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Fig. 1 The overview of experiment design and aims of the present study. This study was divided into two major parts. The first part evaluated the effects of ten selected painkillers on zebrafish behaviors after a caudal fin amputation procedure. Later two painkillers with the best overall performance were selected to be further studied in the next part. In the second part, molecular docking analysis was conducted to measure each painkiller’s binding energy to COX-1 and COX-2. Later, the combination effect of two selected painkillers via oral administration and waterborne exposure was also evaluated, followed by biochemical analysis in fish brain tissue to measure the expression level of several important biomarkers.