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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003ENeuropathic pain is common in patients with diabetes but is not always treated. This article discusses treating patients with neuropathic pain by targeting pain, depression, and anxiety. In addition, she advised screening patients for cardiovascular autonomic neuropathy, teaching foot care, maintaining tight glycemic control, and investing in patient education.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes \u0026amp; Metabolic Syndrome\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHyperglycemia\/Hypoglycemia\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EEndocrinology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes \u0026amp; Metabolic Syndrome\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHyperglycemia\/Hypoglycemia\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003ENeuropathic pain is common in patients with diabetes but is not always treated. Pat Rafferty, PharmD, St. Louis College of Pharmacy, St. Louis, Missouri, USA, recommended aggressively treating patients with neuropathic pain by targeting pain, depression, and anxiety. In addition, she advised screening patients for cardiovascular autonomic neuropathy, teaching foot care, maintaining tight glycemic control, and investing in patient education.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EData from a 2011 English cohort of 15,962 patients with diabetes showed that 21% had painful diabetic peripheral neuropathy (PDPN) [Abbott CA et al. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 2011]. Another study in 350 diabetic patients with chronic PDPN reported that only 39% had never received treatment for pain [Daousi C et al. \u003Cem\u003EDiabet Med\u003C\/em\u003E 2004]. Health care costs are 3 times higher for patients with PDPN than for matched controls [Smith HS, Argoff CE. \u003Cem\u003EDrugs\u003C\/em\u003E 2011]. Diabetic neuropathies vary in their presentation and can be either diffused or focal. Dr. Rafferty focused her presentation on 2 diffused neuropathies: distal symmetric polyneuropathy, which accounts for 75% of all diabetic neuropathies, and cardiovascular autonomic neuropathy.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThe American Diabetes Association guidelines suggest that all patients be screened for diabetic peripheral neuropathy and for the signs and symptoms of cardiovascular autonomic neuropathy. This screening should occur at the time of diagnosis in patients with type 2 diabetes and 5 years after diagnosis in patients with type 1 diabetes.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EThe symptoms of diabetic peripheral neuropathy are as follows:\u003C\/p\u003E\u003Cul class=\u0022list-unord \u0022 id=\u0022list-1\u0022\u003E\u003Cli id=\u0022list-item-1\u0022\u003E\n            \u003Cp id=\u0022p-6\u0022\u003ETingling\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-2\u0022\u003E\n            \u003Cp id=\u0022p-7\u0022\u003EPain\u2014burning, shooting, aching\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-3\u0022\u003E\n            \u003Cp id=\u0022p-8\u0022\u003EEvoked pain\u2014allodynia, hyperesthesia\u003C\/p\u003E\n         \u003C\/li\u003E\u003Cli id=\u0022list-item-4\u0022\u003E\n            \u003Cp id=\u0022p-9\u0022\u003EUnusual sensations\u2014swelling, cold, walking on pebbles\u003C\/p\u003E\n         \u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-10\u0022\u003EThey are often more severe at night and may also be described as numbness or a \u201cdead\u201d feeling. Symptoms occur symmetrically, in a \u201cstocking and glove pattern.\u201d The toes are affected first, and patients can lose their vibration and proprioceptive sensations, which can put them at risk for falls.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EDiabetic peripheral neuropathy can be classified as peripheral or central. The causes of peripheral diabetic peripheral neuropathy are multifactorial and include changes in sodium, calcium, and potassium channel distribution and expression, altered neuropeptide expression, altered peripheral blood flow, axonal atrophy and degeneration, damage to small fibers, or increased glycemic flux. Central sensitization refers to the hyperexcitability of peripheral neurons with increasing input to the central nervous system.\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EThere are many ways to assess pain severity in these patients. The visual analog scale and Brief Pain Inventory Short Form are very general and can assess any type of pain. The Neuropathic Pain Symptom Inventory, the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale, the painDETECT questionnaire, and the McGill Pain Questionnaire and McGill Neuropathic Pain Questionnaire are specific for neuropathic pain. Other useful assessment tools are the Norfolk Quality of Life Scale for assessing neuropathy-specific measures of quality of life. The Hospital Anxiety and Depression Scale and the Beck Depression Inventory are helpful for assessing depression.\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EDrugs used in the treatment of diabetic peripheral neuropathy target multiple pathways. Lidocaine and carbamazepine block nerve potentials. Similarly, ezogabine, already approved for partial seizures, is in early development for use in painful neuropathy. Gabapentin and pregabalin can block the release of neurotransmitters such as substance P that are directly related to the sensation of pain from voltage-gated calcium channels.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003EDiabetic peripheral neuropathy follows multiple pathogenic pathways, all of which lead to pain. In the polyol pathway, hyperglycemia activates an aldose reductase enzyme, leading to cell damage, nerve demyelination, and excess activation of inflammatory pathways via protein kinase C activation. Hyperglycemia is associated with an accumulation of advanced glycation end products in the neural tissue. Hyperglycemia ultimately leads to oxidative stress, nerve ischemia, and impaired nerve growth. Diabetic polyneuropathy damages myelinated and unmyelinated nerve fibers and can occlude the vasa nervorum.\u003C\/p\u003E\u003Cp id=\u0022p-15\u0022\u003ERealistic expectations for the management of diabetic polyneuropathy include a 50% reduction in pain intensity and improvements in functional measures (quality of life, sleep, and mood), glycemic control, and possibly cardiovascular risk factors.\u003C\/p\u003E\u003Cp id=\u0022p-16\u0022\u003EFor patients with type 1 diabetes, there is high-quality evidence from the Diabetes Control and Complications Trial [DCCT; DCCT Research Group. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 1993], conducted from 1983 to 1993, showing that keeping blood glucose levels close to normal slows the onset and progression of diabetic retinopathy, nephropathy, and neuropathy.\u003C\/p\u003E\u003Cp id=\u0022p-17\u0022\u003EThe follow-up registry, the Epidemiology of Diabetes Interventions and Complications trial [EDIC; DCCT\/EDIC Study Research Group. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2005], reported a 42% reduced risk for any cardiovascular disease event and a 57% reduced risk for nonfatal heart attack, stroke, or death from cardiovascular disease more than 10 years after the end of the DCCT.\u003C\/p\u003E\u003Cp id=\u0022p-18\u0022\u003EThe Kumamoto study, conducted in nonobese patients with type 2 diabetes, reported that the cumulative percentages of worsening in retinopathy and nephropathy were significantly lower (p \u0026lt; .05) with intensive treatment compared with conventional therapy [Shichiri M et al. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 2000]. Similar findings were reported in the United Kingdom Prospective Diabetes Study and other trials in this patient population.\u003C\/p\u003E\u003Cp id=\u0022p-19\u0022\u003EThe only analgesics currently approved for diabetic polyneuropathy are duloxetine, pregabalin, and tapentadol. All other medications discussed are for offlabel or investigational use. According to Dr. Rafferty, Cochrane reviews have identified tricyclic antidepressants (TCAs), the serotonin-norepinephrine reuptake inhibitors (SNRIs) duloxetine and venlafaxine, the \u03b1-2-\u03b4 ligands gabapentin and pregabalin, opioids, tramadol, and capsaicin cream as the only treatments achieving at least 50% pain intensity reduction over baseline. Current guidelines recommend TCAs, \u03b1-2-\u03b4 ligands, and SNRIs as first-line therapy. Opioids are reserved for second- or third-line therapy. If first-line therapy drugs are inadequate, a rational approach should include switching to a medication with a different mechanism of action. When using additive therapies, SNRIs and selective serotonin reuptake inhibitors should be avoided in patients taking a TCA or tramadol because of the risk for serotonin syndrome. Topical therapies such as capsaicin, lidocaine, and amitriptyline may be useful. Topical nonsteroidal anti-inflammatory agents are not as effective for neuropathic pain as they are for arthritis pain. Comparative effectiveness trials have shown similar outcomes between duloxetine and amitriptyline [Kaur H et al. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 2011] and between duloxetine and pregabalin [COMBO-DN; Tesfaye S et al. \u003Cem\u003EPain\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-20\u0022\u003EDepression, anxiety, and pain are interrelated. According to Dr. Rafferty, 22% of patients with diabetes meet the diagnostic criteria for depression, while 32% meet the criteria for anxiety [Jain R et al. \u003Cem\u003ECurr Diab Rep\u003C\/em\u003E 2011]. Diabetic patients who are also depressed have an increased risk for neuropathy (OR 1.94) compared with patients who are not depressed [Raval A et al. \u003Cem\u003EIndian J Med Res\u003C\/em\u003E 2010]. Depression is associated with poor medication adherence in patients and poor compliance with exercise and dietary instructions.\u003C\/p\u003E\u003Cp id=\u0022p-21\u0022\u003EAutonomic neuropathies can be difficult to diagnose. Diseases that mimic autonomic neuropathies include idiopathic orthostatic hypotension, multiple-system atrophy with autonomic failure, Addison\u0027s disease, hypopituitarism, hypovolemia, and thyroid disease. Use of certain medications (eg, anticholinergic agents, vasodilators, sympathetic blockers) may also result in symptoms similar to those seen with autonomic neuropathy.\u003C\/p\u003E\u003Cp id=\u0022p-22\u0022\u003EThe clinical manifestations of cardiovascular autonomic neuropathy include exercise intolerance and orthostatic hypotension. Cardiovascular autonomic neuropathy is associated with silent myocardial infarction (RR, 1.96; 95% CI, 1.53 to 2.51; p \u0026lt; .001) and increased mortality (RR, 2.14; 95% CI, 1.83 to 2.51; p \u0026lt; .0001) [Vinik AI, Ziegler D. \u003Cem\u003ECirculation\u003C\/em\u003E 2007]. Subclinical cardiovascular autonomic neuropathy, which is generally what is identified at diagnosis of type 1 or type 2 diabetes, can progress quickly to clinical, symptomatic cardiovascular autonomic neuropathy (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Kuehl M, Stevens MJ. \u003Cem\u003ENat Rev Endocrinol\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/26\/27\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Progression of CAN Following the Diagnoses of Diabetes\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1365421733\u0022 data-figure-caption=\u0022Progression of CAN Following the Diagnoses of Diabetes\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/26\/27\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/26\/27\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/26\/27\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14965\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-23\u0022 class=\u0022first-child\u0022\u003EProgression of CAN Following the Diagnoses of Diabetes\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EBRS=baroreflex sensitivity; CAN=cardiovascular autonomic neuropathy; HRV=heart rate variability.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EKuehl M, Stevens MJ. Cardiovascular autonomic neuropathies as complications of diabetes mellitus. \u003Cem\u003ENat Rev Endocrinol.\u003C\/em\u003E 2012;8:405\u2013416. Reproduced with permission from Nature Publishing Group.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-24\u0022\u003EPatients being tested for cardiovascular autonomic neuropathy should have assessment of heart rate response to Valsalva maneuver, deep breathing, and standing up and blood pressure response to standing up and sustained handgrip. These tests provide assessment of both parasympathetic and sympathetic responses. Ambulatory 24-hour blood pressure monitoring may also be useful.\u003C\/p\u003E\u003Cp id=\u0022p-25\u0022\u003EManagement of patients with cardiovascular autonomic neuropathy should include tight glycemic control. In addition, patients should be on statins, as these drugs may improve the functionality of the tissue within the vasculature. Evidence for the use of antioxidants and angiotensin-converting enzyme (ACE) inhibitors in the treatment of neuropathy is mixed. ACE inhibitors are very useful for hypertension and renal protection in diabetics. Beta-blockers may be used to reestablish parasympathetic-sympathetic balance. Aldose reductase inhibitors block the rate-limiting enzyme of the polyol pathway, thus decreasing the accumulation of sorbitol. In addition to pharmacological therapies, appropriate exercise and patient education are also necessary.\u003C\/p\u003E\u003Cp id=\u0022p-26\u0022\u003EDrugs currently being evaluated for the treatment of diabetic neuropathy treatment include a new opioid receptor agonist, cebranopadol, and new endocannabinoid modulators. The use of vascular endothelial growth factor, stem cell transplantation, \u03b1-lipoic acid, and vitamin E (tocotrienols) for cardiovascular protection is currently being studied may be effective in this patient population.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/26\/27.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzovc1\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzovc1\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}