Effective management of chronic pain is demanded by ethical as well as medical considerations. Although opioid analgesics remain among the most effective pharmacotherapies for ameliorating many types of pain, their use is clouded by concerns regarding their addictive properties, underscored by the current epidemic of prescription opioid abuse and attendant deaths. Medicinal harnessing of endogenous opioid antinociception could provide a strategy for continuing to take advantage of the powerful antinociceptive properties of opioids while avoiding their abuse potential. Based on our studies of endogenous mechanism that suppress and facilitate spinal endomorphin 2 antinociception over the rat reproductive cycle, we identified multiple signaling molecules that could serve as targets for activating endogenous opioid analgesia for chronic pain management in women. Our findings emphasize the need for a precision medicine approach that includes stage of menstrual cycle as an important determinant of drug targets for (activating/harnessing) endogenous opioid antinociceptive systems/ capabilities. Utilization of drugs that harness endogenous opioid antinociception in accordance with varying physiological states represents a novel approach for effective pain management.