Cutaneous nerve fiber and peripheral Nav1.7 assessment in a large cohort of patients with postherpetic neuralgia

Abstract

The mechanisms of pain in postherpetic neuralgia (PHN) are still unclear, with some studies showing loss of cutaneous sensory nerve fibers that seemed to correlate with pain level. We report results of skin biopsies and correlations with baseline pain scores, mechanical hyperalgesia, and the Neuropathic Pain Symptom Inventory (NPSI) in 294 patients who participated in a clinical trial of TV-45070, a topical semiselective sodium 1.7 channel (Nav1.7) blocker. Intraepidermal nerve fibers and subepidermal Nav1.7 immunolabeled fibers were quantified in skin punch biopsies from the area of maximal PHN pain, as well as from the contralateral, homologous (mirror image) region. Across the entire study population, a 20% reduction in nerve fibers on the PHN-affected side compared with that in the contralateral side was noted; however, the reduction was much higher in older individuals, approaching 40% in those aged 70 years or older. There was a decrease in contralateral fiber counts as well, also noted in prior biopsy studies, the mechanism of which is not fully clear. Nav1.7-positive immunolabeling was present in approximately one-third of subepidermal nerve fibers and did not differ on the PHN-affected vs contralateral sides. Using cluster analysis, 2 groups could be identified, with the first cluster showing higher baseline pain, higher NPSI scores for squeezing and cold-induced pain, higher nerve fiber density, and higher Nav1.7 expression. While Nav1.7 varies from patient to patient, it does not seem to be a key pathophysiological driver of PHN pain. Individual differences in Nav1.7 expression, however, may determine the intensity and sensory aspects of pain.

Cutaneous targets for topical pain medications in patients with neuropathic pain: individual differential expression of biomarkers supports the need for personalized medicine

“…Previous research has demonstrated ipsilateral SFN among cohorts of patients with PHN, as well as other innervation alterations; however, not all patients with PHN show ipsilateral fiber loss. 24,56,59 Therefore, for this study, we used an enriched cohort of PHN patient biopsies that were known to fit the prevailing notion that a loss of IENF occurs on the ipsilateral (pain) side compared with contralateral (nonpain). The following criteria were used for the selection of the innervation-standardized PHN patient cohort biopsies used for this research study from review of the 271 total PHN patient tissue database:(1) An initial study VAS score ≥5.5 (average VAS score for the 271 patient study was 5.5).(2) A contralateral IENF density that was within one standard deviation of the 271 patient study average (10.3 fibers/mm length of epidermis).(3) A 30% to 50% reduction of the ipsilateral IENF density compared with contralateral IENF density.…”

“…Deidentified PHN human research tissue for this study was collected before any drug treatments from an unrelated clinical study ( ClinTrials.gov NCT02365636/TEVA Pharmaceuticals) where each subject provided a contralateral and ipsilateral biopsy from the same thoracic dermatome. 24 All patients fully consented to the deidentified use of biopsy material in additional basic research projects under the direction of Integrated Tissue Dynamics, LLC (INTiDYN). Previous research has demonstrated ipsilateral SFN among cohorts of patients with PHN, as well as other innervation alterations; however, not all patients with PHN show ipsilateral fiber loss.…”

“…Previous research has demonstrated ipsilateral SFN among cohorts of patients with PHN, as well as other innervation alterations; however, not all patients with PHN show ipsilateral fiber loss. 24,56,59 Therefore, for this study, we used an enriched cohort of PHN patient biopsies that were known to fit the prevailing notion that a loss of IENF occurs on the ipsilateral (pain) side compared with contralateral (nonpain). The following criteria were used for the selection of the innervationstandardized PHN patient cohort biopsies used for this research study from review of the 271 total PHN patient tissue database:…”

“… 2 , 5 , 9 , 22 , 30 , 53 , 66 Small fiber neuropathy (SFN) refers to a loss of small caliber IENF detected within the epidermis and has been demonstrated in several diverse conditions with pain as a chief complaint, including, for example, the neuropathic pain (NP) condition postherpetic neuralgia (PHN) and the largely described as nociplastic pain condition fibromyalgia. 2 , 3 , 24 The epidermis is the richly innervated outermost layer of skin that functions as a sensory transduction organ and includes a nociceptor population, and a β-endorphin–mediated cannabinoid receptor 2 (CB2)–activated inhibitory mechanism among the keratinocytes. 2 , 37 , 41 , 54 , 62 Although somewhat counterintuitive that a loss of nociceptive fibers would lead to enhanced chronic pain, accumulated evidence demonstrates additional peripheral mechanisms involved in the generation of nociceptor hyperexcitability, particularly signaling from cutaneous terminal structures and cells, including epidermal keratinocytes, dermal vasculature, adnexal organs, and/or immune (mast or Langerhans) cells, as means that damaged or remaining innervation becomes hyperactive and/or ectopically active.…”