From the beginning: The history and applications of Botox

Surgeons share advice on topics from interviewing patients to managing complications in the first of a three-part series on Botox.

The applications for Botox seem endless. Since Allergan’s botulinum toxin type A received approval from the Food and Drug Administration in 1989, its indications have quickly expanded. Once a therapy limited to ocular dystonias, Botox is now used in numerous areas throughout the body, with applications ranging from medicinal to cosmetic.

“An interesting aspect about Botox, from our perspective, is that it has ophthalmology roots. Ophthalmologists, mostly with an oculoplastic surgery background, have treated eyelid spastic disorders with botulinum toxin for years, so at first it was an easy transition to its use for aesthetic purposes,” said Steven Fagien, MD, an oculoplastic surgeon in Boca Raton, Fla. “But by and large the general ophthalmologist was not using Botox until now.”

Nearly all of the surgeons interviewed about Botox for this article said that they have seen a steady rise in its popularity and that their colleagues continue to find off-label uses for the product. In this first article in a three-part series, Ocular Surgery News recounts the history of Botox and examines its current applications.

In the next two installments, we will explore what may be next for Botox and how physicians can incorporate it into their practices.

Historical perspective

Surgeons first tested botulinum toxin A in humans in 1978, when Alan B. Scott, MD, received permission from the FDA to study the drug’s effect on strabismus. Ten years later, Allergan acquired the rights to distribute the drug, marketed first as Oculinum, and conducted additional trials for indications including benign essential blepharospasm and cervical dystonia.

Allen M. Putterman, MD, SC, who participated in the first FDA trials at the University of Illinois, noted that early studies focused on treating eye muscle hyperactivity and blepharospasm, and researchers “absolutely [did] not” realize the potential for other applications with Botox.

“At that time, I think the main [concerns] were not knowing where to inject or how much to inject,” said the Chicago-based surgeon, who has been administering Botox for more than 20 years. “There was a lot of trial and error in determining the sites and the dosages.”

In 1992, Alastair Carruthers, MD, MRCP, FRCPC, and his wife Jean Carruthers, MD, FRCPC, FRCOphth, issued the first report suggesting that Botox could be used for cosmetic purposes.

“From functional patients, they made the transition to actually begin treating for cosmetic indications,” said William Lipham, MD, FACS, of Bloomington, Minn. “Since that time, a number of individuals in a variety of disciplines, including outside of ophthalmology, have noted that Botox can be used to inactivate muscles that cause lines to develop.”

Five common Botox complications and how to prevent or manage them

Complication Prevention/Management
Pinpoint bleeding Apply pressure with gauze pad
Infection of injection site Cleanse skin with alcohol prior to injection
Diplopia Avoid the inferior oblique muscles
Ecchymosis Instruct patients to avoid anticoagulants (including asprin, blood thinners and large doses of vitamin E) for 1 to 2 weeks before injection; apply ice immediately after injection
Ptosis Usually resolves within 2 to 3 weeks without intervention; 2.5% phenylephrine solution may also be administered on the inside of the upper eyelid

Source: Surgeon interviews

Mechanism of action

Dr. Lipham said that most patients and even some physicians hold misconceptions about how Botox works. “Botox exerts its effect by inactivating nerves that stimulate muscles to contract,” he said. “And the way it does that is that it is [blocking] the release of acetylcholine, which is a neurotransmitter, from the nerve.”

He said that the most common fallacy among cosmetic patients is that Botox can “fill” lines. Botox actually works by inactivating muscles that are responsible for overactive facial expression. It does not target wrinkles, but the muscles that cause them to develop, he said.

“Because it’s working in this fashion, it tends to be a preventative type of cosmetic product or indication. So you’re typically not giving Botox to fill lines that are present at rest,” Dr. Lipham said.

Without acetylcholine, the muscle atrophies, according to Allergan representatives. It takes 3 to 4 months for the old nerve terminal activity to be restored.

“The best analogy [for] when I’m trying to explain it to patients is that the Botox molecule doesn’t sit around and do something actively for 3 months. I think that’s the biggest misconception. Really what happens is that [Botox] does its job in about 3 to 4 days,” Dr. Lipham said.

Customizing procedures

Dr. Fagien, who codirects the Plastic Surgery Education Initiative supported by an unrestricted educational grant from Allergan, said that many surgeons also tend to get “distracted” by the idea of the use of Botox simply as a line eradicator.

“Actually we can do much more, including … considering it as an agent for facial shaping,” he said.

Surgeons must understand not only facial anatomy but also how different individuals use their muscles, he added.

“What we are doing is affecting animation,” he said. “And until [surgeons] really understand that, you can’t even begin to understand the advanced applications of Botox.”

Surgeons can glean a lot of necessary information about their patients during the interview, Dr. Fagien noted.

“Look at how [patients] look in repose, when they are at rest; look what happens even while you’re speaking with them – watch how they animate. That will give you certain clues about what they do all the time,” he said. “When you look at these patients, you also must think anatomically.”

Figure 1 Figure 2
Treatment of mild to moderate blepharospasm: Injection of the pretarsal and preseptal portion of the orbicularis muscle. Typical initial doses consist of 2.5 units of Botox to the medial and lateral aspect of the upper eyelid along the eyelid crease. Since the skin is only 60 µm thick in this region, the injection is given subcutaneously to avoid penetrating the underlying septum and inducing ptosis of ther upper eyelid.
Figure 3 Figure 4
Contraction of the lateral orbicularis oculi muscleis responsible for the creation of active lines or wrinkles that radiate from the lateral canthal angle which are commonly referred to as “smile lines” or “crow’s feet.” Injection of this area with botulism toxin softens these lines, as seen in this patient (A) prior to botulinum toxin administration and (B) 1 month after injection.
(Images courtesy of Cosmetics and Clinical Applications of Botulinum Toxin; SLACK Incorporated.)

Learning curve

Dr. Fagien suggested that surgeons who are just beginning to use Botox start by treating only the upper one-third of the face because muscle anatomy becomes more complex in the lower regions.

Mark R. Levine, MD, a Cleveland surgeon who participated in the early blepharospasm trials, said physicians may need to perform as many as a dozen procedures before they become proficient.

“It’s really technique-driven,” he said. “[Novices] can get some unfortunate results.”

Many complications can be avoided with proper placement of the injection, he added. For instance, an injection that misses its target may interfere with the patient’s ability to raise his or her eyebrows and cause asymmetry of the brows. When surgeons inject Botox in the upper lid, they increase the risk of causing a ptosis. Improperly placed injections in the lower lid may cause diplopia or ectropion, Dr. Levine said.

The technique is not difficult to learn, and many books and articles have been written on how to do it, he said.

Dr. Fagien also urged surgeons to read as much as they can on the subject, from studies in medical journals to articles in the lay press. “There are few things that we do in our practices that are so effective and predictable if you have a good fund of knowledge and a greater appreciation of its aesthetics,” he said.

Complications

Dr. Lipham noted that the risk for complications often depends on where the injection is administered. Patients with blepharospasm and hemifacial spasm, for instance, require Botox injections along the eyelid crease and are at a greater risk for developing upper eyelid ptosis, he said.

Upper eyelid ptosis is caused when Botox diffuses behind the orbital septum and weakens the levator muscle, Dr. Lipham said. He estimated that this complication occurs in about 10% of patients treated for blepharospasm or hemifacial spasm. The incidence of upper eyelid ptosis when Botox is injected for cosmetic indications, however, is much lower, and it rarely occurs when the product is administered properly.

Patients should not receive Botox if they have a neuromuscular disorder, if they are taking aminoglycoside antibiotics, which cause an increased sensitivity to the drug, or if they are pregnant, trying to conceive or breast-feeding, according to Dr. Lipham.

In addition, patients with egg allergies may have an increased likelihood of an allergic reaction since the Botox molecule is stabilized by human albumin, a protein that is similar to egg albumin, Dr. Lipham said.

Allergan representatives said a cross-reaction is a very low probability.

Botox over time

Dr. Putterman, who participated in early clinical trials with Botox, said there is no data to suggest that patients should limit the number of injections they undergo. He said he still treats some of the same patients who started Botox injections 20 years ago, and they have experienced no adverse reactions.

Patients generally return for an injection within 3 to 6 months, surgeons said. The dose depends on the patient’s muscle mass and sex, but it is usually in the range of 2 units to 5 units per 0.1 cc.

While some literature suggests that patients may develop a tolerance to Botox, Dr. Putterman said he has also seen the opposite effect. “You can become immune to [Botox], where it’s not as effective as it was to begin with,” he said. “But on the other hand, at times, these muscles that you are injecting into atrophy because they’re not being utilized. So sometimes the effect is even better with time.”

He estimated that 10% to 20% of his patients may need a greater dosage or require more frequent injections. Less than 5% of patients will develop a complete immunity to Botox, he said. In these instances, Dr. Putterman said he either prescribes another drug (such as botulinum toxin type B) or recommends surgical intervention.

For Your Information:

  • 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.
  • Mark R. Levine, MD, can be reached at 1611 S. Green Road, Suite 306A, S. Euclid, OH 44121; (216) 291-9823; fax: (216) 291-0550; e-mail: m.levine@eye-lids.com. Dr. Levine 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: (612) 920-0441; 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.
  • Allen M. Putterman, MD, SC, can be reached at 111 N. Wabash, Suite 1722, Chicago, IL 60602; (312) 372-2256; fax: (312) 372-1762; e-mail: puttermanmd@hotmail.com. Dr. Putterman 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.

References:

  • Fagien S. Botulinum Toxin Type A for Facial Aesthetic Enhancement: Role in Facial Shaping. Plastic Reconstr Surg. 2003;112 (Suppl.): 6S.
  • Fagien S. Botox for the Treatment of Dynamic and Hyperkinetic Facial Lines and Furrows: Adjunctive Use in Facial Aesthetic Surgery. Plast Reconst Surg. 1999;103:701.
  • Fagien, S. Treatment of Hyperkinetic Facial Lines with Botulinum Toxin. In: Putterman A, ed. Cosmetic Oculoplastic Surgery: Eyelid, Forehead, and Facial Techniques. 3rd ed. Philadelphia, PA: W.B. Saunders Co.; 1998:377-388.

The applications for Botox seem endless. Since Allergan’s botulinum toxin type A received approval from the Food and Drug Administration in 1989, its indications have quickly expanded. Once a therapy limited to ocular dystonias, Botox is now used in numerous areas throughout the body, with applications ranging from medicinal to cosmetic.

“An interesting aspect about Botox, from our perspective, is that it has ophthalmology roots. Ophthalmologists, mostly with an oculoplastic surgery background, have treated eyelid spastic disorders with botulinum toxin for years, so at first it was an easy transition to its use for aesthetic purposes,” said Steven Fagien, MD, an oculoplastic surgeon in Boca Raton, Fla. “But by and large the general ophthalmologist was not using Botox until now.”

Nearly all of the surgeons interviewed about Botox for this article said that they have seen a steady rise in its popularity and that their colleagues continue to find off-label uses for the product. In this first article in a three-part series, Ocular Surgery News recounts the history of Botox and examines its current applications.

In the next two installments, we will explore what may be next for Botox and how physicians can incorporate it into their practices.

Historical perspective

Surgeons first tested botulinum toxin A in humans in 1978, when Alan B. Scott, MD, received permission from the FDA to study the drug’s effect on strabismus. Ten years later, Allergan acquired the rights to distribute the drug, marketed first as Oculinum, and conducted additional trials for indications including benign essential blepharospasm and cervical dystonia.

Allen M. Putterman, MD, SC, who participated in the first FDA trials at the University of Illinois, noted that early studies focused on treating eye muscle hyperactivity and blepharospasm, and researchers “absolutely [did] not” realize the potential for other applications with Botox.

“At that time, I think the main [concerns] were not knowing where to inject or how much to inject,” said the Chicago-based surgeon, who has been administering Botox for more than 20 years. “There was a lot of trial and error in determining the sites and the dosages.”

In 1992, Alastair Carruthers, MD, MRCP, FRCPC, and his wife Jean Carruthers, MD, FRCPC, FRCOphth, issued the first report suggesting that Botox could be used for cosmetic purposes.

“From functional patients, they made the transition to actually begin treating for cosmetic indications,” said William Lipham, MD, FACS, of Bloomington, Minn. “Since that time, a number of individuals in a variety of disciplines, including outside of ophthalmology, have noted that Botox can be used to inactivate muscles that cause lines to develop.”

Five common Botox complications and how to prevent or manage them

Complication Prevention/Management
Pinpoint bleeding Apply pressure with gauze pad
Infection of injection site Cleanse skin with alcohol prior to injection
Diplopia Avoid the inferior oblique muscles
Ecchymosis Instruct patients to avoid anticoagulants (including asprin, blood thinners and large doses of vitamin E) for 1 to 2 weeks before injection; apply ice immediately after injection
Ptosis Usually resolves within 2 to 3 weeks without intervention; 2.5% phenylephrine solution may also be administered on the inside of the upper eyelid

Source: Surgeon interviews

Mechanism of action

Dr. Lipham said that most patients and even some physicians hold misconceptions about how Botox works. “Botox exerts its effect by inactivating nerves that stimulate muscles to contract,” he said. “And the way it does that is that it is [blocking] the release of acetylcholine, which is a neurotransmitter, from the nerve.”

He said that the most common fallacy among cosmetic patients is that Botox can “fill” lines. Botox actually works by inactivating muscles that are responsible for overactive facial expression. It does not target wrinkles, but the muscles that cause them to develop, he said.

“Because it’s working in this fashion, it tends to be a preventative type of cosmetic product or indication. So you’re typically not giving Botox to fill lines that are present at rest,” Dr. Lipham said.

Without acetylcholine, the muscle atrophies, according to Allergan representatives. It takes 3 to 4 months for the old nerve terminal activity to be restored.

“The best analogy [for] when I’m trying to explain it to patients is that the Botox molecule doesn’t sit around and do something actively for 3 months. I think that’s the biggest misconception. Really what happens is that [Botox] does its job in about 3 to 4 days,” Dr. Lipham said.

Customizing procedures

Dr. Fagien, who codirects the Plastic Surgery Education Initiative supported by an unrestricted educational grant from Allergan, said that many surgeons also tend to get “distracted” by the idea of the use of Botox simply as a line eradicator.

“Actually we can do much more, including … considering it as an agent for facial shaping,” he said.

Surgeons must understand not only facial anatomy but also how different individuals use their muscles, he added.

“What we are doing is affecting animation,” he said. “And until [surgeons] really understand that, you can’t even begin to understand the advanced applications of Botox.”

Surgeons can glean a lot of necessary information about their patients during the interview, Dr. Fagien noted.

“Look at how [patients] look in repose, when they are at rest; look what happens even while you’re speaking with them – watch how they animate. That will give you certain clues about what they do all the time,” he said. “When you look at these patients, you also must think anatomically.”

Figure 1 Figure 2
Treatment of mild to moderate blepharospasm: Injection of the pretarsal and preseptal portion of the orbicularis muscle. Typical initial doses consist of 2.5 units of Botox to the medial and lateral aspect of the upper eyelid along the eyelid crease. Since the skin is only 60 µm thick in this region, the injection is given subcutaneously to avoid penetrating the underlying septum and inducing ptosis of ther upper eyelid.
Figure 3 Figure 4
Contraction of the lateral orbicularis oculi muscleis responsible for the creation of active lines or wrinkles that radiate from the lateral canthal angle which are commonly referred to as “smile lines” or “crow’s feet.” Injection of this area with botulism toxin softens these lines, as seen in this patient (A) prior to botulinum toxin administration and (B) 1 month after injection.
(Images courtesy of Cosmetics and Clinical Applications of Botulinum Toxin; SLACK Incorporated.)

Learning curve

Dr. Fagien suggested that surgeons who are just beginning to use Botox start by treating only the upper one-third of the face because muscle anatomy becomes more complex in the lower regions.

Mark R. Levine, MD, a Cleveland surgeon who participated in the early blepharospasm trials, said physicians may need to perform as many as a dozen procedures before they become proficient.

“It’s really technique-driven,” he said. “[Novices] can get some unfortunate results.”

Many complications can be avoided with proper placement of the injection, he added. For instance, an injection that misses its target may interfere with the patient’s ability to raise his or her eyebrows and cause asymmetry of the brows. When surgeons inject Botox in the upper lid, they increase the risk of causing a ptosis. Improperly placed injections in the lower lid may cause diplopia or ectropion, Dr. Levine said.

The technique is not difficult to learn, and many books and articles have been written on how to do it, he said.

Dr. Fagien also urged surgeons to read as much as they can on the subject, from studies in medical journals to articles in the lay press. “There are few things that we do in our practices that are so effective and predictable if you have a good fund of knowledge and a greater appreciation of its aesthetics,” he said.

Complications

Dr. Lipham noted that the risk for complications often depends on where the injection is administered. Patients with blepharospasm and hemifacial spasm, for instance, require Botox injections along the eyelid crease and are at a greater risk for developing upper eyelid ptosis, he said.

Upper eyelid ptosis is caused when Botox diffuses behind the orbital septum and weakens the levator muscle, Dr. Lipham said. He estimated that this complication occurs in about 10% of patients treated for blepharospasm or hemifacial spasm. The incidence of upper eyelid ptosis when Botox is injected for cosmetic indications, however, is much lower, and it rarely occurs when the product is administered properly.

Patients should not receive Botox if they have a neuromuscular disorder, if they are taking aminoglycoside antibiotics, which cause an increased sensitivity to the drug, or if they are pregnant, trying to conceive or breast-feeding, according to Dr. Lipham.

In addition, patients with egg allergies may have an increased likelihood of an allergic reaction since the Botox molecule is stabilized by human albumin, a protein that is similar to egg albumin, Dr. Lipham said.

Allergan representatives said a cross-reaction is a very low probability.

Botox over time

Dr. Putterman, who participated in early clinical trials with Botox, said there is no data to suggest that patients should limit the number of injections they undergo. He said he still treats some of the same patients who started Botox injections 20 years ago, and they have experienced no adverse reactions.

Patients generally return for an injection within 3 to 6 months, surgeons said. The dose depends on the patient’s muscle mass and sex, but it is usually in the range of 2 units to 5 units per 0.1 cc.

While some literature suggests that patients may develop a tolerance to Botox, Dr. Putterman said he has also seen the opposite effect. “You can become immune to [Botox], where it’s not as effective as it was to begin with,” he said. “But on the other hand, at times, these muscles that you are injecting into atrophy because they’re not being utilized. So sometimes the effect is even better with time.”

He estimated that 10% to 20% of his patients may need a greater dosage or require more frequent injections. Less than 5% of patients will develop a complete immunity to Botox, he said. In these instances, Dr. Putterman said he either prescribes another drug (such as botulinum toxin type B) or recommends surgical intervention.

For Your Information:

  • 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.
  • Mark R. Levine, MD, can be reached at 1611 S. Green Road, Suite 306A, S. Euclid, OH 44121; (216) 291-9823; fax: (216) 291-0550; e-mail: m.levine@eye-lids.com. Dr. Levine 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: (612) 920-0441; 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.
  • Allen M. Putterman, MD, SC, can be reached at 111 N. Wabash, Suite 1722, Chicago, IL 60602; (312) 372-2256; fax: (312) 372-1762; e-mail: puttermanmd@hotmail.com. Dr. Putterman 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.

References:

  • Fagien S. Botulinum Toxin Type A for Facial Aesthetic Enhancement: Role in Facial Shaping. Plastic Reconstr Surg. 2003;112 (Suppl.): 6S.
  • Fagien S. Botox for the Treatment of Dynamic and Hyperkinetic Facial Lines and Furrows: Adjunctive Use in Facial Aesthetic Surgery. Plast Reconst Surg. 1999;103:701.
  • Fagien, S. Treatment of Hyperkinetic Facial Lines with Botulinum Toxin. In: Putterman A, ed. Cosmetic Oculoplastic Surgery: Eyelid, Forehead, and Facial Techniques. 3rd ed. Philadelphia, PA: W.B. Saunders Co.; 1998:377-388.