Editing Botulinum toxin (section)

==Research==

===Blepharospasm and strabismus===
{{See also|Botulinum toxin therapy of strabismus}}

University-based ophthalmologists in the US and Canada further refined the use of botulinum toxin as a therapeutic agent. By 1985, a scientific protocol of injection sites and dosage had been empirically determined for treatment of [[blepharospasm]] and strabismus.<ref>{{cite journal |vauthors = Flanders M, Tischler A, Wise J, Williams F, Beneish R, Auger N |title = Injection of type A botulinum toxin into extraocular muscles for correction of strabismus |journal = Canadian Journal of Ophthalmology. Journal Canadien d'Ophtalmologie |volume = 22 |issue = 4 |pages = 212–217 |date = June 1987 |pmid = 3607594 }}</ref> Side effects in treatment of this condition were deemed to be rare, mild and treatable.<ref>{{cite journal | vauthors =  | title = Botulinum toxin therapy of eye muscle disorders. Safety and effectiveness. American Academy of Ophthalmology | journal = Ophthalmology | volume = 96 | issue = Suppl 37-41 | pages = 37–41 | date = September 1989 | pmid = 2779991 | doi = 10.1016/s0161-6420(89)32989-7 }}</ref> The beneficial effects of the injection lasted only four to six months. Thus, blepharospasm patients required re-injection two or three times a year.<ref>{{cite journal |vauthors = Hellman A, Torres-Russotto D |title = Botulinum toxin in the management of blepharospasm: current evidence and recent developments |journal = Therapeutic Advances in Neurological Disorders |volume = 8 |issue = 2 |pages = 82–91 |date = March 2015 |pmid = 25922620 |pmc = 4356659 |doi = 10.1177/1756285614557475 }}</ref>

In 1986, Scott's micromanufacturer and distributor of Botox was no longer able to supply the drug because of an inability to obtain product liability insurance. People became desperate, as supplies of Botox were gradually consumed, forcing him to abandon people who would have been due for their next injection. For a period of four months, American blepharospasm patients had to arrange to have their injections performed by participating doctors at Canadian eye centers until the liability issues could be resolved.<ref name="Boffey_1986">{{Cite news |vauthors=Boffey PM |date=14 October 1986 |title=Loss Of Drug Relegates Many To Blindness Again |work=[[The New York Times]] |url=https://www.nytimes.com/1986/10/14/science/loss-of-drug-relegates-many-to-blindness-again.html |access-date=14 July 2010 |archive-date=26 January 2011 |archive-url=https://web.archive.org/web/20110126045116/http://www.nytimes.com/1986/10/14/science/loss-of-drug-relegates-many-to-blindness-again.html |url-status=live }}</ref>

In December 1989, Botox was approved by the US FDA for the treatment of strabismus, blepharospasm, and [[hemifacial spasm]] in people over 12 years old.<ref name=alg>{{cite web |date=30 April 2009 |title=Re: Docket No. FDA-2008-P-0061 |publisher=U.S. [[Food and Drug Administration]] (FDA) |url=https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/UCM143989.pdf |access-date=26 July 2010 |archive-url=https://web.archive.org/web/20100706104512/https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/UCM143989.pdf |archive-date=6 July 2010 |url-status=dead}} {{PD-notice}}</ref>

In the case of treatment of [[infantile esotropia]] in people younger than 12 years of age, several studies have yielded differing results.<ref name="Ocampo_2012">{{cite web |vauthors=Ocampo VV, Foster CS |url=http://emedicine.medscape.com/article/1198876-treatment#showall |title=Infantile Esotropia Treatment & Management |publisher=[[Medscape]] |date=30 May 2012 |access-date=6 April 2014 |archive-date=28 November 2014 |archive-url=https://web.archive.org/web/20141128091146/http://emedicine.medscape.com/article/1198876-treatment#showall |url-status=live }}</ref><ref>{{cite journal |vauthors = Koudsie S, Coste-Verdier V, Paya C, Chan H, Andrebe C, Pechmeja J, Leoni S, Korobelnik JF |title = [Long term outcomes of botulinum toxin injections in infantile esotropia] |journal = Journal Français d'Ophtalmologie |volume = 44 |issue = 4 |pages = 509–518 |date = April 2021 |pmid = 33632627 |doi = 10.1016/j.jfo.2020.07.023 |s2cid = 232058260 }}</ref>

===Cosmetic===<!-- Much of this is already covered under history – should be merged/removed -->

The effect of botulinum toxin type-A on reducing and eliminating forehead wrinkles was first described and published by Richard Clark, a plastic surgeon from [[Sacramento, California]]. In 1987 Clark was challenged with eliminating the disfigurement caused by only the right side of the forehead muscles functioning after the left side of the forehead was paralyzed during a facelift procedure. This patient had desired to look better from her facelift, but was experiencing bizarre unilateral right forehead eyebrow elevation while the left eyebrow drooped and she emoted with deep expressive right forehead wrinkles while the left side was perfectly smooth due to the paralysis. Clark was aware that botulinum toxin was safely being used to treat babies with strabismus and he requested and was granted FDA approval to experiment with botulinum toxin to paralyze the moving and wrinkling normal functioning right forehead muscles to make both sides of the forehead appear the same. This study and case report on the cosmetic use of botulinum toxin to treat a cosmetic complication of a cosmetic surgery was the first report on the specific treatment of wrinkles and was published in the journal ''Plastic and Reconstructive Surgery'' in 1989.<ref name="Clark_1989">{{cite journal |vauthors = Clark RP, Berris CE |title = Botulinum toxin: a treatment for facial asymmetry caused by facial nerve paralysis |journal = Plastic and Reconstructive Surgery |volume = 84 |issue = 2 |pages = 353–355 |date = August 1989 |pmid = 2748749 |doi = 10.1097/01.prs.0000205566.47797.8d }}</ref> Editors of the journal of the American Society of Plastic Surgeons have clearly stated "the first described use of the toxin in aesthetic circumstances was by Clark and Berris in 1989."<ref name="Rohrich_2003" />

J. D. and J. A. Carruthers also studied and reported in 1992 the use of botulinum toxin type-A as a cosmetic treatment.[78] They conducted a study of participants whose only concern was their glabellar forehead wrinkle or furrow. Study participants were otherwise normal. Sixteen of seventeen participants available for follow-up demonstrated a cosmetic improvement. This study was reported at a meeting in 1991. The study for the treatment of [[glabella]]r frown lines was published in 1992.<ref name="Carruthers JD 19922" /> This result was subsequently confirmed by other groups (Brin, and the Columbia University group under Monte Keen<ref name="Keen_1994">{{cite journal |vauthors = Keen M, Kopelman JE, Aviv JE, Binder W, Brin M, Blitzer A |title = Botulinum toxin A: a novel method to remove periorbital wrinkles |journal = Facial Plastic Surgery |volume = 10 |issue = 2 |pages = 141–146 |date = April 1994 |pmid = 7995530 |doi = 10.1055/s-2008-1064563 |s2cid = 29006338 }}</ref>). The FDA announced regulatory approval of botulinum toxin type A (Botox Cosmetic) to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines) in 2002 after extensive clinical trials.<ref>{{cite web |date=29 October 2009 |title=Botulinum Toxin Type A Product Approval Information – Licensing Action 4/12/02 |publisher=U.S. [[Food and Drug Administration]] (FDA) |url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080509.htm |access-date=26 July 2010 |archive-url=https://web.archive.org/web/20100308063343/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080509.htm |archive-date=8 March 2010 |url-status=dead}} {{PD-notice}}</ref> Well before this, the cosmetic use of botulinum toxin type A became widespread.<ref>{{cite journal |doi=10.1509/jm.10.0406 |title=How Doppelgänger Brand Images Influence the Market Creation Process: Longitudinal Insights from the Rise of Botox Cosmetic |year=2012 |vauthors=Giesler M |journal=Journal of Marketing |volume=76 |issue=6 |pages=55–68 |s2cid=167319134}}</ref> The results of Botox Cosmetic can last up to four months and may vary with each patient.<ref>{{cite web |date=22 January 2014 |title=Botox Cosmetic (onabotulinumtoxinA) Product Information |publisher=[[Allergan]] |url=http://www.botox.com/ |access-date=1 March 2018 |archive-date=21 July 2021 |archive-url=https://web.archive.org/web/20210721001858/https://www.botox.com/ |url-status=live }}</ref> The US [[Food and Drug Administration]] (FDA) approved an alternative product-safety testing method in response to increasing public concern that [[LD50]] testing was required for each batch sold in the market.<ref name="Allergan_2011">{{cite web |date=24 June 2011 |title=Allergan Receives FDA Approval for First-of-Its-Kind, Fully in vitro, Cell-Based Assay for Botox and Botox Cosmetic (onabotulinumtoxinA) |publisher=Allergan |url=http://agn.client.shareholder.com/releasedetail.cfm?ReleaseID=587234 |access-date=26 June 2011 |url-status=dead |archive-url=https://web.archive.org/web/20110626185759/http://agn.client.shareholder.com/releasedetail.cfm?ReleaseID=587234 |archive-date=26 June 2011}}</ref><ref name="The Washington Post_2008">{{cite news |date=12 April 2008 |title=In U.S., Few Alternatives To Testing On Animals |newspaper=[[The Washington Post]] |url=https://www.washingtonpost.com/wp-dyn/content/article/2008/04/11/AR2008041103733.html |access-date=26 June 2011 |archive-date=12 November 2012 |archive-url=https://web.archive.org/web/20121112163835/http://www.washingtonpost.com/wp-dyn/content/article/2008/04/11/AR2008041103733.html |url-status=live }}</ref>

Botulinum toxin type-A has also been used in the treatment of [[gums|gummy]] smiles;<ref name="pmid25654058">{{cite journal |vauthors = Nayyar P, Kumar P, Nayyar PV, Singh A |title = BOTOX: Broadening the Horizon of Dentistry |journal = Journal of Clinical and Diagnostic Research |volume = 8 |issue = 12 |pages = ZE25–ZE29 |date = December 2014 |pmid = 25654058 |pmc = 4316364 |doi = 10.7860/JCDR/2014/11624.5341 }}</ref> the material is injected into the hyperactive muscles of upper lip, which causes a reduction in the upward movement of lip thus resulting in a smile with a less exposure of [[gums|gingiva]].<ref name="pmid19123705">{{cite journal |vauthors = Hwang WS, Hur MS, Hu KS, Song WC, Koh KS, Baik HS, Kim ST, Kim HJ, Lee KJ |title = Surface anatomy of the lip elevator muscles for the treatment of gummy smile using botulinum toxin |journal = The Angle Orthodontist |volume = 79 |issue = 1 |pages = 70–77 |date = January 2009 |pmid = 19123705 |doi = 10.2319/091407-437.1 |doi-access = free |title-link = doi }}</ref> Botox is usually injected in the three lip elevator muscles that converge on the lateral side of the ala of the nose; the [[levator labii superioris]] (LLS), the [[levator labii superioris alaeque nasi muscle]] (LLSAN), and the [[Zygomaticus minor muscle|zygomaticus minor]] (ZMi).<ref name="pmid20529632">{{cite journal |vauthors = Gracco A, Tracey S |title = Botox and the gummy smile |journal = Progress in Orthodontics |volume = 11 |issue = 1 |pages = 76–82 |date = May 2010 |pmid = 20529632 |doi = 10.1016/j.pio.2010.04.004 }}</ref><ref name="pmid21093661">{{cite journal |vauthors = Mazzuco R, Hexsel D |title = Gummy smile and botulinum toxin: a new approach based on the gingival exposure area |journal = Journal of the American Academy of Dermatology |volume = 63 |issue = 6 |pages = 1042–1051 |date = December 2010 |pmid = 21093661 |doi = 10.1016/j.jaad.2010.02.053 }}</ref>

===Upper motor neuron syndrome===
Botulinum toxin type-A is now a common treatment for muscles affected by the [[upper motor neuron]] syndrome (UMNS), such as [[cerebral palsy]],<ref name=Farag2020/> for muscles with an impaired ability to effectively [[eccentric contraction|lengthen]]. Muscles affected by UMNS frequently are limited by [[weakness]], loss of [[reciprocal inhibition]], decreased movement control, and hypertonicity (including [[spasticity]]). In January 2014, Botulinum toxin was approved by UK's [[Medicines and Healthcare products Regulatory Agency]] (MHRA) for the treatment of ankle disability due to lower limb spasticity associated with stroke in adults.<ref name="DDD">{{cite web |url = http://www.dddmag.com/news/2014/02/uk-approves-new-botox-use?et_cid=3751256&et_rid=657808477&type=cta |title = UK Approves New Botox Use |archive-url = https://web.archive.org/web/20140222135115/http://www.dddmag.com/news/2014/02/uk-approves-new-botox-use?et_cid=3751256&et_rid=657808477&type=cta |archive-date=22 February 2014 |date = February 2014 |work = Drug Discovery and Development }}</ref> Joint motion may be restricted by severe muscle imbalance related to the syndrome, when some muscles are markedly hypertonic, and lack effective active lengthening. Injecting an overactive muscle to decrease its level of contraction can allow improved reciprocal motion, so improved ability to move and exercise.<ref name=Farag2020/>

===Sialorrhea===
[[Sialorrhea]] is a condition where oral secretions are unable to be eliminated, causing pooling of saliva in the mouth. This condition can be caused by various neurological syndromes such as [[Bell's palsy]], intellectual disability, and cerebral palsy. Injection of botulinum toxin type-A into salivary glands is useful in reducing the secretions.<ref>{{cite journal |vauthors = Khan WU, Campisi P, Nadarajah S, Shakur YA, Khan N, Semenuk D, McCann C, Roske L, McConney-Ellis S, Joseph M, Parra D, Amaral J, John P, Temple M, Connolly B |title = Botulinum toxin A for treatment of sialorrhea in children: an effective, minimally invasive approach |journal = Archives of Otolaryngology–Head & Neck Surgery |volume = 137 |issue = 4 |pages = 339–344 |date = April 2011 |pmid = 21242533 |doi = 10.1001/archoto.2010.240 |doi-access = free |title-link = doi }}</ref>

===Cervical dystonia===
Botulinum toxin type-A is used to treat [[cervical dystonia]], but it can become ineffective after a time. Botulinum toxin type B received FDA approval for treatment of cervical [[dystonia]] in December 2000. Brand names for botulinum toxin type-B include Myobloc in the United States and Neurobloc in the European Union.<ref name="Available Neurotoxins" />

===Chronic migraine===
{{See also|Migraine treatment#Botulinum Toxin (Botox)}}

Onabotulinumtoxin A (trade name: Botox) received FDA approval for treatment of chronic [[migraine]]s on 15 October 2010. The toxin is injected into the head and neck to treat these chronic headaches. Approval followed evidence presented to the agency from two studies funded by Allergan showing a very slight improvement in incidence of chronic migraines for those with migraines undergoing the Botox treatment.<ref name=FDA10>{{cite press release |title=FDA approves Botox to treat chronic migraine |publisher=U.S. [[Food and Drug Administration]] (FDA) |date=19 October 2010 |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm229782.htm |archive-url=https://web.archive.org/web/20101019002022/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm229782.htm |archive-date=19 October 2010 |url-status=dead |access-date=23 November 2019}} {{PD-notice}}</ref><ref>{{Cite news |vauthors=Watkins T |date=15 October 2010 |title=FDA approves Botox as migraine preventative |newspaper=[[CNN]] |url=http://us.cnn.com/2010/HEALTH/10/15/migraines.botox/index.html |access-date=16 October 2010 |archive-date=27 July 2020 |archive-url=https://web.archive.org/web/20200727025543/http://us.cnn.com/2010/HEALTH/10/15/migraines.botox/index.html |url-status=live }}</ref>

Since then, several randomized control trials have shown botulinum toxin type A to improve headache symptoms and quality of life when used prophylactically for participants with chronic [[migraine]]<ref>{{cite journal |vauthors = Dodick DW, Turkel CC, DeGryse RE, Aurora SK, Silberstein SD, Lipton RB, Diener HC, Brin MF |title = OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program |journal = Headache |volume = 50 |issue = 6 |pages = 921–936 |date = June 2010 |pmid = 20487038 |doi = 10.1111/j.1526-4610.2010.01678.x |s2cid = 9621285 }}</ref> who exhibit headache characteristics consistent with: pressure perceived from outside source, shorter total duration of chronic migraines (<30 years), "detoxification" of participants with coexisting chronic daily headache due to medication overuse, and no current history of other preventive headache medications.<ref>{{cite journal |vauthors = Ashkenazi A |title = Botulinum toxin type a for chronic migraine |journal = Current Neurology and Neuroscience Reports |volume = 10 |issue = 2 |pages = 140–146 |date = March 2010 |pmid = 20425239 |doi = 10.1007/s11910-010-0087-5 |s2cid = 32191932 }}</ref>

===Depression===
{{See also|List of investigational antidepressants}}

A few small trials have found benefits in people with [[depression (mood)|depression]].<ref>{{cite journal |vauthors = Magid M, Keeling BH, Reichenberg JS |title = Neurotoxins: Expanding Uses of Neuromodulators in Medicine--Major Depressive Disorder |journal = Plastic and Reconstructive Surgery |volume = 136 |issue = 5 Suppl |pages = 111S–119S |date = November 2015 |pmid = 26441090 |doi = 10.1097/PRS.0000000000001733 |s2cid = 24196194 }}</ref><ref name="AdisInsight" /><ref name="Ceolato-Martin_2024">{{Cite journal |vauthors = Ceolato-Martin C, Chevallier-Collins C, Clément JP, Charles E, Lacroix A, Ranoux D |date=January 2024 |veditors = Ai S |title=OnabotulinumtoxinA in Resistant Depression: A Randomized Trial Comparing Two Facial Injection Sites (OnaDEP Study) |journal=Depression and Anxiety |language=en |volume=2024 |issue=1 |doi=10.1155/2024/1177925 |doi-access=free |pmid=40226647 |issn=1091-4269|pmc=11918888 }}</ref> A 2021 meta-analysis supports the usefulness of botox in unipolar depression, but finds significant heterogenity among the findings.<ref>{{cite journal |vauthors = Arnone D, Galadari H, Rodgers CJ, Östlundh L, Aziz KA, Stip E, Young AH |title = Efficacy of onabotulinumtoxinA in the treatment of unipolar major depression: Systematic review, meta-analysis and meta-regression analyses of double-blind randomised controlled trials |journal = Journal of Psychopharmacology |volume = 35 |issue = 8 |pages = 910–918 |date = August 2021 |pmid = 33719696 |pmc = 8366169 |doi = 10.1177/0269881121991827 }}</ref> The main hypothesis for its action is based on the [[facial feedback hypothesis]].<ref>{{cite journal |vauthors = Finzi E, Rosenthal NE |title = Treatment of depression with onabotulinumtoxinA: a randomized, double-blind, placebo controlled trial |journal = Journal of Psychiatric Research |volume = 52 |pages = 1–6 |date = May 2014 |pmid = 24345483 |doi = 10.1016/j.jpsychires.2013.11.006 }}</ref> Another hypothesis involves a connection between the facial muscle and specific brain regions in animals, but additional evidence is required to support or disprove this theory.<ref name="Ceolato-Martin_2024" />

===Premature ejaculation===
{{See also|List of investigational sexual dysfunction drugs}}

The drug for the treatment of [[premature ejaculation]] has been under development since August 2013, and is in [[Phases of clinical research|Phase II]] trials.<ref name="AdisInsight">{{Cite web |url=http://adisinsight.springer.com/drugs/800008810 |title=Onabotulinum toxin A - Allergan - AdisInsight |access-date=5 September 2017 |archive-date=30 October 2017 |archive-url=https://web.archive.org/web/20171030223633/http://adisinsight.springer.com/drugs/800008810 |url-status=live }}</ref><ref>{{ClinicalTrialsGov|NCT01917006|An Exploratory Study of the Safety and Efficacy of Botox for the Treatment of Premature Ejaculation}}</ref>