Dr. Lipton et al. examined the prevalence and associated risk factors of opioid use among respondents in the Chronic Migraine Epidemiology and Outcomes study, a cross-sectional, longitudinal web-based study. Of the 2,388 respondents who were using acute prescription medications for migraine, more than one-third used or kept opioids on hand, contrary to guidance. Male sex, high body mass index, allodynia, increasing monthly headache frequency, Total Pain Index score, anxiety, depression, cardiovascular comorbidities, and emergency or urgent care use for headache in the previous 6 months were associated with opioid use. In response, Dr. Gupta cites his experiences in headache care in India and the United Arab Emirates and suggests intravenous metoclopramide as an alternative to opioid use in patients with severe migraine headaches, noting that it can provide analgesia through arginine-vasopressin and opioid release. Noting the different potential psychological effects of mu and delta opioid receptors and arguing that consensus statements and guidelines are insufficient to overcome the opioid abuse crisis, Dr. Gupta emphasizes the importance of understanding migraine pathophysiology and studying nonopioid medications such as metoclopramide. In another response, Dr. Blumenfeld notes that although this study demonstrates that patients using opioids are worse off in many domains, the causal directions cannot be determined. Dr. Blumenfeld posits that worsening headache likely came first, leading to initial opioid use and wonders whether a lack of education about alternative treatment options, as well as misdiagnosis and poor prescribing of migraine-specific medications, may be the real issue here. In a third response, Dr. Minen compares the study with previous work showing that patients presenting to a headache center reported emergency department providers as being the first to prescribe their opioids, and she advocates for better training for emergency and urgent care physicians in headache management. Dr. Minen also notes the need for more headache-specific training for pain specialists because opioid users are more likely to have their headaches managed by such specialists (versus neurologists or headache specialists) and cites ongoing efforts by the American Academy of Pain Medicine and the Pain Medicine journal that are addressing this issue. Dr. Minen also argues that neurologists or headache specialists may be best suited for managing patients with migraine and cardiovascular comorbidities, being more familiar with nonopioid options. Responding to these comments, the authors agree that opioid treatment of migraine may be particularly problematic in the United States and that intravenous metoclopramide is an important nonopioid option for emergency migraine care. They note that nonsteroidal anti-inflammatory drugs, triptans, gepants, ditans, and neuromodulation are also important acute treatment options. They acknowledge that they cannot determine the causal sequence linking opioid use to migraine features and comorbidities but note that in animal models, prolonged opioid exposure can produce latent sensitization and long-lasting changes to descending pain modulation, suggesting mechanistic links for how opioid use may worsen headaches. They suggest that longitudinal studies with close follow-up and daily diaries may help resolve the causal sequence. The authors suggest that gepants, on the other hand, may not exacerbate headache because they do not produce latent sensitization and that such acute agents may be helpful in longitudinal studies. Finally, they agree that additional training and education in headache management is important for emergency and urgent care physicians and pain specialists. This exchange highlights 3 important aspects of tackling opioid use among patients with migraine—the challenges of disentangling various elements in the causal chain; the importance of high-quality, accessible headache-specific education; and the promising role of the growing armamentarium of migraine-specific acute therapies in mitigating opioid use.