Antinociceptive synergism upon the joint use of methadone and Phα1β in a model of cancer-related pain in C57BL/6J mice.

UNLABELLED: 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.

AIMS: We here evaluate the antinociceptive interaction and adverse events of methadone combined with recombinant Phα1β, an analgesic toxin from Phoneutria nigriventer.

MAIN

METHODS

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.

KEY FINDINGS: 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.

SIGNIFICANCE: Combinatorial treatment with Phα1β and methadone produces synergistic analgesic potentiation with potential implications to pain treatment even under opioid tolerance conditions.