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Opioids are the first-line treatment for cancer pain. Incomplete pain relief and the high rate of adverse effects of these compounds bring a need to combine them with other drugs acting on different targets. We here evaluate the antinociceptive interaction and adverse events of methadone combined with recombinant Phα1β, an analgesic toxin from Phoneutria nigriventer. Melanoma was produced by intraplantar inoculation of B16-F10 cells into the right paw. von Frey filaments measured the paw-withdrawal threshold after administration of methadone, Phα1β, and their combination. The degree of interaction was evaluated using isobolographic analysis. Spontaneous performance and forced motor performance were assessed with the open-field and rotarod tests, respectively. Intestinal function was evaluated by the distance traveled by charcoal and opioid tolerance was induced by daily morphine injections. Co-administration of Phα1β with methadone synergistically reverses the melanoma-induced mechanical hypersensitivity. No motor alterations were observed but mild alterations on intestinal function after treatment with the combination that was also capable of restoring morphine analgesia in the tail-flick test after an opioid-induced tolerance. Combinatorial treatment with Phα1β and methadone produces synergistic analgesic potentiation with potential implications to pain treatment even under opioid tolerance conditions. [ABSTRACT FROM AUTHOR]