Pamabrom is a diuretic that is effective in treating premenstrual syndrome and primary dysmenorrhea. The aim of this study was to examine the effect of metformin and modulators of the opioid receptor–nitric oxide (NO)–cyclic guanosine monophosphate (cGMP)–K⁺ channel pathway on the local antinociception induced by pamabrom. The rat paw 1% formalin test was used to assess the effects. Rats were treated with local administration of pamabrom (200–800 µg/paw) or indomethacin (200–800 µg/paw). The antinociception of pamabrom or indomethacin was evaluated with and without the local pretreatment of the blockers. Local administration of pamabrom and indomethacin produced dose-dependent antinociception during the second phase of the test. Local pretreatment of the paws with naloxone (50 µg/paw), l-nitro-arginine methyl ester (10–100 µg/paw), or 1 H-(1,2,4)-oxadiazolo[4,2- a]quinoxalin-1-one (10–100 µg/paw) reverted the antinociception induced by local pamabrom, but not of indomethacin. Similarly, the K⁺ channel blockers glibenclamide, glipizide, 4-aminopyridine, tetraethylammonium, charybdotoxin, or apamin reverted the pamabrom-induced antinociception, but not of indomethacin. Metformin significantly blocked the antinociception of pamabrom and indomethacin. Our data suggest that pamabrom could activate the opioid receptor–NO–cGMP–K⁺ channel pathway to produce its peripheral antinociception in the formalin test. Likewise, a biguanide-dependent mechanism could be activated by pamabrom and indomethacin to generate antinociception.