Haloperidol potentates the antinociceptive effect of buprenorphine and tramadol in rats

This study aimed to evaluate the pharmacological effects of haloperidol on the antinociceptive effects of buprenorphine and tramadol in rats. Dose–response curves were constructed for the individual administration of haloperidol, buprenorphine, and tramadol in rats subjected to the formalin (1%) test. All the compounds demonstrated dose-dependent antinociceptive effects when administered individually. Pharmacological interactions were assessed using an isobolographic method. The doses required to achieve 50% of the maximal antinociceptive effect (ED 50 ) for each drug were combined at a fixed 1 : 1 ratio to establish a combination series of haloperidol + buprenorphine and haloperidol + tramadol. The results showed that buprenorphine achieved a higher maximal antinociceptive effect (98%) compared with tramadol (85%) and haloperidol (84.9%) when administered individually. Isobolographic analysis revealed that the experimental values ( Z exp ) for haloperidol + buprenorphine ( Z add = 27.6 ± 5.5 vs. Z exp = 5.47 ± 1.2) and haloperidol + tramadol ( Z add = 4987.68 ± 651.5 vs. Z exp = 1678.23 ± 89.8) were significantly lower than the theoretical values ( Z add ), indicating synergistic interactions. On the basis of the experimental data, haloperidol potentiated the antinociception in the following order: haloperidol + buprenorphine, followed by haloperidol + tramadol. These findings suggest that such drug combinations could have potential applications in the ongoing research of treatments for chronic pain, depression-related pain, and cancer-associated pain.