Toothache is a frequent cause of emergency department visits for dental complaints (Lewis et al. 2015). Because emergency departments are not equipped to provide definitive dental care, analgesic medications, including nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen combined with opioids, and topical local anesthetics, are frequently prescribed. However, most clinical trials for acute dental pain have been performed in patients undergoing third molar extraction, as the Food and Drug Administration (FDA) considers dental impaction pain a pivotal surgical model for drugs to receive approval for acute pain (Hersh et al. 2020). In contrast, fewer studies have been performed in patients presenting with spontaneous toothache pain, and several logistical challenges are present compared to postoperative dental pain studies: patients with spontaneous toothache pain cannot be scheduled in advance, toothache patients are often at the very highest end of pain intensity at presentation, and the length of the observation period is limited due to the necessity that definitive dental care (endodontic therapy or exodontia) be performed that day. Consequently, the only placebo-controlled trials in toothache pain patients performed to date have studied the safety and efficacy of topical benzocaine (Hersh et al. 2005, 2013). While recently published guidelines for the treatment of acute dental pain recommend ibuprofen (alone or in combination with acetaminophen) and naproxen sodium as first-line drugs, the conclusions for toothache pain for systemic analgesics were all extrapolated from impacted third molar surgery pain data (Carrasco-Labra et al. 2023). In this issue of the Journal of Dental Research, Chrepa et al. (2023) report the results of a phase 2A study investigating the analgesic effects of cannabidiol (CBD) in toothache pain. This study represents the first placebo-controlled trial of a systemic analgesic in toothache pain and is an important proof of concept for a novel pain management strategy in this patient population.