 Chronic migraine is defined as having at least 15 monthly headache days, of which eight or more are migraine days. This high attack frequency can seriously impair everyday activities and reduce quality of life. Unfortunately, the disease's complexity makes treatment difficult, and many patients have far more than 15 monthly headache days. Two approved preventive treatments for chronic migraine include onopoculinum toxin A and antibody-based inhibitors of calcitonin gene-related peptide, or CGRP. Onopoculinum toxin A is administered to muscles surrounding the head and neck and near-century nerves. At the nerve terminal, it disrupts pain signals by reducing synaptic release of various neurotransmitters and neuropeptides, including CGRP, and by inhibiting insertion of pain-sensitive ion channels. In contrast, CGRP inhibitors in the form of monoclonal antibodies primarily act directly on CGRP receptors or the CGRP ligand and prevent ligand to receptor binding. Preclinical data suggests that the two types of agents inhibit different types of pain fibres implicated in migraine. Onopoculinum toxin A primarily inhibits C fibres, while CGRP inhibitors primarily inhibit A delta fibres. The different mechanisms of action suggest that adding CGRP inhibitors to onopoculinum toxin A treatment may produce additive or synergistic effects, which could be useful for patients who don't achieve sufficient relief from onopoculinum toxin A alone due to disease severity. Clinical reports have indicated benefits of this combination therapy, but no randomized controlled trials have been performed. A retrospective longitudinal chart review recently assessed the effects of onopoculinum toxin A treatment and subsequent combination treatment with CGRP inhibitors and onopoculinum toxin A among 257 patients at a single centre. Safety, tolerability and outcome measures were assessed for up to one year after the CGRP inhibitors were prescribed. Onopoculinum toxin A alone effectively decreased headache frequency and the addition of a CGRP inhibitor significantly reduced the number of monthly headache days even further at all visits. Combined treatment also resulted in significantly lower headache intensity scores at all visits and clinically meaningful improvements in migraine-related disability over 6 to 12 months, compared with the baseline values achieved with onopoculinum toxin A alone. The combination treatment regimen was well tolerated, with no new safety signals reported. The most common adverse event was constipation, which was reported primarily by patients receiving the CGRP inhibitor IRINUMAB. Approximately one quarter of patients discontinued one or both treatments, primarily CGRP inhibitors. Lack of insurance reimbursement was the most common reason for CGRP inhibitor discontinuation, followed by lack of effect. Additional studies, including controlled trials, are warranted to confirm the findings and to address the limitations of this retrospective study. Overall, however, this real-world study did not identify safety concerns with adding CGRP inhibitors to onopoculinum toxin A treatment. And suggests that the combination provides clinically meaningful benefits for patients with chronic migraine.