Abstract
This study investigated quantifiable measures of cutaneous innervation and algesic keratinocyte biomarkers to determine correlations with clinical measures of patient pain perception, with the intent to better discriminate between diabetic patients with painful diabetic peripheral neuropathy (PDPN) compared to patients with low-pain diabetic peripheral neuropathy (lpDPN) or healthy control subjects. A secondary objective was to determine if topical treatment with a 5% lidocaine patch resulted in correlative changes among the quantifiable biomarkers and clinical measures of pain perception, indicative of potential PDPN pain relief. This open-label proof-of-principle clinical research study consisted of a pre-treatment skin biopsy, a 4-week topical 5% lidocaine patch treatment regimen for all patients and controls, and a post-treatment skin biopsy. Clinical measures of pain and functional interference were used to monitor patient symptoms and response for correlation with quantitative skin biopsy biomarkers of innervation (PGP9.5 and CGRP), and epidermal keratinocyte biomarkers (Nav1.6, Nav1.7, CGRP). Importantly, comparable significant losses of epidermal neural innervation (intraepidermal nerve fibers; IENF) and dermal innervation were observed among PDPN and lpDPN patients compared with control subjects, indicating that innervation loss alone may not be the driver of pain in diabetic neuropathy. In pre-treatment biopsies, keratinocyte Nav1.6, Nav1.7, and CGRP immunolabeling were all significantly increased among PDPN patients compared with control subjects. Importantly, no keratinocyte biomarkers were significantly increased among the lpDPN group compared with control. In post-treatment biopsies, the keratinocyte Nav1.6, Nav1.7, and CGRP immunolabeling intensities were no longer different between control, lpDPN, or PDPN cohorts, indicating that lidocaine treatment modified the PDPN-related keratinocyte increases. Analysis of the PDPN responder population demonstrated that increased pretreatment keratinocyte biomarker immunolabeling for Nav1.6, Nav1.7, and CGRP correlated with positive outcomes to topical lidocaine treatment. Epidermal keratinocytes modulate the signaling of IENF, and several analgesic and algesic signaling systems have been identified. These results further implicate epidermal signaling mechanisms as modulators of neuropathic pain conditions, highlight a novel potential mode of action for topical treatments, and demonstrate the utility of comprehensive skin biopsy evaluation to identify novel biomarkers in clinical pain studies.
Highlights
Diabetes continues to be an increasing epidemic as treatment for sequela associated with the disease remain limited [1,2,3,4]
No adverse reactions were observed as a result of the biopsy procedures or during the 4-week topical 5% lidocaine treatment protocol and no subjects withdrew due to negative side-effects associated with treatment
Additional correlational analysis demonstrated that neuropathy duration, previous use of anti-cancer, anti-coagulant, antidepressant, NSAID, or sleeping aid drugs, or previous/current comorbid allergy/immune, asthma, migraine, psychiatric, or thyroid disorders were not correlated with any pre-treatment biopsy measures
Summary
Diabetes continues to be an increasing epidemic as treatment for sequela associated with the disease remain limited [1,2,3,4]. A wide range of peripheral neuropathies, including PDPN, share symptoms of tingling and numbness along with severe, intractable chronic pain for which current therapeutic options have little sustained relief, and most have dose limiting and/or debilitating side effects [2, 5,6,7,8,9]. IMMPACT continues to emphasize the need for more objective, quantifiable biomarker measures with which to validate subjective patient perceptions of pain types, intensities, and therapeutic outcomes. IMMPACT has recommended expanding research using skin biopsies as a highpriority means of identifying objective quantifiable biomarkers to validate subjective patient perceptions of pain severity and therapeutic efficacy [16]
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