Background Transcranial direct current stimulation (tDCS) could counteract the pathophysiological triggers of migraine attacks by modulating cortical excitability. Several pilot randomized controlled trials (RCTs) assessed the efficacy of tDCS for migraine prevention. We reviewed and summarized the state of the art of tDCS protocols for migraine prevention, discussing study results according to the stimulations parameters and patients’ populations. Main body We combined the keywords ‘migraine’, ‘headache’, ‘transcranial direct current stimulation’, and ‘tDCS’ and searched Pubmed, Scopus, and Web of Science, from the beginning of indexing to June 22, 2021. We only included RCTs comparing the efficacy of active tDCS with sham tDCS to decrease migraine frequency, intensity, and/or acute drug utilization. The risk of bias of each RCT was assessed by using the RoB-2 tool (Cochrane Collaboration). Thirteen RCTs (from 2011 to 2021) were included in the review. The included patients ranged from 13 to 135. RCTs included patients with any migraine (n=3), chronic migraine (n=6), episodic migraine (n=3) or menstrual migraine (n=1). Six RCTs used cathodal and five anodal tDCS, while two RCTs compared the efficacy of both cathodal and anodal tDCS with that of sham. In most of the cathodal stimulation trials, the target areas were the occipital regions, with reference on central or supraorbital areas. In anodal RCTs, the anode was usually placed above the motor cortical areas and the cathode on supraorbital areas. All RCTs adopted repeated sessions (from 5 to 28) at variable intervals, while the follow-up length spanned from 1 day up to 12 months. Efficacy results were variable but overall positive. According to the RoB-2 tool, only four of the 13 RCTs had a low risk of bias, while the others presented some concerns. Conclusions Both anodal and cathodal tDCS are promising for migraine prevention. However, there is a need for larger and rigorous RCTs and standardized procedures. Additionally, the potential benefits and targeted neurostimulation protocols should be assessed for specific subgroups of patients.

Migraine is a severe neurovascular disorder of which the pathophysiology is not yet fully understood. Besides the role of inflammatory mediators that interact with the trigeminovascular system, cyclic fluctuations in sex steroid hormones are involved in the sex dimorphism of migraine attacks. In addition, the pituitary-derived hormone prolactin and the hypothalamic neuropeptide oxytocin have been reported to play a modulating role in migraine and contribute to its sex-dependent differences. The current narrative review explores the relationship between these two hormones and the pathophysiology of migraine. We describe the physiological role of prolactin and oxytocin, its relationship to migraine and pain, and potential therapies targeting these hormones or their receptors.In summary, oxytocin and prolactin are involved in nociception in opposite ways. Both operate at peripheral and central levels, however, prolactin has a pronociceptive effect, while oxytocin appears to have an antinociceptive effect. Therefore, migraine treatment targeting prolactin should aim to block its effects using prolactin receptor antagonists or monoclonal antibodies specifically acting at migraine-pain related structures. This action should be local in order to avoid a decrease in prolactin levels throughout the body and associated adverse effects. In contrast, treatment targeting oxytocin should enhance its signalling and antinociceptive effects, for example using intranasal administration of oxytocin, or possibly other oxytocin receptor agonists. Interestingly, the prolactin receptor and oxytocin receptor are co-localized with estrogen receptors as well as calcitonin gene-related peptide and its receptor, providing a positive perspective on the possibilities for an adequate pharmacological treatment of these nociceptive pathways. Nevertheless, many questions remain to be answered. More particularly, there is insufficient data on the role of sex hormones in men and the correct dosing according to sex differences, hormonal changes and comorbidities. The above remains a major challenge for future development.

In migraine patients with a poor response to a calcitonin gene-related peptide monoclonal antibody against the receptor, switching to a calcitonin gene-related peptide monoclonal antibodies against the ligand may be beneficial. This was a long-term real-world prospective analysis conducted in treatment-refractory chronic migraine patients coming from two large tertiary referral headache centres, who did not achieve a meaningful response to erenumab and were switched to fremanezumab. Responders to fremanezumab were considered those who achieved at least 30% reduction in monthly migraine days by month 3, compared to the post-erenumab baseline. Secondary efficacy and disability outcomes were analysed. Thirty-nine patients (female n = 32, 82.1%; median age: 49 years old, IQR = 29.0–56.0) were included. After three months of treatment with fremanezumab, ten out of 39 patients (25.6%) were considered responders. Four of the 11 patients who continued fremanezumab became responders at month 6, increasing the number of responders to 14 patients (35.9%). Responders received a median of 12 injections (IQR = 9.0–18.0) at the time of the analysis. After the last treatment, 13 patients (33.3%) remained responders. The number of mean monthly migraine days significantly decreased from 21.4 at baseline (IQR = 10.7–30.0) to 8.6 (IQR = 3.8–13.9) at the last follow-up. Painkillers intake and HIT-6 score were significantly reduced at the last follow-up. About 1/3 of patients with treatment refractory chronic migraine who have a disappointing response to erenumab and switch to fremanezumab, obtained a meaningful and sustained improvement of their migraine load over time, supporting the appropriateness of this therapeutic approach in clinical practice.