The use of opioids for migraine is still controversial. Evidence-based guidelines do not recommend opioids as first-line treatment of migraine attacks, while clinical and epidemiological surveys demonstrate that the use of opioids is associated with more severe headacherelated disability, symptomology and comorbidities, and greater health-care resource utilization. There are concerns that opioids may be misused or abused, leading to opioid abuse or dependence and migraineurs are particularly prone and at risk for the development of chronic daily headache from opioids overuse. Since clinical and preclinical studies evidence a pathophysiological role of opioids in migraine progression, opioids should be avoided in migraine patients.The role of opioids in clinical practice for migraine: the state-of-the-art Migraine is a common disabling neurologic disorder, characterized by recurrent headache attacks manifesting with unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea and/or photophobia and phonophobia [1]. The goals of acute migraine treatments are to treat attacks rapidly and consistently without recurrence, restore the patient's ability to function, minimize the use of back-up and rescue medications, optimize self-care and reduce subsequent use of resources, be cost-effective for overall management, and have minimal or no adverse events [2]. Acute treatments used for migraine include nonspecific agents such as aspirin, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and barbiturates among others, as well as migraine-specific medications, including ergot alkaloids and triptans [2]. International guidelines recommend triptans and NSAIDs as first-line treatment of migraine attacks [2][3][4]. Use of opioids for treatment of migraine is controversial. Despite evidence-based guidelines do not recommend opioids as first-line treatment of migraine attacks [2][3][4], and no randomized controlled trial has shown any significant effect of opioids on migraine attacks when pain-free was the primary end-point of the study [5], their use in clinical practice [6][7][8] and, even more, in emergency departments (EDs) is very large, especially in USA and Canada [9,10]. Moreover, among studies about the efficacy of opioids as rescue medication for acute migraine in EDs recently revised, only one evidenced a superiority of meperidina 75 mg i.m. versus ketorolac 30 mg i.m., three reported superiority of competitors and eight reported similar results for opioids versus competitors such as DHE, metoclopramide, chlorpromazine, droperidol, and ketorolac [5]. In any case, opioids did not adequately restore the patient's ability to function. The negative impact of opioids on migrainous population is reported in several clinical and epidemiological studies. In fact, opioids use for migraine resulted associated with more severe headache-related disability, symptomology, and comorbidities (primarily, psychiatric, and cardi...