By Arnold William Klein, MD
Botox was the wonderchild of cosmetic enhancement of the 21st century. Although approved in 1989 as an orphan drug for neurologic conditions of the eye, in April 2002 the FDA approved botulinum toxin type A (Botox Cosmetic) to temporarily improve the appearance of moderate to severe frown lines between the eyebrows (glabellar lines). To some, it seemed virtually “goof-proof”. For others, it provided a wonderful reason to throw a party. Doctors who dispensed Botox prospered; most patients were happy; and Allergan, the manufacturer of Botox, got rich. For a time, it seemed that Botox truly was a paradise for all.
The Botox party wouldn’t last for long however. In 2003, unusual things began to happen. The chief consultants for Allergan went to work for other cosmetic companies. Not only did they lobby the FDA to get such new agents as Artefill (injectable plexiglass for wrinkle correction) approved, they injected these new products across America to a euphoric public eager for anything new.
There was however one tiny problem; these consultants were foreign and had neither green cards nor licenses to practice medicine in the U.S. With industry money behind them, however, they became very powerful lobbyists to the FDA to get new toxins approved.
In the same year, these same consultants attempted to get a paper published on why dilution (the ratio of Botox to saline in an injection) of Botox did not matter. Their assertion was that if you added more liquid, increasing the volume of the injection, there were no additional side effects. It would be a boom to the drug company—the easier the formulation for Botox, the greater the draw of potential injectors. This would result in increased sales for Allergan, but at the expense of the general public because the data these consultants collected from their research made no sense.
Common sense dictates that if you add more liquid to a solution, it will spread further when poured out, but that concept was apparently alien to this study. Botox works by arresting the chemical reaction that causes most muscles to contract, thereby temporarily paralyzing the muscle. The greater the volume of Botox used, the larger the spread of this paralysis. If it spreads to a muscle that a person needs to keep moving, such as the eyes, a person would be unable to see. If it spreads to a muscle that is critical for life, such as one that deals with swallowing, then life threatening problems can occur. In response to a negative outcry from one of the doctors who reviewed the study’s findings, the foreign doctors did the ‘logical’ thing—they changed the data (1). With changed data indicating that there were no additional side effects, the company could start raking in the money.
This paper with altered data was held for a few years, but then it was published in 2007 accompanied by a paper on a product called Myobloc, which these consultants deemed safe and effective. These consultants attempted to add two other well known research doctors’ names to this paper, but those doctors refused to be included.
Why? The literature surrounding this agent showed it capable of causing severe side effects distant to the site of injection and Myobloc had been found in foreign studies to be more toxic than U.S. studies had shown. The drug company paid to have the paper published (sans the two doctors’ names) in a competent medical journal (1).
As these consultants lobbied and spread their altered data reports throughout the medical community, a very troubling thing began to happen in the world of cosmetic medicine. Some people fell ill after being injected. Deaths were also reported, but this was more from the use of these products in neurologic conditions than in cosmetic conditions. Nevertheless, these patients were dead from the effects of too much product in the dilutions.
Altering data, patient deaths due to the possibility of a greater spread of the toxin from increased volume, and questions about how a government agency didn’t examine the findings more closely seems like fodder for a dime store spy novel, not for the world of cosmetic medicine. But the facts are there. The conclusions we can draw from it make the U.S. seem like a 3rd world corrupt power, not the world leader and innovator that Americans think we are.
In January of 2008, Dr. Sidney Wolfe and the Public Citizen Health Research Group petitioned the FDA to respond to what was happening: they wanted an explanation as to the spread of toxin from the site of injection, the associated weaknesses some patients had after injections, the inability to swallow, and, of course, the causes of death in extreme cases. They also requested that the FDA require patients who have had a Botox treatment to be given a “written warning” to make them aware of the toxin spreading to other parts of the body. Other countries, including Germany and England, already required patients be given pamphlets to recognize symptoms, including difficulty breathing and swallowing. A report in a German Weekly news magazine Focus announced that the London Based European Medicines Agency had, by August 2007, recorded more than 600 cases of negative effects potentially linked to Botox. In 28 cases, Botox users died, and in Germany, the Federal Institute for Medication and Medical Products had received 210 reports with a suspected link to Botox—five of the cases were lethal (13). In Canada, Health Canada (the Canadian equivalent of the FDA) and Allergan had already dealt with these problems as well.
One must wonder why the U.S. FDA was not aware of this information and why it took Sidney Wolfe and his Public Citizen Health Research Group to petition the agency to look into the matter?
The FDA response came from Janet Woodcock, Director of the Center for Drug Evaluation at the FDA. This 19 page response really does not provide the breadth of information available on toxins. Issues that were not touched upon include:
1) Dilution: A review of all the available studies on children with spasticity in two medical search sources revealed that concentration and volume of the diluted toxin can affect the spread. Furthermore, injection techniques were highly variable from center to center (2). Though the FDA previously cautioned Allergan about dilution, that information, which would be important, cannot be found in the FDA response to Wolfe (3).
2) Myobloc: While Dysphagia (difficulty swallowing) can be associated with botulinum toxin type A, it occurs with a much greater frequency with type B. Even when treating the distal legs, doctors have seen difficulty swallowing with type B and it has been noted even when the toxin is used to control excess sweating. The company Skin Medica at one point was considering acquiring this toxin, but a clinical trial for treatment of the glabella revealed such severe side effects that the purchase was never completed by the company.
3) Mechanism of Action: Inhibition of the release of Acetylcholine: This was once considered its only mode of action, but how could this explain the manner in which it relieved pain in patients who had shingles or even improvement in migraines? Furthermore, this is not the manner in which it affects spasticity. Research has shown that botulinum toxin type A decreases spasticity by its action primarily on muscle spindles which are bodies found in almost all muscles of the limbs. These spindles then give signals to other spindles within the area which accounts for the profound effect of Botox on spasticity, which is greater than the normal zone of diffusion. Additionally, when correctly injected, Botox will affect spasticity without creating muscle weaknesses. In regards to pain, this is most probably due to a blockade of neurotransmitters such as substance P-glutamate and calcitonin gene-related peptide (7,8,9). Thus, the inhibition of acetylcholine release is only one mode of action and in no way explains its action on pain or spasticity.
The response article attempts to treat all toxins the same. This is a very dangerous assumption to be making in a scholarly reply. Furthermore, it attempts to use the same injection pattern for all toxins. This pattern was developed specifically for Botox based on its diffusion (10). Toxins such as Purtox, Xeomin, Myobloc and Dysport have a lighter molecular weight and thus diffuse to a greater extent than Botox. You cannot compare a Type B toxin to a Type A (12). Type B is known to have severe distant side effects! Furthermore, 2000U of Myobloc was used to treat the frown in a study where 20 units of Botox were used. The ratio of units required would, at higher levels, be lethal. Myoboc is not safe and effective and should never be compared to Botox. Unfortunately, the literature developed by the lobbyists and paid for by the drug company says it is safe and effective. It is the written word that doctors believe.
Somehow, somewhere there should be a source of information which is independent of the drug companies, and reflects what is truly known in this field. Yet we are at a time in medicine where the truth is considered a source of great controversy. And unfortunately, that utopian Botox Paradise of 2002 now has become a Paradise Lost and for some patients, a nightmare.
Who regulates the FDA? Foreign lobbyists on drug company payrolls? It appears that may just be the case.
1) Dilution Volume of Botulinum Toxin Type A for the Treatment of
Glabellar Rhytides: Does It Matter?
Carruthers, A; Carruthers, J; and Cohen, J
Dermatologic Surgery 2007; 33:S97–S10
2) 1: Am J Phys Med Rehabil 2004 Oct; 83(10 Suppl):S59-64
Botulinum toxin A injections in children: technique and dosing issues
Kinnett D.
3) Francisco GE
Botulinum toxin: dosing and dilution.
Am J Phys Med Rehabil (2004 Oct); 83(10 Suppl):S30-7
4) Rossi, RP; Strax, TE; Di Rocco, A
Severe Dysphagia after botulinum toxin B injection to the lower limbs and lumbar paraspinal muscles
Am J Phys Med Rehabil (2006 Dec); 85(12):1011-3
5) Arch Dermatol Feb 2003; 139:226-227 (get author)
6) Information on file: Skin Medica and Elan
7) On, AY; Kirazli, Y; Kismali, B; Aksit, R
Mechanisms of action of phenol block and botulinus toxin Type A in relieving spasticity: electrophysiologic investigation and follow-up
8) Am J Phys Med Rehabil (1999 Jul-Aug); 78(4):344-9
Botulinum Toxin and Possible Central Effects
Aoki, R
J Neurol April 2001; 248(Suppl 1)1/3-1/10
9) Dressler, D; Adib Saberi, F
Botulinum toxin: mechanisms of action
Eur Neurol (2005); 53(1):3-9
10) The therapeutic potential of botulinum toxin
Klein, AW
Dermatol Surg (2004 May); 30(3):452-5
11) Cosmetic therapy with botulinum toxin, Anecdotal memoirs
Klein, AW
Dermatol Surg (1996 Sept); 22(9):757-9
12) Dolly, JO; Aoki, KR
The structure and mod of action of different botulinum toxins
Eur J Neurol (2006 Dec); 13 Suppl 4:1-9
13) Focus, German weekly news magazine (2008 Sept 1)
Arnold William Klein, MD 