Entering the 4th decade of Botox (onabotulinumtoxinA): A narrative review of its development and impact on patients and medicine.

Preface
More than three decades ago, the locally injected neurotoxin known today as Botox (onabotulinumtoxinA) was granted initial regulatory approval in the United States. This marked the first time a botulinum toxin-containing product was approved for patient treatment and led to a multi-decade development journey that has included tens of thousands of patients and thousands of physicians across numerous medical specialties. Today, onabotulinumtoxinA is approved in 100 countries for 15 main indications involving pediatric patients, adolescents, and adults, as outlined in the third article of this supplement.
Development began with strabismus, a condition in which onabotulinumtoxinA—then known as Oculinum—reduces contraction of the extraocular muscles and promotes ocular realignment.[1] At the same time, onabotulinumtoxinA was approved for the treatment of blepharospasm, where it reduces muscle contractions that force eyelid closure. This was followed by approval for cervical dystonia to reduce the severity of abnormal head position and neck pain. In addition to its action on cholinergic neurons that innervate muscles, onabotulinumtoxinA inhibits release of acetylcholine from autonomic cholinergic neurons, which led to its investigation and approval for axillary hypherhidrosis to reduce severe underarm sweating. OnabotulinumtoxinA was subsequently approved to reduce pain in patients suffering from chronic migraines; decrease incontinence in patients with detrusor overactivity and overactive bladder; and provide relief from spasticity, in which patients may experience disfiguring and often painful muscle contractions.[2,3] Approval of onabotulinumtoxinA for glabellar, forehead, and crow’s feet lines has transformed the treatment approach in aesthetic medicine. These indications are approved in adults, with some pediatric age groups approved for strabismus, blepharospasm, spasticity and neurogenic detrusor overactivity.
The work described in this supplement was made possible by innumerable patients, physicians, and scientists who contributed their time, observations, insights, research and drug development expertise. Several of the indications began serendipitously with patients reporting their experiences to physicians who then conducted studies. Additionally, patients with conditions for which other treatment options were insufficient pressed their physicians to explore onabotulinumtoxinA. Several of the indications began with physicians and scientists intentionally evaluating onabotulinumtoxinA in novel conditions based on a logical extension of its local mechanism of action, whereas others challenged conventional wisdom. Researchers not only elucidated several mechanisms of action for onabotulinumtoxinA, but also used it as a tool to improve understanding of disease and health, including synaptic function and motor and sensory programming. Indeed, onabotulinumtoxinA has influenced our perception of disease pathophysiology, with clinical findings informing basic science research and vice-versa.
The development history of onabotulinumtoxinA is one of innovation, not only by the many patients, physicians, and scientists, but also by Allergan, which needed to develop approval programs for which no regulatory precedents existed. In many of the indications for which onabotulinumtoxinA is approved, there were no prior standards or templates to guide development toward approval. Allergan worked internally and externally with physicians to develop dosing and injection paradigms, outcome measures, and precise disease definitions that reflected clinical practice and were acceptable to regulatory agencies. This was particularly challenging for conditions such as chronic migraine and spasticity that are complex, heterogeneous, and difficult to measure, with similar challenges for the aesthetic indications which were novel at the time.
In this supplement, some of the many pioneers and experts discuss their early experiences, challenges, and advances with onabotulinumtoxinA (Fig. 1). The historical narrative was compiled based on review of the literature and interviews with the authors. The articles include investigation of onabotulinumtoxinA's mechanism of action, and the development of clinical indications for therapeutic and aesthetic indications. Today, Allergan continues as Allergan Aesthetics and AbbVie, maintaining its commitment to developing patient-centric indications, as outlined in the final article in this supplement on future innovations.
In closing, I would like to thank the authors for their participation, expertise, and wisdom. This especially includes Dr. Alan Scott—the clinician who first administered botulinum toxin type A (as Oculinum) to patients. Dr. Scott passed away on December 16, 2021 at age 89, 32 years after onabotulinumtoxinA was first approved by the FDA for clinical use. I would also like to thank the leaders at Allergan who had the foresight to fund the development of onabotulinumtoxinA, as well as the multitude of cross-functional project team members who applied their skills tirelessly to move development through global regulatory approvals. Thanks also to the many additional researchers and clinicians not included as authors who have studied botulinum toxins over the years, whose work has benefited patients worldwide. Furthermore, the advances described would not have been possible without the generous engagement with patients, who have enabled and informed this journey.[4]