Accepted

Oxaliplatin, the first-line chemotherapeutic agent against colorectal cancer (CRC), induces peripheral neuropathies, which can lead to dose limitation and treatment discontinuation. Downregulation of potassium channels, which involves histone deacetylase (HDAC) activity, has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. MS-275, a class I histone deacetylase inhibitor (HDACi), prevents acute oxaliplatin-induced peripheral neuropathy (OIPN). Moreover, MS-275 exerts anti-tumor activity in several types of cancers, including CRC. We thus hypothesized that MS-275 could exert both a preventive effect against OIPN and potentially a synergistic effect combined with oxaliplatin against CRC development. We first used RNAseq to assess transcriptional changes occurring in DRG neurons from mice treated by repeated injection of oxaliplatin. Moreover, we assessed the effects of MS-275 on chronic oxaliplatin-induced peripheral neuropathy development in vivo on mice and on cancer progression when combined with oxaliplatin, both in vivo on mice and in a mouse model of an orthotopic allograft of the CT26 cell line as well as in vitro in T84 and HT29 human CRC cell lines. We found 741 differentially expressed genes (DEGs) between oxaliplatin- and vehicle-treated animals. While acute OIPN is known as a channelopathy involving HDAC activity, chronic OIPN exerts weak ion channel transcriptional changes and no HDAC expression changes in peripheral neurons from OIPN mice. However, MS-275 prevents the development of sensory neuropathic symptoms induced by repeated oxaliplatin administration in mice. Moreover, combined with oxaliplatin, MS-275 also exerts synergistic antiproliferative and increased survival effects in CT26-bearing mice. Consistently, combined drug associations exert synergic apoptotic and cell death effects in both T84 and HT29 human CRC cell lines. Our results strongly suggest combining oxaliplatin and MS-275 administration in CRC patients in order to potentiate the antiproliferative action of chemotherapy, while preventing its neurotoxic effect.

Burn injury pain manifests as a combination of inflammatory, nociceptive, and neuropathic features. While opioids are the mainstay of burn pain management, non-opioid medications, such as gabapentinoids, have also been considered as they target the central nervous system. Increased opioid adverse events and overdose deaths in the United States led to the 2014 and 2016 guidelines to reduce opioid prescribing and consider alternatives, such as gabapentinoids. In the context of burn, the rate of gabapentinoid prescribing at the national level is unknown and it is unclear whether any shift has occurred in prescribing practices over time. We conducted a population level cohort study of adult burn patients from 2012 to 2018 to evaluate the rates and determinants of gabapentinoid prescribing, with and without opioids. Of 98,001 patients with burn, 22,521 (22.98%) received opioids and/or gabapentinoids (GABA). GABA represented 2.4% of prescriptions in 2012, but increased to 7.2% by 2018, while GABA-opioid co-prescriptions increased from 2.3% to 5.1%. The rate of increase in GABA prescriptions was higher for those aged 50-65 years or residing in the South. After adjustment, GABA was 44% more likely to be prescribed in 2017 and 2018 compared to 2012 and 2013, opioids were 38% less likely, while co-prescribing did not show a statistically significant change. Our study showed a modest increase in gabapentinoids' outpatient prescribing for burn patients after the 2014 and 2016 guidelines, indicating more opportunities for prescribers to expand non-opioid pain management in this population.