Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Prog Brain Res. 2020;255:171-206. doi: 10.1016/bs.pbr.2020.05.013. Epub 2020 Jun 30.
The earliest descriptions of botulism were in the early 19th century, and was reported by the German physician Justinus Kerner. The term "botulism" was derived from the Latin word botulus, indicating its original association with sausages. It took another 150 years or so to come into clinical use. The first clinical application was strabismus, and was developed by the American ophthalmologist Alan B. Scott, whose effort led to the pharmaceutical product known as onabotulinumtoxinA today. The therapeutic benefit in migraine was an incidental finding in a report by the American plastic surgeon William J. Binder, which inspired a series of clinical studies in headache disorders. The doses and injection techniques in the earlier reports were variable, so were the results. It was until the Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) 1 and 2 studies when its efficacy and safety, as well as the indication, i.e., chronic migraine (CM), were ascertained. Even though there were criticisms regarding the heterogeneities in the results between the PREEMPT 1 and 2 studies, the data on efficacy endpoints and safety were generally consistent, which were subsequently confirmed by the open-label extension of the PREEMPT 1 and 2 studies, and three open-label studies, namely the Chronic Migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL), the REal-life use of botulinum toxin for the symptomatic treatment of adults with chronic migraine, measuring healthcare resource utilization, and Patient-reported OutcomeS observed in practice (REPOSE) studies, and the CM Post-Authorization Safety Study (CM PASS) studies. On the other hand, the results were challenged by the Chronification and Reversibility of Migraine (CHARM) study, which involved CM patients with medication overuse. It was concluded that the clinical improvement was attributed to early withdrawal of the overused acute medications, rather than onabotulinumtoxinA injections. However, fundamental differences in the patient profile and methodology between the CHARM and PREEMPT studies existed, and cautious should be exercised when interpreting and comparing the results. According to the practical guidelines and reimbursement regulations in many countries, its use is limited to CM patients, and is reserved for those who fail at least 2-3 preventive medications, due to either lack of efficacy or intolerability. Cessation of treatment is recommended in patients who do not respond to 2-3 injection cycles, or in patients whose headache frequency has dropped to <10-15 days a month. Even in the era of calcitonin-gene-related peptide monoclonal antibodies, onabotulinumtoxinA injection remains a treatment option of reasonable cost-effectiveness in carefully selected patients.
肉毒中毒的最早描述可追溯到 19 世纪初，由德国医生 Justinus Kerner 报道。“肉毒中毒”一词源自拉丁语 botulus，表明其最初与香肠有关。又过了大约 150 年，它才开始在临床上应用。第一个临床应用是斜视，由美国眼科医生 Alan B. Scott 开发，他的努力导致了今天的药物产品——肉毒杆菌毒素 A。偏头痛治疗中的治疗益处是美国整形医生 William J. Binder 报告中的一个意外发现，这激发了一系列头痛疾病的临床研究。早期报告中的剂量和注射技术各不相同，结果也各不相同。直到 III 期预防偏头痛治疗的研究（PREEMPT）1 和 2 研究，其疗效和安全性，以及适应症，即慢性偏头痛（CM）得到了确定。尽管关于 PREEMPT 1 和 2 研究结果的异质性存在批评，但疗效终点和安全性的数据总体上是一致的，随后通过 PREEMPT 1 和 2 研究的开放标签扩展以及三项开放标签研究，即慢性偏头痛 OnabotulinuMtoxinA 延长疗效开放标签（COMPEL）、使用肉毒毒素对成人慢性偏头痛进行症状治疗、衡量医疗资源利用和实践中观察到的患者报告结果（REPOSE）研究以及 CM 授权后安全性研究（CM PASS）研究得到了证实。另一方面，Chronification 和偏头痛逆转（CHARM）研究对结果提出了挑战，该研究涉及药物过度使用的慢性偏头痛患者。研究结论认为，临床改善归因于早期停用过度使用的急性药物，而不是肉毒杆菌毒素 A 注射。然而，CHARM 和 PREEMPT 研究之间在患者特征和方法学方面存在根本差异，在解释和比较结果时应谨慎。根据许多国家的实践指南和报销规定，其使用仅限于 CM 患者，并且仅保留给那些至少对 2-3 种预防性药物无反应或不耐受的患者。对于未对 2-3 个注射周期有反应的患者，或头痛频率已降至每月<10-15 天的患者，建议停止治疗。即使在降钙素基因相关肽单克隆抗体时代，肉毒杆菌毒素 A 注射仍然是在精心挑选的患者中具有合理成本效益的治疗选择。
