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RECENT ADVANCES IN ENDOCRINOLOGY : 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 (ALA), Acetyl- L carnitine and Benfotiamine are potential 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 .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 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. (summarised in Table). Epalrestat is the only ARI currently available commercially Till now only and 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 ER prevented the deterioration of median motor NCV and ( agonist and 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 (, milder disease, whose diabetes is under better control pregabalin), tricyclic antidepressants (TCAs), and Selective with a more realistic goal of slowing disease progression. noradrenaline reuptake inhibitors (SNRIs — Immunosuppressants venlafaxine, and duloxetine) as first-line treatments and Immunosuppressing therapies have been used in diabetic support opioid and 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 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 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 20 -80 mgday dependence, Tapentadol and tramadol can entire neuraxis) 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 hepatic/renal dysfunction.

Topical Depletes substance P from nerve Tapentadol 100-600 mg/day (4-6 Worsens neuropathic symptoms terminals divided doses) Extended release for first 2-4 weeks of application. formulation 100-500 mg/day (twice daily). Also acts as norepinephrine reuptake inhibitor Topical capsaicin (0.075%) is applied sparingly 3-4 times per day to affected area Other drugs: , Isosorbide dinitrate spray, derivative - ABT 594, , levodopa and patch. and duloxetine, respectively. If pain is inadequately nortryptiline and ) — Several well designed controlled despite titration to maximum tolerated dose, one studies have proven the efficacy of tricyclic can switch to an alternative first line agent. Combination of antidepresssants in the treatment of diabetic neuropathic 1st line therapies may be considered if there is pain, despite pain. While the EFNS guidelines do not recommend a a change in first-line monotherapy. If pain still persists specific out of the class, AAN guidelines recommend such as tramadol and oxycodone may be added as the use of amitryptyline. Amitryptyline is started at a dose second line agents. The algorithm is summarised in Figure. A of 10 mg 2 hours before going to bed and increased in 10 brief description of the first and second line drugs is given mg increments every 5 days to the required dose (usual below. dose 25-100mg/day). After reaching 50mg, the dose can be stepped up in 25mg increments.6 A particular First Line Agents advantage of amitryptyline is that it helps in sleep  Triyclic antidepressant (amitryptyline, imipramine, initiation even at low dose. This is particularly beneficial as

J Pak Med Assoc Diabetic Neuropathy: Part 2 849 neuropathic pain becomes worse at night making it novel opioid agonist that has recently been shown to be difficult for the person to fall asleep. Common dose superior to placebo in reducing neuropathic pain in a related side effects include dry mouth, constipation, randomized trial cohort of 395 subjects with diabetic urinary retention, orthostatic hypotension, somnolence neuropathy.25 and confusion. As elderly patients can develop heart block, an electrocardiogram (ECG) should be done before Non pharmacological therapy starting these drugs.6 It should also be avoided in diabetic Lack of response and unwanted side effects of patients with cardiovascular disease (risk of sudden conventional drug treatments forces many sufferers to try cardiac death at dose >100mg/day20 and autonomic alternative therapies such as acupuncture , near-infrared neuropathy (exacerbates postural hypotension). Patients phototherapy, low intensity light amplification by taking inhibitors should not take stimulated emission of radiation (LASER) therapy, tricyclics.6 magnetic field therapies, transcutaneous electrical stimulation (TENS), frequency modulated  Serotonin Noradrenaline reuptake inhibitors - Both the electromagnetic neural stimulation (FREMS) therapy, high EFNS and AAN guidelines support the use of duloxetine frequency external muscle stimulation and as a last resort, (dose 60-120 mg/day) and venlafaxine (dose 75- implantation of electrical spinal cord stimulator.16 225mg/day).21 Common side effects include nausea, somnolence, dry mouth, and constipation. Appetite A recent follow-up of patients fitted with electrical spinal suppression is common, but is often regarded as a benefit cord stimulators found that stimulators continued to be of the drug. Venlafaxine should be avoided in coexistent effective 10 years after implantation.26 But it is reserved as cardiac disease (produces clinically significant ECG a last option as the procedure is invasive and is available changes)22 and duloxetine should be avoided in liver only at specialist centres. disease. New Therapies on Horizon  α-2-δ agonist — Pregabalin is classified as effective with Various agents at different stages of development are level A evidence by both the EFNS and the AAN currently in the pipeline as disease modifying or guidelines. The recommended dose for pregabalin is 300- symptomatic agents. The future probably belongs to 600mg a day.21 Dose escalation of pregabalin can begin at targeted therapies like gene therapy because of their 75mg twice daily, and increase by 75mg increments to theoretical ability to target a therapy specifically to the 150mg twice daily.6 Gabapentin is also classified as nerve or neuron without encountering off target side effective and the recommended dose is 900-3600mg/day effects. For example, one study of IM injection of a (level A evidence by the EFNS, level B drug by AAN).21 plasmid containing the vascular endothelial growth factor Dose escalation of gabapentin should begin at 300mg A gene, VEGFA, demonstrated a small benefit by (taken 2 hours before bedtime), increasing in 300mg improving the nerve conduction velocity, IENFD and increments every 3 to 7 days to 600mg three times daily.6 neurological impairment score.27 Side effects include dizziness, somnolence and oedema. Other drugs under evaluation are PKC (Protein Kinase C) Second line agents inhibitors like Ruboxistaurin mesylate, NMDA receptor antagonists like Indantadol, newer antiepileptics like  Opioid agonists — Opioid agonists have a defined role as adjunctive therapies in the treatment of diabetic , acetyl L-carnitine, Olesoxime — a cholesterol neuropathic pain and have been recommended by both like compound with neuroprotective, neuroregenerative AAN and EFNS guidelines. The major concern of treating and analgesic action, various antioxidants, lipid lowering physicians with the use of opioids is dependence and therapy, nerve growth factors like Coleneuramide, addiction. Physical dependence does occur but it is rarely Iroxanadine (p38 kinase activator), C-peptide and Islet 27 a problem. However one has to be cautious if there is neogenesis associated protein. history of and drug abuse. Constipation is the Prevention of Complications most common side effect of low-dose oral Patients with diabetic neuropathy are at increased risk of ( and oxycodone) use. Prophylactic falls especially when walking on uneven surfaces. Hence institution of a bowel control regimen helps prevent they should be counselled regarding risk of falls and given constipation. Tramadol (opioid agonist and serotonin- physical therapy intervention after gait evaluation. norepinephrine reuptake blocker) alone or in combination with is also effective and does Foot ulceration and consequent digit, foot, or limb not produce significant tolerance.23,24 Tapentadol is the amputation is another common diabetic complication.

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Daily self-examination, with a foot mirror if necessary; Benfotiamine in diabetic polyneuropathy (BENDIP): results of a podiatric consultation and maintenance for toenails and randomised, double blind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes 2008 ;116:600-5. bunions; orthotic foot support, and use of protective, 12. Hotta N, Akanuma Y, Kawamori R, Matsuoka K, Oka Y, Shichiri M, et wide based shoes with adequate toe box and ankle al. Long-term clinical effects of epalrestat, an aldose reductase support are recommended for patients at risk for ulcers. If inhibitor, on diabetic : the 3-year, stasis ulcers develop, nonsurgical debridement, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial. Diabetes Care 2006 ;29:1538-44. application of hydrogels, and empiric antibiotic coverage 13. Attal N, Cruccu G, Haanpää M, Hansson P, Jensen TS, Nurmikko T, for wound flora are appropriate therapy. et al. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol 2006 ;13:1153-69. Summary 14. Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, et al. To conclude, effective management of hyperglycaemia, EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010 ;17:1113-e88. symptom control, and prevention of foot ulcers and 15. Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, et infection through screening and surveillance remain al. Evidence-based guideline: Treatment of painful diabetic mainstays of diabetic neuropathy management. neuropathy: report of the American Academy of Neurology, the Traditional and rational diabetic neuropathy treatments American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and will be supplemented by novel cell based therapy and Rehabilitation. 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New perspectives on the management of diabetic the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathic pain. Diab Vasc Dis Res 2006 ;3:108-19. peripheral neuropathy in type 1 diabetes during the 19. Dworkin RH, O'Connor AB, Audette J, Baron R, Gourlay GK, Epidemiology of Diabetes Interventions and Complications (EDIC) Haanpää ML, et al. Recommendations for the pharmacological Study. Diabetes Care 2010 ;33:1090-6. management of neuropathic pain: an overview and literature 3. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et update. Mayo Clin Proc 2010;85:S3-14. al. Association of glycaemia with macrovascular and 20. Ray WA, Meredith S, Thapa PB, Hall K, Murray KT. Cyclic microvascular complications of type 2 diabetes (UKPDS 35): antidepressants and the risk of sudden cardiac death. Clin prospective observational study. BMJ 2000;321:405-12. Pharmacol Ther 2004 ;75:234-41. 4. 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