This study aimed to evaluate the secondary outcomes of gender and arch and their impact on pain reduction following initial endodontic therapy. 185 medications, including placebo were prepared, and 170 participants completed the trial. Group 1, received a single dose of Paracetamol alone (G-1), Group 2 received combined Ibuprofen/Paracetamol (G-2). Group 3 received combined Mefenamic acid/Paracetamol (G-3), group 4 received combined Diclofenac K/Paracetamol (G-4) and Group 5 received a placebo (G-5). There were no statistically significant differences in pain reduction between males and females whilst there were statistically significant differences between them and the placebo group. All combinations of Paracetamol performed better in pain reduction than the placebo among females, while there were no statistically significant differences among males. In conclusion, there were no differences in pain reduction between males and females, and arch for the tested analgesics taken immediately following initial endodontic therapy in teeth with irreversible pulpitis.