NICE guidelines for the management of painful diabetic neuropathy

Neuropathic pain commonly presents in primary care and one of its most frequent causes is diabetes mellitus.1 A definition of neuropathic pain in diabetes, adapted from the original of the International Association for the Study of Pain, is: ‘Pain arising as a direct consequence of abnormalities in the somato-sensory system in people with diabetes.’2 The prevalence of neuropathic pain in the diabetic population is difficult to estimate as definitions have varied enormously amongst studies; however, it is crudely estimated that between 3% and 25% of patients might experience this.3 A recent population based study from South Wales reported a prevalence of just over 25%, but this study emphasised the importance of excluding other causes of lower limb pain.4 In practice, the diagnosis of painful neuropathy is a clinical one, relying upon the patient's description of pain. The symptoms are distal, symmetrical, associated with nocturnal exacerbations and are commonly described as prickling, sharp, electric shock like or burning;1-3 hyperalgesia and, frequently, allodynia may be found on examination. It must be remembered that neuropathic pain may be the presenting feature of type 2 diabetes and, as more recently observed, occurs with increased incidence in people with impaired glucose tolerance.5 The diagnosis of diabetic peripheral neuropathy (DPN) can only be made after a careful clinical examination, and is one of exclusion.3 There is no investigation that will confirm that the neuropathy in any given patient is caused by diabetes. Investigations should be ordered as dictated by clinical findings and might typically include the serum B12, renal function and a chest X-ray. A combination of typical symptomatology and distal sensory loss with absent reflexes, or signs in the absence of symptoms, is highly suggestive of DPN. Treatment approaches can be divided into the pathogenetic treatments that might impact on the underlying cause of DPN, or symptomatic treatments that relieve the painful symptoms without generally having any effect on the natural history of the condition, which is one of progressive loss of nerve fibres. Blood glucose control is important not only in the prevention of DPN, but in the initial management of painful symptomatology. It has been shown that blood glucose flux might be associated with neuropathic pain,3 and that stability of blood glucose control is important in the initial management of painful DPN. Of all the potential pathogenetic therapies that have been proposed for the treatment of symptomatic DPN, with the exception of near-normoglycaemia, only the anti-oxidant, alpha-lipoic acid, has shown positive efficacy but is not currently available in the UK.6 Unfortunately, research leading to the discovery and confirmation of successful pathogenetic treatments for DPN has a long and painful history. Many drugs that have shown promise in animal models have failed to confirm sufficient efficacy in man, examples of which include nerve growth factors and protein kinase C-inhibitors. Thus, the mainstay in the management of painful DPN at present relies upon pharmacological treatment of the unpleasant symptomatology that is characteristic of the condition. There is little evidence to support the use of simple analgesics or non-steroidal anti-inflammatory drugs in the management of neuropathic pain, and the latter group, of course, should be avoided in patients who might also have diabetic nephropathy. Thus, the main classes of pharmacological agents that have been used for the management of symptomatic DPN have been anticonvulsant and antidepressant agents. Previously published statements and monographs on this condition have reviewed the evidence base for these two groups of treatments.1,3,7,8 The strongest evidence for efficacy exists for gabapentin and pregabalin.1,8 The efficacy of these agents is supported by multiple, randomised controlled trials (RCTs); whereas gabapentin requires thrice daily dosing, pregabalin has the advantage of twice daily dosing from 75–300mg bd. As with all treatments for painful DPN, side effects are not uncommon with either of these agents. Strong evidence from multiple RCTs again exists to support the use of the tricyclic antidepressants (amitriptyline, imipramine) and, more recently, the serotonin and norepinephrine reuptake inhibitor (SNRI) duloxetine. Although not specifically licensed for use in neuropathic pain, the tricyclic drugs are regularly used because of their efficacy, although up to one-third of patients cannot tolerate these drugs because of predictable anticholinergic and central side effects. Despite this, they remain useful agents in this condition in many patients. The SNRI duloxetine has both analgesic and antidepressant effects, and again is supported by several RCTs in the dosage of 60–120mg daily. The efficacy of both pregabalin and duloxetine in the management of painful DPN has been confirmed by pooled analyses of several RCTs.9,10 In summary, prior to the publication of the recent National Institute for Health and Clinical Excellence (NICE) guidelines,11 the main symptomatic therapies used in the UK for patients with painful diabetic neuropathy have been gabapentin, pregabalin, duloxetine and the tricyclic antidepressants. Earlier this year, NICE published guidelines on the management of neuropathic pain in non-specialist settings in which the management of painful DPN featured prominently. NICE's guidelines for first line treatment for painful neuropathy in general was to offer oral amitriptyline or pregabalin as first line treatments but, in painful diabetic neuropathy, oral duloxetine is recommended as first line treatment with amitriptyline to be used in those in whom duloxetine is contraindicated. For second line treatment, pregabalin or duloxetine combined with pregabalin is recommended. While NICE ranked the level of evidence for pain outcomes with duloxetine as moderate-to-high-quality evidence, it ranked the outcomes on pain for patients in trials of pregabalin as high-quality evidence. Thus, the proposal by NICE that duloxetine should be the first line drug for painful DPN, does not appear to be based upon efficacy alone as both duloxetine and pregabalin have moderate or high-quality evidence supporting their efficacy. The NICE group also employed modelling to assess cost effectiveness of treatments in diabetes, simulating a cohort of 2000 patients. Because of a reported lack of published data, resource use was estimated by a survey to gain expert opinion. In this model, duloxetine proved to be the most cost-effective treatment. In a review of recent guidelines on the management of neuropathic pain, Freynhagen and Bennett1 provided treatment recommendations based upon recently published guidelines. They proposed a tricyclic antidepressant or gabapentin or pregabalin as first line approaches. They also recommended that the SNRI, duloxetine, could be first or second line treatment. Guidelines from the Canadian Pain Society12 had similar proposals, with tricyclics and anticonvulsants (gabapentin or pregabalin) being first line treatments and the SNRIs as second line. Finally, the European Federation of Neurological Society's guidelines propose that first line treatments might comprise the tricyclic antidepressants, SNRIs, gabapentin or pregabalin.13 All these reports comment on the dearth of comparative trials and, in this regard, the results of an ongoing trial of pregabalin and duloxetine, either in combination or as monotherapies, are awaited with interest. The management of painful diabetic neuropathy remains challenging for physicians, with many agents having been shown to be efficacious. However, both the NICE and other national/international guidelines suggest that the strongest efficacy has been proven for two groups of agents – that is, antidepressant and anticonvulsant agents. Strong evidence supports the efficacy of the tricyclic antidepressants, gabapentin, pregabalin and duloxetine; frequent side effects have reduced the overall usage of the tricyclics but these remain useful drugs in many patients. Both pregabalin and duloxetine have been shown to be useful in the management of diabetic neuropathic pain in several well-designed RCTs and pooled analyses. It appears that the recommendation for duloxetine as the first line choice in painful DPN is based upon the cost-effectiveness analysis whereas the efficacy for both duloxetine and pregabalin is equivalent. Professor Boulton has served on advisory boards for Eli Lilly and Pfizer.

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