Thermosensory Loss is Correlated with Primary Afferent Nociceptive Fibers Deletion in Postmortem Dorsal Root Ganglion and Spinal Cord in a Cancer Patient Treated with Resiniferatoxin

Pain from advanced cancer is often intractable leading to significant impairment of quality of life. The standard of care for relieving cancer pain often relies on opioids, which can be highly or incompletely efficacious, and cause adverse effects such as addiction and respiratory suppression. A major priority of the pain field is the development of novel non-opioid analgesic strategies to improve patient care. In this study we correlate the clinical presentation of a single well-characterized patient treated with lumbar intrathecal RTX to a molecular phenotype from postmortem DRG and SC tissue collected from this patient at autopsy (approximately 4-5 months after RTX injection). This patient was enrolled in a Phase 1 Study evaluating safety and efficacy of intrathecal RTX treating pain in advanced cancer (NCT00804154). We stained the DRG and SC with markers of nociceptive sensory afferents such as calcitonin gene-related peptide (CGRP) and Substance P (SP) to map the denervation and potential cell loss at different spinal levels. In the SC, a marked decrease in primary afferent-derived SP and CGRP was observed at all rostro-caudal levels, consistent with the clinical presentation showing decreased sensation to heat to all extremities and torso. In the DRG, quantitative cell counts for mRNA expression and nociceptive protein markers showed minimal cell loss consistent with our previous work. Numerical pain rating scorThis clinical observation formed the basis for a reverse translational effort to assess the effects of dose, rate, and volume on RTX spread in the intrathecal space of rats and pigs.