Pathophysiology of Neuropathic Pain in Type 2 Diabetes

Abstract

OBJECTIVENeuropathic pain due to small-fiber sensory neuropathy in type 2 diabetes can be diagnosed by skin biopsy with quantification of intra-epidermal nerve fiber (IENF) density. There is, however, a lack of noninvasive physiological assessment. Contact heat–evoked potential (CHEP) is a newly developed approach to record cerebral responses of Aδ fiber–mediated thermonociceptive stimuli. We investigated the diagnostic role of CHEP.RESEARCH DESIGN AND METHODSFrom 2006 to 2009, there were 32 type 2 diabetic patients (20 males and 12 females, aged 51.63 ± 10.93 years) with skin denervation and neuropathic pain. CHEPs were recorded with heat stimulations at the distal leg, where skin biopsy was performed.RESULTSCHEP amplitude was reduced in patients compared with age- and sex-matched control subjects (14.8 ± 15.6 vs. 33.7 ± 10.1 μV, P < 0.001). Abnormal CHEP patterns (reduced amplitude or prolonged latency) were noted in 81.3% of these patients. The CHEP amplitude was the most significant parameter correlated with IENF density (P = 0.003) and pain perception to contact heat stimuli (P = 0.019) on multiple linear regression models. An excitability index was derived by calculating the ratio of the CHEP amplitude over the IENF density. This excitability index was higher in diabetic patients than in control subjects (P = 0.023), indicating enhanced brain activities in neuropathic pain. Among different neuropathic pain symptoms, the subgroup with evoked pain had higher CHEP amplitudes than the subgroup without evoked pain (P = 0.011).CONCLUSIONSCHEP offers a noninvasive approach to evaluate the degeneration of thermonociceptive nerves in diabetic neuropathy by providing physiological correlates of skin denervation and neuropathic pain.

Contact Heat-Evoked Potential Stimulation for the Evaluation of Small Nerve Fiber Function

“…Several studies have shown reduced CHEPS amplitudes and prolonged latencies in patients with skin denervation and sensory neuropathy of different causes. [23][24][25][26] Here, we further confirm these findings, suggesting that CHEPS can be used as a reliable, sensitive, and noninvasive measure for Ad thermonociceptive fibers in people with diabetic neuropathy. Our ROC analysis shows the efficacy of CHEPS in detecting nerve fiber abnormalities, comparable to other measures of small and large fiber dysfunction.…”

“…[22][23][24] To the best of our knowledge, there have been only two studies specifically investigating the utility of CHEPS in the evaluation of DPN with satisfactory results. 25,26 Both concluded that CHEPS provides a noninvasive and sensitive approach to assess the involvement of small, thermonociceptive nerve fibers in patients with diabetes and that it has great potential for application to interventional studies.…”

Diabetic Neuropathic Pain Pathophysiology and Pain Management

“…In a recent comparative trial,only two side effects differentiated gabapentin andnortriptyline: dry mouth (more frequent with nortriptyline)and concentration disorders (more frequent with gabapentin). [4] Opioids agonist Oxycodone, tramadol and tramadol/ acetaminophencombination reduce pain in diabetic PPN.Side effects include mainly nausea and constipation,but long-term use of opioids may be associated withmisuse (2.6% in a recent 3-year registry study ofoxycodone in mainly diabetic NP, although higherrates were also reported). [4,34] Tramadol should beused with caution in elderly patients because of risk ofconfusion and is not recommended with drugs actingon serotonin reuptake such as SSRIs.…”

“…The tramadol/acetaminophen combination appears better tolerated. [4] Opioids The Opioids analgesics have unequivocally shown effectiveness in the treatment of PDPN. Whilethese agents, specifically tramadol, oxycodone, and morphine,are recommended as second-line therapy inrecent practice guidelines, their long-term utility has yet to be elucidated.…”

“…This number may well be an underestimation. [3,4] Pain Relief Treatment of painful diabetic neuropathy are oral medications. People with severe nerve pain may benefit from a combination of medications or treatments and should consider talking with a health care provider about treatment options.…”