Migraine is a severe disabling brain disorder characterized by bouts of unilateral pain resulting from activation of trigeminal sensory neurons and sensitization of nociceptive processing. The frequent use of acute migraine therapies including the triptans, non-steroidal anti-inflammatory drugs and opiates can lead to the development of medication overuse headache (MOH) in migraineurs. MOH is characterised by frequent headache (> 15 days per month) combined with regular overuse of acute migraine therapies. MOH has been ranked the 18th most disabling disorder globally highlighting MOH as a major public health problem. Given the highly disabling vicious cycle of MOH, the poor treatment outcomes and the high rate of recurrence it is critical to understand the potential impact of current and novel acute therapies on MOH development. Therefore, we sought to determine the impact of the commonly used non-steroidal anti-inflammatory drugs (NSAID) ibuprofen and naproxen and the emerging CGRP receptor antagonists (gepants) and 5-HT1F receptor agonists on medication overuse (MO)-like phenotypes in a preclinical model of MOH. Our results demonstrated a differential effect of chronic NSAID exposure, whereby ibuprofen but not naproxen resulted in an MO-like phenotype in mice. In agreement with a beneficial effect of naproxen, we further identified that naproxen was able to block and reverse the induction of triptan-induced MO phenotypes in mice and that ibuprofen and naproxen had differential effects on cyclooxygenase expression. Taken together our data suggests that naproxen is a potential therapeutic target for MOH. With the emergence of novel acute migraine therapies, we sought to determine the potential impact of olcegepant (CGRP receptor antagonist) and LY344864 (5-HT1F receptor agonist) on MO-like phenotypes in mice. Our results demonstrate that LY344864, but not olcegepant induced a MO-like phenotype in mice. As such, we have identified a potential MOH-risk with increased exposure to 5-HT1F agonists (ditans) that has important implications, given the first in class lasmiditan has been recently approved from the FDA for acute treatment for migraine.