The pluripotential evolution and journey of Botox (onabotulinumtoxinA).

Clinical use of onabotulinumtoxinA evolved based on strategic, hypothesis-driven applications, as well as serendipitous observations by physicians and patients. The success of onabotulinumtoxinA in blepharospasm and strabismus led to its study in other head and neck dystonias, followed by limb dystonia, tremor, and spasticity. The aesthetic use of onabotulinumtoxinA followed initial reports from patients of improved facial lines after injections for facial dystonias and hemifacial spasm. Although patients with dystonias and spasticity regularly reported that their local pain improved after injections, onabotulinumtoxinA was not systematically explored for chronic migraine until patients began reporting headache improvements following aesthetic injections. Clinicians began assessing onabotulinumtoxinA for facial sweating and hyperhidrosis based on its inhibition of acetylcholine from sympathetic cholinergic nerves. Yet another line of research grew out of injections for laryngeal dystonia, whereby clinicians began to explore other sphincters in the gastrointestinal tract and eventually to treatment of pelvic sphincters; many of these sphincters are innervated by autonomic nerves. Additional investigations in other autonomically mediated conditions were conducted, including overactive bladder and neurogenic detrusor overactivity, achalasia, obesity, and postoperative atrial fibrillation. The study of onabotulinumtoxinA for depression also grew out of the cosmetic experience and the observation that relaxing facial muscle contractions associated with negative emotions may improve mood. For approved indications, the safety profile of onabotulinumtoxinA has been demonstrated in the formal development programs and post-marketing reports. Over time, evidence has accumulated suggesting clinical manifestations of systemic effects, albeit uncommon, particularly with high doses and in vulnerable populations. Although onabotulinumtoxinA is approved for approximately 26 indications across multiple local regions, there are 15 primary indication uses that have been approved in most regions, including the United States, Europe, South America, and Asia. This review describes many uses for which AbbVie has not sought and/or received regulatory approval and are mentioned for historical context only.