Title: A feasibility study investigating novel longitudinal cutaneous markers of neuropathic pain
Funder: The Academy of Medical Sciences

Abstract: Neuropathic pain is a prevalent, disabling condition associated with many aetiologies. No interventions are available to prevent neurological injury associated with neuropathic pain and analgesic options are limited. Lack of access to human tissue from the nervous system limits exploration of pathogenesis and monitoring response to therapy. Intra-epidermal nerve fibre density (IENFD) loss in skin is a diagnostic tool for small fibre neuropathy but correlates poorly with sensory function and pain, and provides minimal information about pathogenesis. A recent study identified a novel cutaneous glial cell that modulates pain behaviours in rodents, and small human studies have now quantified changes in non-neuronal cutaneous cells that correlate with nerve dysfunction. Association of such markers with patient-reported outcomes and an understanding of their contribution to the initiation, as we all as persistence, of pain is required. Since most neuropathic pain syndromes are insidious in onset, critical illness, such as sepsis, offers a unique model to explore longitudinal changes in nerve injury. Severe IENFD loss occurs within days of, and pain is prevalent following, ICU admission. However, little is known about the role of cutaneous cells in critical illness and any association with nerve function. This is a feasibility study aiming to: • Determine ability to conduct skin biopsies/sensory phenotyping in ICU environment. • Identify novel, longitudinal cutaneous markers with potential to predict risk of neuropathic pain in a full-scale study It involves collecting skin biopsies for immunohistochemical interrogation, testing of sensory thresholds and completion of symptom questionnaires during, and following, critical illness.

Lay abstract: Pain that arises as a result of injury to the nervous system, called ‘neuropathic pain’ effects between 7-10% of the population. It is particularly disabling and very few treatment options are available to prevent or manage the condition. This is in part due to the fact that little is known about the processes involved in nerve injury. Often the condition develops slowly, and symptoms start after substantial nerve damage has occurred. Neuropathic pain can occur during and following severe illness requiring intensive care unit (ICU) admission. During critical illness, onset of nerve injury is fast, and changes can be tracked over time, offering a unique opportunity to monitor nerve injury and recovery. Nerve injury can be assessed by examining specific features of nerve and non-nerve cells in the skin using a tiny biopsy, but these features are newly identified and limited studies in patients exist. It is also important to check that changes in the skin match with symptoms reported by patients. Ultimately this could be used to predict risk of developing neuropathic pain, and inform treatment to prevent nerve injury. This study aims to determine whether patients are willing and able to participate in a study during and following ICU admission where they will be asked to provide small skin samples, undergo testing to report how they perceive temperature, pressure and vibration and report their experience of pain. It will also inform exactly what skin structures could be used as risk predictors for pain in a future larger study.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL