Migraine is a common headache disease, affecting approximately 15% of the population and occurring more commonly in females (Vos et al., 2016). Without effective treatments, migraines can reduce living quality, increase the economic burden, and weaken production capacity (Linde et al., 2012; Vos et al., 2016). Moreover, migraine attacks remain an issue for patients despite the availability of acute and prophylactic treatments (Linde et al., 2013a,b). Meanwhile, relevant studies (Ekkert et al., 2019) confirmed that the visual cortex excitability might be linked to higher disability.

Botulinum-A toxin or botulinum toxin type A (BTX-A) had been demonstrated to relieve pain associated with a variety of conditions, including migraine headaches (Ranoux et al., 2008). It is speculated that this is achieved through blockage of sensory pain signals to the central nervous system, thereby promoting a reduction in central sensitization (Gazerani et al., 2006). It is well established that inflammatory mediators sensitize peripheral pain receptors through a cascade reaction, which in turn leads to the sensitization of central receptors and persistent pain (Gazerani et al., 2006). BTX-A is known to interfere with these inflammatory pathways. In the peripheral nerves, pain stimulation leads to calcitonin gene-related peptide and substance P release, which in turn induces the release of histamine and cytokines, thereby directly sensitizing or activating pain sensation. In addition to acting on peripheral pain-related vasoactive substances and receptors, some experiments have confirmed that BTX-A may directly inhibit central pain transmission, and its mechanism may be similar to endogenous opioids (Mazzocchio and Caleo, 2015). However, Gazerani et al. (2006) found that the BTX-A inhibits peripheral sensitization of nociceptive fibers and indirectly reduces central sensitization. The exact mechanism of BTX-A is still controversial, but existing research has demonstrated that BTX-A had a particular effect on the prevention of chronic migraine attacks, but the mechanism of analgesia is still unclear, and there are still differences between the experimental studies. During the migraine cycle (a period when health and pain alternate), the brain's abnormal functions fluctuate according to specific moments in the cycle itself. During the onset period, migraine brains are characterized by low levels of preactivation of all sensory and associative cortices. The response of the affected cortex to external repeated stimuli was initially low, and then the nerve activity gradually increased as the stimulus continued (de Tommaso et al., 2014).

Based on a six-month study of 162 patients, Binder (1998) filed a patent for the use of BTX-A in the treatment of migraine at the onset of headache symptoms). Subsequently, several clinical studies have confirmed the feasibility and efficacy of this approach (Elkind et al., 2006; Evers et al., 2004; Relja et al., 2007; Silberstein et al., 2000). In 2010, the US Food and Drug Administration approved BTX-A for the treatment of chronic migraine, based on the findings of the PREEMPT studies (Aurora et al., 2010; Diener et al., 2010). To date, the intramuscular formulation of BTX-A is the only treatment approved for the prevention of chronic migraine in the European Union (Frampton and Silberstein, 2018). Uncertainty remains, however, regarding the place of BTX-A among oral pharmacological prophylactics, its role in different migraine subtypes, its dosage, and optimal treatment duration. Questions also persist around which patient-related factors might predict response to different treatment protocols (Clare et al., 2019; Jackson et al., 2012; Teunis, 2019). As a further source of uncertainty, national guidance differs in their recommendations, while guidance from (for example) the European Federation of Neurological Societies has not been updated since 2009 and thus does not mention BTX-A at all ( Negro et al., 2015; Pedraza et al., 2015). Rational use of therapies is important, not only from the healthcare economics perspective but in terms of reducing disability and improving patients’ quality of life. To encapsulate the body of data generated so far on this topic, we performed a systematic review and meta-analysis to investigate the impact of BTX-A as a therapeutic regimen for the management of adult migraine disorders.

This meta-analysis combined 18 studies to confirm that BTX-A can reduce patients’ headache episodes per month. There were, however, some discrepancies in the efficacy of BTX-A that were revealed when we stratified our analysis by treatment duration, with the finding that a significant difference in the change in headache episodes per month between BTX-A and placebo occurred after 16 weeks, but not at 12 or 24 weeks. Despite this, our findings at 12 weeks are similar to those of the recent meta-analysis by (Bruloy et al., 2019), wherein a mean difference in the change of migraine frequency of -0.23 (95 percent CI, -0.47 to 0.02; P = 0.08) was reported. Furthermore, our overall results are consistent with those of Herd et al. (Herd et al., 2019) regarding changes in headache episodes per month. Intramuscular BTX-A for chronic migraine prevention is based on a previous study of its effectiveness in transient muscle relaxation (Burstein et al., 2014; Gooriah and Ahmed, 2015; Simpson, 2004). While our meta-analysis found that patients with episodic migraine did not benefit from BTX-A, it was therapeutically effective in chronic migraine. However, in reviewing the results of original studies of chronic migraine, only one study (Frampton and Silberstein, 2018) showed that the changes in headache episodes per month were significant after treatment with BTX-A, and none of them (Cady et al., 2014; Evers et al., 2004; Lauretti et al., 2014; Sandrini et al., 2011; Vo et al., 2007) was effectively relieved. Of course, in addition to considering the impact of migraine headaches, effective individualized treatment requires the careful evaluation of the clinical features and overall medical history in each chronic migraine patient (Barbanti and Ferroni, 2017).

Regarding safety, this meta-analysis found that treatment-related AEs were significantly increased with BTX-A relative to placebo. These differences remained significant when considering specific complications, including headache, injection-site pain, musculoskeletal stiffness, myalgia, neck pain, paresthesias, muscle weakness, palpebral fissure, and blepharoptosis. Related studies (Herd et al., 2019) have also reported that BTX-A increases treatment-related AEs, but event types were reportedly mild and short-lived.

At present, the consensus of most research institutes is to prevent the onset of a migraine, especially for chronic migraines. Measures to prevent chronic migraines mainly include orally administered drugs, behavioral management techniques, alternative physical therapies, and nutraceutical therapies (Agostoni and Barbanti, 2019). Orally administered medications, such as beta-blockers, anticonvulsants, serotonin antagonists, and calcium-channel blockers, are used in the management of chronic migraine (Sarchielli et al., 2012). If drug interventions are not found to be effective, other preventive approaches may be used (Agostoni and Barbanti, 2019). These include patient education, substance abuse management, lifestyle changes, and management of comorbidities.

This meta-analysis evaluated the efficacy and safety of BTX-A for the management of adult migraine disorders based on systematic review and meta-analysis of published studies on the topic. We demonstrated that BTX-A as a therapeutic regimen can improve the impact of chronic migraine after 16 weeks of therapy, but that this effect is not found in episodic migraine.

LW had full access to all of the data in the research and took responsibility for the integrity of the data and the accuracy of the data analysis. BS and LW designed the research. BS and LW developed and tested the data collection form. BS and LW acquired the data. LW conducted the analysis and interpreted the data. BS and LW drafted the manuscript.

This research was supported by the National Natural Science Foundation of China (No. 81703991).

The authors declare no conflict of interest.