(241) Gabapentin Efficacy in Chronic and Vaso-Occlusive Crises-Induced Acute Sickle Cell Disease Pain

Abstract

Pain is the leading cause of hospitalization for patients with sickle cell disease (SCD). Currently, opioids are the main therapy for both chronic “steady state” SCD pain and acute pain that results from vaso-occlusive crises. However, opioids are often ineffective at fully alleviating pain, are associated with unwanted side effects, and do not target the underlying pain mechanism. Thus, new pain therapies are desperately needed for those suffering from SCD pain. Recent quantitative sensory testing in patients and electrophysiological studies in mouse models have identified a neuropathic component of SCD pain; SCD patients and mice exhibit robust mechanical and cold hypersensitivity that is further exacerbated following a vaso-occlusive event. As a result, we tested the analgesic effects of gabapentin, one of the first line therapies for neuropathic pain, in male and female transgenic SCD mice. A single dose of gabapentin (30 mg/kg) alleviated steady state mechanical hypersensitivity in the hindpaw but had no effect on steady state cold hypersensitivity, deep muscle pain, or facial mechanical hypersensitivity. In a separate experiment, gabapentin was administered daily for 4 weeks to model neuropathic pain patient therapy. This chronic administration did not alleviate steady state mechanical hypersensitivity, cold hypersensitivity, or deep muscle pain in SCD mice. However, chronic gabapentin treatment did prevent hypoxia-induced exacerbation of mechanical hypersensitivity in SCD mice. Notably, a single dose of gabapentin administered shortly after hypoxia treatment alleviated ischemia-induced mechanical hypersensitivity to a greater extent than chronic gabapentin treatment. Finally, the effects of gabapentin on spontaneous pain-like behaviors and spontaneous neuronal activity were assessed using conditioned place preference and ex vivo skin nerve recordings respectively. Collectively, these data demonstrate that the drivers of acute vaso-occlusive crisis pain and chronic mechanical hypersensitivity may be caused by different factors, the former of which may be alleviated by gabapentin treatment.