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RECENT ADVANCES in ENDOCRINOLOGY Diabetic Neuropathy: Part 2 Anu Gupta,1 Yashdeep Gupta2

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RECENT ADVANCES in ENDOCRINOLOGY Diabetic Neuropathy: Part 2 Anu Gupta,1 Yashdeep Gupta2 846 RECENT ADVANCES IN ENDOCRINOLOGY Diabetic Neuropathy: Part 2 Anu Gupta,1 Yashdeep Gupta2 Introduction Treatment of other risk factors Diabetic neuropathy (DN) is a major cause of disability Growing evidence indicates that factors other than and reduced quality of life. In the previous review we hyperglycaemia play a role in neuropathy risk and discussed the prevalence, classification, clinical features, pathogenesis. Among 1172 patients with type 1 diabetes pathophysiology and recent advances in the diagnosis of without baseline neuropathy followed in the Eurodiab diabetic neuropathy. This section will focus on the study, hypertension, smoking, obesity, and serum traditional and the upcoming therapeutic modalities of triglycerides were independent risk factors for this common and troublesome complication of diabetes. neuropathy.5 The effective management of hypertension, hyperlipidaemia, obesity and smoking might modify the Advances in Management course of neuropathy in diabetes but this still needs to be The existing treatment for Diabetic neuropathy can be proven in future clinical trials. subdivided into pathogenesis based and/or symptom based therapy. Currently, the only well-established Reduction of oxidative stress effective therapeutic modality is intensified metabolic Oxidative stress is an important component in diabetic control. neuropathy pathogenesis. Alpha lipoic acid (ALA), Acetyl- L carnitine and Benfotiamine are potential drugs which Pathogenesis Based Treatment reduce oxidative stress and have a direct effect on Glycaemic Control neuropathic injury.6 The first step in the management of any diabetic Alpha lipoic acid is a potent antioxidant and serves a polyneuropathy is good glycaemic control. The effect of critical role in mitochondrial energy metabolism.7 The intensive glucose control on the incidence of efficacy of intravenous ALA (600 mg IV for 3 weeks) has polyneuropathy in T1DM was initially studied in DCCT been established by a meta-analysis of 4 prospective trial. Intensive therapy led to an overall risk reduction of trials, wherein it was found to improve both positive 60% in the development of clinical diabetic neuropathy at neuropathic symptoms and neuropathic deficits.8 5 years.1 The EDIC (Epidemiology of Diabetes Evidence for oral treatment is still conflicting.9 Oral ALA Interventions and Complications) study has further may be started at a dose of 300 mg daily and titrated to substantiated this information by following the patients 600 mg twice daily. of DCCT trial for another 13-14 years.2 Acetyl-L carnitine, another antioxidant was found On the other hand data from studies of T2DM is less efficacious in alleviating pain and improving nerve fibre convincing. While the UKPDS study (United Kingdom regeneration and vibration perception in patients with Prospective Diabetes Study) found significantly reduced established diabetic neuropathy in two parallel risk of neuropathy in the group receiving intensive randomized, blinded controlled trials on 1257 subjects glycaemic control,3 the ACCORD study (Action to Control after 52 weeks of treatment.10 Two doses were tested - 500 Cardiovascular Risk in Diabetes) found no reduction in the mg and 1000mg. The higher dose was found to be more risk of new neuropathy in the intensive arm.4 This data effective. suggests that other risk factors like obesity, dyslipidaemia may be important contributors to the risk of neuropathy Benfotiamine or S-benzoylthiamine O-monophosphate is in T2DM. a vitamin B1 derivative with antioxidant properties. In a randomized placebo controlled phase III study using 300 mg and 600 mg Benfotiamine (165 diabetic neuropathy 1Department of Neurology, Postgraduate Institute of Medical Education & subjects), significant improvement was seen in Research, 2Department of Medicine, Government Medical College & Education, neuropathic Total Symptom Score and its pain subscore Chandigarh, India. over 6 weeks with greater benefit in the 600 mg dose Correspondence: Yashdeep Gupta. Email: [email protected] group.11 J Pak Med Assoc Diabetic Neuropathy: Part 2 847 Aldose Reductase Inhibitors (ARIs) Academy of Neurology (AAN), the American Association Aldose reductase is an enzyme in the polyol pathway, the of Neuromuscular and Electrodiagnostic Medicine, and activation of which is believed to be an important the American Academy of Physical Medicine and contributor to the development of diabetic neuropathy. Rehabilitation.15 According to these guidelines several However the efficacy of ARIs in reversing clinical diabetic classes of drugs are effective in treating diabetic neuropathy is still not clearly established. neuropathic pain (summarised in Table). Epalrestat is the only ARI currently available commercially Till now only duloxetine and pregabalin were formally and has been approved in Japan since 1992. In a 3-year approved by the FDA for the treatment of diabetic open-label RCT in 594 DN subjects, epalrestat 150 mg/day peripheral neuropathic pain.16 Recently Tapentadol ER prevented the deterioration of median motor NCV and (opioid agonist and norepinephrine reuptake inhibitor) minimum F wave latency.12 Patients' symptoms (such as has received FDA approval for the same.17 numbness, sensory abnormality and cramping) improved Several treatment algorithms have been designed for the significantly with epalrestat. Ranirestat and Fidarestat are treatment of neuropathic pain, the important ones being other ARIs undergoing evaluation in phase 3 clinical trials. those from Jensen et al,18 the EFNS14 and Dworkin et al.19 All The effort now is to test these drugs in patients with three algorithms recommend α-2-δ agonist (gabapentin, milder disease, whose diabetes is under better control pregabalin), tricyclic antidepressants (TCAs), and Selective with a more realistic goal of slowing disease progression. serotonin noradrenaline reuptake inhibitors (SNRIs — Immunosuppressants venlafaxine, and duloxetine) as first-line treatments and Immunosuppressing therapies have been used in diabetic support opioid analgesics and tramadol as second-line lumbosacral radiculoneuropathy, based on the evidence treatments. The choice of the first line agent is made taking that it may have an autoimmune basis. Therapies tried into account the co-morbidities and contraindications. For include corticosteroids and immunoglobulins.6 example, TCAs are relatively contraindicated in diabetic patients with a history of heart disease, elderly patients on Symptomatic treatment other concomitant medications such as diuretics and Pain management still remains the mainstay of treatment antihypertensives and patients with co-morbid orthostatic in patients with diabetic neuropathy as it significantly hypotension. In those with liver disease duloxetine should affects the quality of life. Research into this aspect has not be prescribed and pregabalin or gabapentin should be generated several guidelines, the most thorough and avoided in those with oedema. Cost is another important recent ones being, the 2006 and 2010 guidelines from the issue that needs consideration especially in resource poor European Federation of Neurological Societies (EFNS) task settings. TCAs are the most affordable of the first line agents. force13,14 and the 2011 guidelines from the American Gabapentin and venlafaxine are cheaper than pregabalin Figure: Treatment algorithm for painful diabetic neuropathy. Vol. 64, No. 7, July 2014 848 A. Gupta, Y. Gupta Table-1: Pharmacological treatment for painful diabetic neuropathy. Class Mechanism of action Dose Adverse effects Special comments Tricyclic antidepressants (TCAs) Block the reuptake pumps at the Amitryptylline 25-100 mg/day Anticholinergic effects - dry Evidence from several RCTs serotonergic and noradrenergic Imipramine 10-150 mg/day mouth, postural dizziness, Avoid in diabetic patients with synapses sedation, constipation, cardiovascular disease (risk of urinary hesitancy, heart block sudden cardiac death at dose > in elderly 100 mg/day Avoid in autonomic neuropathy (exacerbates postural hypotension) Selective serotonin noradrenaline Increase synaptic availability of Duloxetine 60-120 mg/day Somnolence, nausea, Avoid venlafaxine in coexistent reuptake inhibitors (SNRIs) 5-HT and noradrenaline in the Venlafaxine 150-225 mg/day hypertension cardiac disease descending pathways that are Venlafaxine causes clinically Avoid duloxetine in liver disease inhibitory to pain impulses significant ECG changes Anticonvulsants Gabapentin and pregabalin bind Gabapentin 900-3600 mg/day Dizziness Avoid gabapentin and pregabalin to the α-2-δ subunit of the Pregabalin 300-600 mg/day Somnolence in peripheral oedema calcium channel reducing calcium flux, and thus resulting in reduced neurotransmitter release in the hyperexcited neurone. Opioid agonists Analgesia mediated by µ receptor Tramadol 200-400 mg/day Constipation, drowsiness, Contraindicated in respiratory agonist effect (widely distributed (Also blocks reuptake of serotonin nausea, vomiting, dizziness, depression, hypersensitivity, GI on structures involved in and norepinephrine) physical and psychological obstruction nociceptive processing along Oxycodone 20 -80 mgday dependence, analgesic Tapentadol and tramadol can entire neuraxis) Morphine sulphate SR 20-80 mg/day tolerance, withdrawal with precipitate serotonin syndrome abrupt discontinuation, when used with any serotonergic worsening of depression, drugs (SSRIs, SNRIs, TCAs, sleep disturbances, Triptans, MAOIs). amenorrhea, impotence Do not use in severe
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