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Letters to the Editor  |   May 2007
Response
Author Affiliations
  • Eric S. Felber, DO
    Frankford Hospitals—Jefferson Health System, Philadelphia, Pennsylvania
Article Information
Neuromusculoskeletal Disorders / Ophthalmology and Otolaryngology / Pain Management/Palliative Care / Headache
Letters to the Editor   |   May 2007
Response
The Journal of the American Osteopathic Association, May 2007, Vol. 107, 173-174. doi:
The Journal of the American Osteopathic Association, May 2007, Vol. 107, 173-174. doi:
I thank Dr Taylor for his interest in my October 2006 article published in JAOA—The Journal of the American Osteopathic Association.1 To address Dr Taylor's first point, the package insert of Botox Cosmetic (Allergan Inc, Irvine, Calif) does read, “Once opened and reconstituted, it [Botox] should be stored in a refrigerator (2°C to 8°C) and used within four hours.”2 However, there exists more than just “industry data” to indicate that botulinum toxin type A (BTX-A, or Botox), remains viable for as long as 4 weeks.3 
Carruthers and Carruthers3 are famous for their pioneering discovery of the cosmetic use of BTX-A, and they remain worldwide authorities on cosmetic medical procedures. In 2005, Carruthers and Carruthers3 stated that evidence now indicates that reconstituted BTX-A can be stored refrigerated for 1 week or longer without loss of efficacy. Their evidence about the reconstitution and use of this product was derived from a double-blind, randomized controlled trial by Alam et al.4 Interestingly, Alam et al4 also concluded that reconstitution with preserved saline solution does not impair the stability of BTX-A, and administration of such a reconstituted product is less painful to patients than when the toxin is reconstituted with nonpreserved saline solution. 
I agree with Dr Taylor regarding the importance of distinguishing between on- and off-label uses of BTX-A. As indicated by Dr Taylor, the only cosmetic use of BTX-A that is approved by the US Food and Drug Administration (FDA) is the treatment of patients with glabellar wrinkles.5 To clarify the other on-label uses, BTX-A has been approved since 1989 for the treatment of patients with strabismus and blepharospasm associated with dystonia6; since 2000 for patients with cervical dystonia and “associated abnormal head position and neck pain”6; and since 2004 for patients with primary axillary hyperhidrosis that cannot be managed by topical agents such as prescription antiperspirants.7 
Despite these limited FDA approvals, BTX-A is increasingly being used for various off-label uses with favorable results for patients. In 2002 alone, there were approximately 1.1 million to 1.6 million patients using cosmetic botulinum toxin, and many of these cases involved such off-label uses as elimination of forehead wrinkles.6,8 It is also interesting to note that only one fatal case of anaphylaxis has been recorded in the vast usage of BTX-A.2 That fatality occurred when lidocaine was used as a diluent, and, consequently, the causal agent of the fatality could not be reliably determined.2 
In regard to my proposed mechanism for how BTX-A relieves migraines,1 the proposal is, indeed, theoretical considering the fact that the mechanism of migraine itself remains unknown. My rationale for proposing that BTX-A may cause changes in intracranial pressure and pressure on cerebral vasculature by acting on pericranial muscles is that many patients describe headaches, especially tension headaches, as a “tightening,” “squeezing,” or “pressing” pain. Those terms sound muscular in nature and, thus, it is logical to propose that a product like BTX-A, which causes selective muscle paralysis, might alleviate these symptoms. Furthermore, Zalvan9 states, “The exact mechanism of this action [BTX-A relief of headaches] is unknown; however, the effect appears to be mediated by both a decrease in muscular tension and a central modulation of the afferent pathways.” 
I agree with Dr Taylor that ptosis is a significant risk of BTX-A administration, and that only well-trained physicians should administer BTX-A, as I stated in my JAOA article.1 The injections for a brow lift shown in the third image of Figure 11 referred to by Dr Taylor must be given to patients at least 1 cm above the superior orbital margin, starting at the midpupillary line and extending to the lateral brow. I repeatedly and strongly urged this precaution in my paragraph describing the brow lift procedure.1 
Once again, I thank Dr Taylor for his interest in this fascinating field. 
Felber ES. Botulinum toxin in primary care medicine. J Am Osteopath Assoc. 2006;106:609-614. Available at: http://www.jaoa.org/cgi/content/full/106/10/609. Accessed May 9, 2007.
Administering Botox cosmetic—prescribing information [Allergan Inc Web site]. Available at: http://www.botoxcosmetic.com/botox_physician_info/administering_botox/prescribing_info.aspx. Accessed May 18, 2007.
Carruthers A, Carruthers J. Botulinum toxin type A. J Am Acad Dermatol. 2005;53:284-290.
Alam M, Dover JS, Arndt KA. Pain associated with injection of botulinum A exotoxin reconstituted using isotonic sodium chloride with and without preservative: a double-blind, randomized controlled trial. Arch Dermatol. 2002;138:510-514.
US Food and Drug Administration. BOTOX COSMETIC (Botulinum Toxin Type A) Purified Neurotoxin Complex. Rockville, Md: US Food and Drug Administration; 2002. Available at: http://www.fda.gov/cder/foi/label/2002/botuall041202LB.pdf. Accessed May 9, 2007.
US Food and Drug Administration. Medical Officer's Review: Botulinum Toxin Type A. Rockville, Md: US Food and Drug Administration; March 4, 2002. NDA/BLA 103000.5000. Available at: http://www.fda.gov/cder/biologics/review/botuall041202r2.pdf. Accessed May 9, 2007.
US Food and Drug Administration. FDA Approves Botox to Treat Severe Underarm Sweating [talk paper]. Rockville, Md: US Food and Drug Administration; July 20, 2004. T04-26. Available at: http://www.fda.gov/bbs/topics/answers/2004/ANS01301.html. Accessed May 9, 2007.
Cote TR, Mohan AK, Polder JA, Walton MK, Braun MM. Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases. J Am Acad Dermatol. 2005;53:1080-1082.
Zalvan C, Bentsianov B, Gonzalez-Yanes O, Blitzer A. Noncosmetic uses of botulinum toxin [review]. Dermatol Clin. 2004;22:187-195.