Beyond the orbit: Applications for Botox extend past dystonias

Manufacturers compete to market botulinum toxin; surgeons worldwide are finding new functional and cosmetic indications. Part 2 of a 3-part series.

The applications for botulinum toxin type A have undergone an explosion since the drug was first studied as a treatment for strabismus and focal dystonias such as benign essential blepharospasm and hemifacial spasm more than 20 years ago.

Today it is common to find a physician using Botox (botulinum toxin type A, Allergan) for a variety of indications. Practitioners in numerous specialties have incorporated this therapy into their practices, but ophthalmologists have remained at the forefront of these developments, both within the confines of facial anatomy and beyond.

The pharmaceutical industry has also capitalized on this expansion, and a second company is hoping to capture part of Allergan’s market share. Inamed Corp, a leading manufacturer of breast implants, this year undertook a clinical development program for Dysport (clostridium botulinum type A toxin-haemaglutinin complex), a form of botulinum toxin type A that is clinically similar to Allergan’s Botox.

Inamed secured North American and Japanese marketing rights from the Beaufour Ipsen Group, which markets the drug in Europe. Dysport is currently awaiting the start of Food and Drug Administration phase 3 clinical trials for cosmetic indications, according to an Inamed spokesperson.

Battle of the botulinums

Brian Leatherbarrow, FRCS, FRCOphth, an oculoplastic surgeon in Manchester, England, has used both Botox and Dysport. First introduced to Botox during his fellowship in the United States, Mr. Leatherbarrow said he switched to Dysport “simply because that was what was available” in England.

He said he has used Dysport almost exclusively since he started his practice 12 years ago.

“I know Dysport, and I trust it. I know the dilution; I know the effect it’s going to give me. I just haven’t seen the need to change to Botox,” he said.

Mr. Leatherbarrow said he has used Dysport for many of the same indications for which Botox is used in the United States. These applications include benign essential blepharospasm (BEB), hemifacial spasm, facial palsy and, more rarely, thyroid eye disease.

He said his cosmetic uses primarily include periocular rhytids and glabellar frown lines.

Complications, which are more commonly seen in patients receiving the drug for functional purposes, are similar to those of Botox, and most commonly include bruising, ptosis, diplopia, difficulty blinking and dry eye, he said.

Sharing the market

Peter Nicholson, Inamed’s vice president of investor relations and corporate communications, said it is too soon to determine how Botox and Dysport will compete in the United States.

Mr. Leatherbarrow, however, insisted that when all is said and done, the economics are virtually the same.

“Each company will give their own biased opinion as to its cost. In real terms … once you’ve taken into consideration the dilution factors and the time it takes to wear off, I don’t honestly feel there’s a great difference between the two,” he said.

Headache therapy

The popularity of botulinum toxin has grown around a number of off-label uses, both cosmetic and functional.

Oculoplastic surgeon Steven Fagien, MD, estimated that at least 30% of patients who receive Botox in the eye and forehead area request additional injections in the lip area and lower face or to reduce the appearance of platysma bands.

According to some surgeons, the most significant off-label functional indication has been for the prevention of migraines. Headache therapy has already gained acceptance among some health insurance companies for its cost-effectiveness, and may open a portal to other pain prevention applications.

Wayne T. Cornblath, MD, a neuro-ophthalmologist at the Kellogg Eye Center at the University of Michigan, has been using Botox to prevent headaches for about 3 years. He and a resident in his department have also conducted a clinical study of patients treated for severe headache.

The physicians asked 40 patients who had received two or more injections of Botox to rate the frequency and severity of their headaches before and after receiving treatment. They found that 80% of patients, who experienced 15 to 30 headaches in a typical month, reported at least some improvement in the grade and duration of their symptoms.

Dr. Cornblath said about 30% of patients reported a 25% to 49% improvement in their headaches and 40% noted a 50% to 99% improvement. About 10% of patients reported complete headache relief during the 2 to 5 months when Botox exerts its effect.

He added that more than one in five insurance companies now provide reimbursement for Botox injections, which can reduce prescriptions for migraine medications and trips to the emergency room.

Patients also raised quality-of-life benefits such as fewer side effects and missed days of work, Dr. Cornblath said.

Distinguishing characteristics

Headache therapy requires a larger dose of Botox than blepharospasm. Dr. Cornblath said he typically injects a total of 50 units of Botox in 10 locations: in both temples, three sites on the forehead and five sites along the back of the hairline. He adjusts the strength of each injection depending on the location of the headache.

“If you inject only on the headache side, what happens in these folks is that headaches shift to the other side,” he said. “Nobody wants that. So I will always do both sides but will shift the dosage a little.”

The onset of action is about 2 weeks, which is more than twice as long as the onset of action for the treatment of blepharospasm, Dr. Cornblath said. Complications primarily include bruising.

“You’re injecting in a different location than our more standard eye injections, so I think it’s a very different side effect profile than what we would normally talk about with Botox injections done for BEB or hemifacial spasm by ophthalmologists,” he said.

How it works

While other studies have reported similar success in using Botox to prevent headaches, the exact mechanism of action is still unclear.

One theory is that Botox relieves the muscle tension that can trigger migraines. Researchers already understand how Botox blocks the release of acetylcholine, causing nerves that stimulate muscles to atrophy.

Some researchers also believe that by blocking acetylcholine, they can treat a host of other disorders. A study from the University of California, San Francisco found that Botox reduced the excessive sweating associated with hyperhidrosis. An Indiana University study reported that Botox might relieve symptoms of post-stroke spasticity; other studies have also found evidence to suggest that the drug may help children with cerebral palsy.

A second theory about Botox’s mechanism of action, according to William J. Lipham, MD, FACS, Ocular Surgery News Oculoplastics and Reconstructive Surgery Board member, is that Botox blocks the release of nociceptive neuropeptides (such as substance P and glutamate), causing sensory nerves to atrophy and decreasing pain sensitivity.

Dr. Lipham, who has treated more than 30 headache sufferers, said the interest in headache therapy is potentially significant.

“Nearly 15% of all women suffer from migraine headaches at some time in their life. That’s a huge demographic,” he said.

Pain relief

Dr. Cornblath offered a third theory, which may affect the largest demographic yet: that the botulinum toxin may be taken up by the spinal cord.

While there is no evidence yet to support this theory, research is being conducted. Researchers in one study observed that when rats received a Botox injection in the foot, they did not exhibit the typical pain response when the foot was later subjected to pain stimuli.

“For a lot of the pains for which Botox has been administered, it’s thought that those pains are a result of a spastic or overactive muscle. I think it will be interesting to see if it can be used when there’s not a spastic or overactive muscle,” Dr. Cornblath said.

If the spinal cord theory is correct, Botox may have applications in nerve-based disorders such as trigeminal neuralgia or reflex sympathetic dystrophy, he added.

Botox is currently undergoing clinical trials to study its applications for pain management, according to information on the Allergan Web site.

For Your Information:

• Brian Leatherbarrow, FRCS, FRCOphth, can be reached at Bupa Hospital, Russell Rd., Wahlley Range, M168AJ Manchester, England; (44) 161-232-2435; fax: (44) 161-232-2255; e-mail: bollin@mighty-micro.co.uk; Web site: www.eyelidsurgery.co.uk. Mr. Leatherbarrow has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
• Steven Fagien, MD, can be reached at 660 Glades Road, Suite 210, Boca Raton, FL 33431; (561) 393-9898; fax: (561) 347-0772. Dr. Fagien has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
• Wayne T. Cornblath, MD, can be reached at the Kellogg Eye Center, Neuro-Ophthalmology Service, Room 2415, Box 0714, 1000 Wall St., Ann Arbor, MI 48105; (734) 936-9503; fax: (734) 936-2340; e-mail: wtc@mich.edu. Dr. Cornblath has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
• William J. Lipham, MD, FACS, can be reached at Minnesota Eye Consultants, 9117 S. Lyndale Ave., Bloomington, MN 55420; (612) 813-3600; fax: (952) 885-9942; e-mail: wjlipham@mneye.com. Dr. Lipham has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

• Allergan, maker of Botox, can be reached at 2525 Dupont Drive, Irvine, CA 92612; (800) 433-8871; fax: (714) 246-5913; Web site: www.allergan.com.
• Inamed can be reached at 5540 Ekwill St., Santa Barbara, CA 93111; (805) 692-5400; fax: (805) 692-5432; Web site: www.inamed.com.

References:

• Brashear A, Gordon MF, et al. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med. 2002;347:395-400.
• Fagien S. Botulinum toxin type A for facial aesthetic enhancement: role in facial shaping. Plast Reconstr Surg. 2003;112(Suppl):6S-18S.
• Fagien S. Botox for the treatment of dynamic and hyperkinetic facial lines and furrows: adjunctive use in facial aesthetic surgery. Plast Reconstr Surg. 1999;103:701-713.
• Glogau RG. Botulinum A neurotoxin for axillary hyperhidrosis. No sweat Botox. Dermatol Surg. 1998;24:817-819.