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Up Front | Jun 2002

New Applications for BOTOX

Recently approved for cosmetic use, BOTOX can easily be incorporated into the ophthalmologist's armamentarium.

As an ophthalmologist, I initially offered botulinum toxin A (BTX-A) in 1995 for the treatment of blepharospasm and hemifacial spasm in select patients. I was also performing cosmetic laser skin resurfacing, and I began to explore BOTOX's potential for reducing dynamic wrinkles in conjunction with treating actinic skin damage. Prior to performing laser skin resurfacing, I would use BOTOX to permit smooth healing of the new skin without the postoperative corrugation of rhytids that would disrupt the newly forming collagen. My interest in BTX-A grew to include cosmetic injections without resurfacing for glabellar folds, crow's feet, and platysmal bands of the neck. In addition, I began using it to treat chronic tension-type headaches, migraines, bruxism, and TMJ-associated headaches at patients' requests. I have been happy to provide these services, and the time demand is minimal compared to the personal rewards. I feel BTX-A is an important adjunct to the armamentarium of today's comprehensive ophthalmologist, and public awareness and sophistication make it an essential aspect of any progressive surgical practice.

BTX-A is the most highly purified and most studied neurotoxin serotype produced by Clostridium botulinum. There are seven serotypes, A through G. BTX-A has a dichain polypeptide with a heavy chain that is linked by a disulfide bond to a light chain. The heavy chain binds to a neural membrane and the light chain cleaves SNAP-25. BTX-A affects the neuromuscular junction through binding, internalization, and inhibiting acetylcholine release. It inhibits the docking and fusion of acetylcholine vesicles at the presynaptic membrane with a duration of action that usually lasts 3 to 4 months, and up to 6 months.1 BTX-A functionally denervates the injected muscle, thereby inducing muscle relaxation by inhibiting acetylcholine release at the neuromuscular junction. The effect is dose-dependent, and reversible by the regeneration or sprouting of blocked nerves that form new neuromuscular junctions.1

Botulinum toxin B (Myobloc; Elan Pharmaceuticals, Inc., Cedar Knolls, NJ) is more stable than type A, and differs from type A in that 5,000 units of type B are equivalent to 20 units of type A. Although cross-reactivity from A to B has not been reported, individuals can become sensitized from higher doses. Potential side effects of botulinum A and B may be caused by aminoglycoside antibiotics or other drugs interfering with neuromuscular transmission. Additionally, surgeons should exert caution when ascertaining whether patients have neuromuscular disorders such as myasthenia gravis and myotonic dystrophy, and they should avoid administering BOTOX to such individuals. Surgeons should also advise their patients that it may take 3 to 5 days for the full benefit of BOTOX to be realized due to the manner in which the drug works. Moreover, some patients may not have a demonstrable result and/or may develop antibodies over time that render the BTX-A ineffective. Also, the maximum suggested dose should not exceed 200 units in a 30-day period.

The FDA first approved BTX-A in 1989 for strabismus, blepharospasm, and hemifacial spasm in patients older than age 12. In December 2000, the FDA granted approval for the treatment of cervical dystonia with BTX-A and Myobloc. Doctors have also used BTX-A off-label for spasticity due to multiple sclerosis, cerebral palsy, spinal cord injury, stroke, spasmodic dysphonia, and achalasia. Additional off-label uses of BTX-A include hyperhidrosis of the forehead and underarm, cosmetic uses for rhytids in the glabellar region, crow's feet, and frontalis. As of April 15, 2002, BTX-A, marketed as BOTOX (Allergan, Inc., Irvine, CA), has been approved for the temporary treatment of glabellar rhytids.

In the US, headache is the most common type of pain, accounting for greater than 10 million physician visits annually. Migraine headache is prevalent for a lifetime in 15 to 18% of women and 6% of men, and tension-type headaches are episodic in 86% of patients and chronic in 3%. Seventy-one percent of women and 56% of men have episodic tension-type headaches, and 5% of women and 2% of men have chronic tension-type headaches.2 Serendipitously, in 1998, Binder et al noted a decrease in migraines and tension headaches in patients receiving BTX-A for facial rhytids.3 This work, as well as that of others,2-11 led to off-label uses for BTX-A for migraines and tension-type headaches, in addition to TMJ/bruxism.

Currently, researchers hypothesize that BOTOX's mechanism of action in headache treatment involves reducing pericranial muscular tension and contractions that contribute to headaches, while it reduces muscle spindle activity, which decreases sensory feedback. Additionally, BOTOX may have a direct effect on sensory nerves by inhibiting neuropeptide-containing fibers. Generally, treatment injection paradigms follow two options: fixed site, in which injections are given in the same location for all patients, and follow-the-pain, which allows injections into regions where pain and tenderness/trigger areas exist.

Create a pleasant environment with a comfortable chair or examination table, and prepare accessible blood pressure equipment and hypochlorite solutions of 5% concentration for cleaning up spills. Emesis basins should be available, as well as epinephrine for treatment of possible anaphylactic reactions. BOTOX should be stored at -5&Mac251;C until reconstituted; it arrives packed in dry ice and should not be thawed. Materials available for preparation include latex gloves; alcohol wipes; 1 cc tuberculin syringes with 27-gauge needles; single-use, preservative-free saline for injection; small ice-packs (preinjection for anesthesia, postinjection to minimize bruising); and a curved hemostat for the removal and/or tightening of needles or syringes.

Sterile, preservative-free normal saline (0.9% sodium chloride) is recommended as a diluent. It should be injected gently into the vial with a 22-gauge needle, and the surgeon must take precautions to avoid bubbling and violent agitation, which can denature the lyophilized product upon reconstitution. If the vacuum does not pull the diluent into the vial, discard and return it to Allergan, Inc./BOTOX, 901 Grayson Street, Berkeley, CA 94710, Attn: Customer Returns. The mixed product should be used within 4 hours for maximum potency.

A safe dilution permitting dispersion control of the injected drug is 2.0 cc of diluent for 5 units per 0.1 mL. Suggested treatment (regardless of dilution) is 2.0 to 2.5 units per area for rhytids, 20.0 to 25.0 units per glabellar region, 30.0 to 35.0 units total per frontalis area, and 15 units per side/three injection points per side for crow's feet. Blepharospasm and hemifacial spasm require more units at 30.0 and 40.0 to 45.0, respectively.

When treating blepharospasm with BOTOX, the side effects can include ptosis, irritation or tearing, ectropion, keratitis, diplopia, and entropion. Surgeons can reduce the risk of ptosis by avoiding injection of the drug into the medial supra-orbital area. Also, avoid overdilution and the subsequent need for larger volumes in areas in order to minimize side effects related to diffusion. The most common adverse events following an injection of BOTOX that were reported in the FDA study for the drug—headache, respiratory infection, flu syndrome, blepharoptosis, and nausea—tended to be mild and transient in nature. Out of the study group of 405 patients, 3%, mostly women under age 50, noted pain in the face, redness at the injection site, and muscle weakness, but these were all temporary reactions.

In summary, BTX-A may be efficacious in the off-label treatment of headaches (migraine and tension) and TMJ/bruxism by reducing the frequency and severity of such events, as well as decreasing the acute medication usage with few adverse effects. BOTOX, with recent and long-standing FDA approval, effectively treats spasm and rhytids, thereby adding a new tool to our armamentarium against chronic pain and our quest for rejuvenation. Ultimately, we need more studies to determine the optimal injection sites, doses, and patient selection criteria.

Susan H. Senft, MD, FRCOphth, is in private practice at Island Eye Care in Kailua-Kona, Hawaii. She does not hold any financial interest in any product mentioned herein. Dr. Senft may be reached at (808) 329-3937; shsenft@aol.com
Material adapted from Dr. Senft's presentation entitled “New Indications for BOTOX” given at the Royal Hawaiian Eye Meeting on January 24th, 2002.
1. dePaiva A, Meunier FA, Molgo J, et al: Functional repair of motor endplates after botulinum neurotoxin type A poisoning: Biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci 96:3200-3205, 1999
2. Freund BJ, Schwartz M: Treatment of chronic cervical-associated headache with botulinum toxin A: A pilot study. Headache 40:231-236, 2000
3. Binder W, Brin MF, Blitzer A, et al: Botulinum toxin type A (BTX-A) for migraine: An open label assessment. Mov Disord 13:241 (p.4-104), 1998 (abstr) (suppl 2)
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11. Wheeler AH: Botulinum toxin A, adjunctive therapy for refractory headaches associated with pericranial muscle tension. Headache 38:468-471, 1998
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