Administration of CYP3A4 inhibitors (i.e., PIs, integrase inhibitors) can not only increase the plasma opioid concentrations and prolong analgesic effects, but they might also cause adverse opioid-induced effects, e.g., respiratory depression [52,53].However, administration of CYP3A4 inducers (NNRTIs) can decrease the plasma opioid concentrations, leading to therapeutic failure and onset of a withdrawal syndrome in patients who developed physical dependence to tramadol [51]. Here, CYP3A4 is linked to substance withdrawal syndrome.