Intraoperative abobotulinumtoxinA alleviates pain after surgery and improves general wellness in a translational animal model

Abstract

Pain after surgery remains a significant healthcare challenge. Here, abobotulinumtoxinA (aboBoNT-A, DYSPORT) was assessed in a post-surgical pain model in pigs. Full-skin-muscle incision and retraction surgery on the lower back was followed by intradermal injections of either aboBoNT-A (100, 200, or 400 U/pig), vehicle (saline), or wound infiltration of extended-release bupivacaine. We assessed mechanical sensitivity, distress behaviors, latency to approach the investigator, and wound inflammation/healing for 5–6 days post-surgery. We followed with immunohistochemical analyses of total and cleaved synaptosomal-associated protein 25 kD (SNAP25), glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor protein-1(Iba1), calcitonin gene-related peptide (CGRP) and substance P (SP) in the skin, dorsal root ganglia (DRG) and the spinal cord of 400 U aboBoNT-A- and saline-treated animals. At Day 1, partial reversal of mechanical allodynia in aboBoNT-A groups was followed by a full reversal from Day 3. Reduced distress and normalized approaching responses were observed with aboBoNT-A from 6 h post-surgery. Bupivacaine reversed mechanical allodynia for 24 h after surgery but did not affect distress or approaching responses. In aboBoNT-A-treated animals cleaved SNAP25 was absent in the skin and DRG, but present in the ipsilateral dorsal horn of the spinal cord. In aboBoNT-A- versus saline-treated animals there were significant reductions in GFAP and Iba1 in the spinal cord, but no changes in CGRP and SP. Analgesic efficacy of aboBoNT-A appears to be mediated by its activity on spinal neurons, microglia and astrocytes. Clinical investigation to support the use of aboBoNT-A as an analgesic drug for post-surgical pain, is warranted.

Cellular and molecular mechanisms involved in the analgesic effects of botulinum neurotoxin: A literature review

“…Additionally, pain conditions in humans are often characterized by non‐evoked pain, whereas most evidence for evaluating pain‐related behaviors relates to evoked pain. Therefore, evaluating spontaneous (non‐evoked) pain tests, such as the Distress Behavior Score Test, can improve the translational and generalizable nature of results related to the analgesic mechanisms of BoNTs (Cornet, 2022).…”

“…Translational models in large species can help to better understand the optimal conditions for the analgesic effect of BoNTs, and provide direct support to clinicians. (Cornet, 2022).…”

“…For instance, in a study conducted by Cornet et al in 2022, the analgesic effect of BoNT/A on a postoperative pain model in pigs was found to be similar and correlated with some examples of its clinical use. The researchers demonstrated that intraoperative administration of BoNT/A at concentrations of 100, 200, and 400 U reversed mechanical allodynia and induced prolonged pain relief, in a dose‐ and time‐dependent manner (Cornet, 2022). Consistent with these animal results, a clinical study conducted on patients undergoing mastectomy showed that intraoperative intramuscular injection of 100 U BoNT/A significantly alleviated immediate postoperative pain (Layeeque et al, 2004).…”

Intramuscular Botulinum Neurotoxin Serotypes E and A Elicit Distinct Effects on SNAP25 Protein Fragments, Muscular Histology, Spread and Neuronal Transport: An Integrated Histology-Based Study in the Rat

“…Although this must be experimentally confirmed, we can postulate that the lower ability of BoNT/E to undergo such a phenomenon could be due to a potential targeting of other types of cargo less involved in neuronal transport. Many works support the importance of neuronal transport in the antinociceptive activity of BoNT/A [20,45,46]. As such behavior is limited in BoNT/E, it might restraint its therapeutic use for such conditions, maybe explaining the paucity of published data on the subject.…”