Improving pain management for murine orthotopic xenograft models of acute lymphoblastic leukemia.

Abstract

Despite ongoing research, realistic in vitro models for acute lymphoblastic leukemia (ALL) that can mimic the complex pathology are still not available, highlighting the need for continuous animal-based investigation. As part of the 3R principles, constant refinement of animal experiments is mandatory. Therefore, reviewing the effectiveness of used analgesics is essential for animal model-specific refinement. Here we evaluate whether metamizole-previously used in our institute-or tramadol is more suitable as on-demand analgesia in mouse models of ALL. The murine orthotopic xenograft models were induced by intravenous injection of either the human precursor ALL cell lines RS4;11 or SEM into immune-deficient male and female NSG mice. Mice were weighed and checked daily for basic behavior and well-being, while detailed welfare parameters, such as burrowing behavior, nesting activity, perianal temperature, liquid intake, fecal corticosterone metabolites, mouse grimace scale and tumor cell proliferation were monitored weekly. Upon leukemic progression, when signs of pain or discomfort were observed, metamizole (3 mg/ml) or tramadol (1 mg/ml) was administered via drinking water for analgesic treatment, and detailed welfare parameters were assessed daily. Following the initiation of treatment, mice receiving either metamizole or tramadol continued to show a decline in body weight, liquid intake and other welfare parameters, suggesting that neither drug was sufficient to fully counteract the effects of late-stage ALL. Combining the data with the relative severity assessment algorithm revealed that metamizole treatment appeared less effective than tramadol in mitigating the detrimental effects of the disease. Therefore, the opioid tramadol should replace metamizole as the analgesic compound of choice for hematological xenograft models to improve animal welfare in future studies.