosages, costs and adverse effects of the selected medications.
TCAs act centrally to reduce the perception of pain. Their analgesic effect has been shown to be independent of their antidepressant effect.10 Amitriptyline is one of the most extensively studied drugs in PDN. Randomized controlled trials (RCTs) have demonstrated a moderate response compared to placebo.11 In a 2005 Cochrane Review, the NNT for amitriptyline’s effectiveness was 1.3.12 The benefits of TCAs, however, are offset by their significant adverse effects (Table 2). Nortriptyline and desipramine, though, have less serotonergic and anti-cholinergic activity as compared to amitriptyline and therefore are often better tolerated.9
Pregabalin and gabapentin are alpha-2-delta agonists that reduce excitatory neurotransmitter release. Pregabalin is the only anticonvulsant that’s been approved by the FDA for treatment of PDN. Doses of 300-600 mg/day have been shown to be efficacious in many studies.13,14 The NNT to achieve at least 50% pain relief over baseline is 5.6.15 For gabapentin, however, the evidence is conflicting. In one RCT, gabapentin reduced pain and improved QOL over placebo. The results were significant but the effect size was small. In another RCT there was no significant effect seen with gabapentin.11 Both medications are generally well tolerated.13 Lamotrigine and carbamazepine are considered 4th-line agents and neither has shown to be significantly effective in those with PDN.9,11
Duloxetine was the first medication approved by the FDA for treatment of PDN. There’s strong evidence that duloxetine 60 mg and 120 mg daily are efficacious for treating pain and improving QOL. Fifty percent of patients experience a 50% or greater reduction in pain.16 The NNT for 50% pain reduction is 6.17 Venlafaxine (at dosages 150-225 mg/day) is also effective in reducing pain in PDN.18 Generally, SNRIs have fewer side effects and are better tolerated than TCAs.
Opioids and tramadol
Tramadol and oxycodone CR have been shown to be effective in reducing pain.19,20 But a major shortcoming of these trials is their short-term follow-up. Given that oxycodone has significant side effects including risk of dependency, its use as a monotherapy should be evaluated carefully.21 Due to growing concerns over the addictive nature of opiates, Health Canada has been actively engaged in developing strategies to prevent opiate abuse. As evidence of this, recently, OxyContin, a long-acting form of oxycodone, was discontinued due to it high abuse potential. Tramadol, on the other hand, has lower abuse potential than opioids.
Capsaicin is an alkaloid derived from cayenne chilies and it works by depleting substance P from sensory nerves. Although studies have shown efficacy,22 capsaicin has many disadvantages including frequent and painful application, which may compromise patient compliance. For topical lidocaine, no randomized trials are available; however, in an open label trial, the use of 5% lidocaine transdermal patches was shown to reduce pain and improve QOL in over 50% of patients with PDN.23
Alpha-lipoic acid (ALA) is an anti-oxidant that’s thought to decrease the oxidative stress associated with DPN. Its use in reducing pain in PDN has been demonstrated in randomized trials, whereby 600 mg/day was associated with a 50% reduction in pain seen in 50-60% of patients vs placebo.24-25 Due to the short duration of these studies, long-term benefits of ALA is unknown.
The decision to combine two different classes of medications should take into consideration their mechanism of action and their side-effect profiles. Combination therapy with gabapentin and an opioid has been shown to achieve better analgesia relative to either drug alone.26 In contrast, avoid combining TCAs, SNRIs and tramadol due to the increased risk of serotonin syndrome.27
Choice of therapy
Given the similar benefits of treatment through 1st-line medications, any one of the drugs can be initiated in a patient with PDN. Improvement in pain should be evident within 3 weeks of treatment. If a patient does not respond adequately once dosages are titrated appropriately, or experiences adverse effects, then switching to another first-class agent, 2nd-line agent or combination therapy may be considered.