From Botulism to Botox

Rebecca J. Anderson, PhD

On December 14, 1895, a group of Belgian musicians in the village of Ellezelles performed at the funeral of 87-year-old Antoine Creteur (1-3). Afterwards, as was the custom, the mourners and musicians gathered for a meal at Le Rustic, a local inn (2, 3). Within a few days, 34 people in the group developed symptoms of botulism, and three of the musicians died. Ten others nearly died (2, 3). Some of those survivors experienced visual problems for 6-8 months (2)

Poisoned Sausages

Humans have probably known about food poisoning as long as they have tried to preserve and store food. Although there are scanty descriptions in the ancient literature, long-standing dietary laws and taboos attest to concerns about eating certain foods (3, 5).

The first documented cluster of food poisoning cases occurred at the end of the 18th century in the German Kingdom of Württemberg (now the German Federal State of Baden-Württemberg) (4, 6, 7).

The Napoleonic Wars had caused widespread poverty, resulting in a decline in hygienic standards for rural food production (3-6). Some people were stricken with an odd pattern of symptoms including blurry vision, drooping eyelids, slurred speech, difficulty swallowing, and severe muscle weakness (6). The symptoms were linked to the consumption of meat, especially a favorite rural dish called Saumagen, which was pork stomach stuffed with blood sausage (3)

After a spike in food poisoning fatalities, government officials in the state capital of Stuttgart took action. In July 1802, they issued a warning to the public on the “harmful consumption of smoked blood sausage” (4-6)

Health officials attributed the Württemberg sausage deaths to contamination with prussic acid (i.e., hydrogen cyanide) (3, 4, 6). But they also asked the medical faculty at the nearby University of Tübingen for their opinion. The professors disputed the prussic acid theory and suspected the poison was organic.

Johann Heinrich Ferdinand Autenrieth, possibly the most influential Tübingen medical professor, was especially intrigued and probed deeper. He studied the medical records sent by the health officers and attending physicians, who had made detailed observations of their poisoned patients. Autenrieth then compiled and issued a list of “sausage poisoning” symptoms (gastrointestinal problems, double vision, and dilated pupils) and concluded that the sausages had not been boiled long enough (3, 4).

In 1815, Autenrieth received seven case reports from JG Steinbuch, a health officer in Herrenberg, Württemberg. All of the victims had eaten a meal of liver sausage and peas, and three of them died. Steinbuch also sent Autenrieth his autopsy results on the deceased victims (3, 4)

At the same time, Justinus Andreas Christian Kerner, a 29-year-old medical officer in Welzheim, Württemberg, also sent a case report of lethal food poisoning to Autenrieth, who had been his medical school professor at Tübingen. Autenrieith considered

Steinbuch’s and Kerner’s reports to be accurate and important medical contributions. He published their observations in 1817 in the Tübinger Papers for Natural Sciences and Pharmacology (3, 4)

A Complete Description

Kerner continued documenting cases of “sausage poisoning” and published his initial findings in 1820. This monograph summarized the case histories of 76 patients and contained the first complete clinical description of what neurologists now recognize as botulism (3, 4)

Those symptoms included stomach cramps, diarrhea, vomiting, intestinal paralysis, dry mouth, reduced secretion of tears, sweat, nasal mucus, and ear wax, weakened muscles of the esophagus, stomach, and bladder, dilated pupils, blurry vision, droopy eyelids, double vision, paralysis of pharyngeal and respiratory muscles, and generalized weakness (3). Kerner also concluded that the brain was not affected, because the patients remained conscious.

Kerner then moved to Weinsberg, Württemberg, to take the post of medical officer, and he intensified his clinical research of “sausage poisoning.” Altogether, he documented 155 cases, including postmortem exams (3, 4).

Kerner’s Experiments

In 1821, Kerner received a small grant from the state government to continue his research (3, 4). He developed a method for extracting and isolating the unknown toxic substance from spoiled sausages. He then mixed this extract with honey and fed it to birds (4 ravens, 2 owls, 2 sparrows, 3 robins, 1 pigeon, and 1 titmouse), 12 cats, and 4 rabbits, as well as frogs, flies, locusts, and snails (3, 4, 6, 8). The animals exhibited the same adverse effects as he had seen in the patients suffering from “sausage poisoning” (6)

Kerner also recognized the poison’s clinical similarities to known neurological poisons, such as nicotine and snake venom. Like Autenrieth, he concluded that the “sausage poison” was probably of biological or animal origin (3, 6). So, he reviewed the various recipes and ingredients of the spoiled sausages, looking for the source of the toxin.

The only common ingredients were fat and salt. He discounted salt, a widely used preservative, and concluded that the toxin must have been produced in the fat (3, 4). He, therefore, referred to the toxin variously as “fatty poison” and “fatty acid,” as well as “sausage poison” (3, 5).

In other experiments, Kerner inserted his sausage extracts into small incisions in the thighs of rabbits and cats. The paralytic effect was restricted to the toxin-treated tissue, and the animals recovered (6). He concluded that “…the fatty acid, if applied to a wound, has only a very slow effect on the animal’s body, especially if the wounds are on the extremities” (7).

Kerner’s final experiment was testing the sausage extract on himself, despite the deaths of two of his colleagues who had previously attempted similar experiments (7). It tasted sour, much like the spoiled sausages (6). “A few drops of this acid placed onto the tongue cause…this feeling of contraction and choking in the area of the larynx” (7)

After taking a larger dose, he said, “a feeling of listlessness and tension in the eyelids results, the eyes go stupid, one feels a slight burning in the urea, dull pain in the stomach, constipation, and very dry palms and soles of the feet” (7). When Professor Autenrieth heard about these self-administration experiments, he urged Kerner to stop (3)

From his clinical and experimental observations, Kerner concluded that the toxin develops in bad sausages under anaerobic conditions, is a biological substance, is potent and lethal even in small doses, and acts selectively on the motor and autonomic nervous systems without affecting sensory transmission or the brain (3, 4, 6-8). Death was caused by extreme muscle weakness leading to respiratory and cardiac failure (3, 7). “The capacity of nerve conduction is interrupted by the toxin in the same way as in an electrical conductor by rust,” he said (4). Although pathogens and bacteria were unknown at that time, Kerner’s conclusions were remarkably insightful.

In 1822, Kerner published all of his clinical and animal results in a 368-page monograph. Based on his findings, he said, poisoning could be prevented by thoroughly boiling sausages, storing them under aerobic and dry conditions, and avoiding consumption of the “bad parts” (3, 4)

For those who were suffering from “sausage poisoning,” Kerner could only recommend symptomatic treatment. Among those treatments, he invented an elastic tube that permitted patients to receive adequate nutrition and avoid aspiration. This invention is considered the first documented application of a successful gastric tube (3, 4)

Wurst-Kerner

In the final chapter of his 1822 monograph, Kerner speculated that the toxin might reduce or block hyperactivity and hyperexcitability states of the motor and autonomic nervous systems (3, 4, 7, 8). Small doses could actually be therapeutic.

He favored using the toxin to treat St. Vitus’s dance (Sydenham chorea) and to reduce excessive sweating and mucus (3, 4, 7). He also suggested more diverse therapeutic applications, such as treating infections, ulcers from malignant diseases, burns, tumors, viper bites, delusions, rabies, plague, consumption (tuberculosis), and yellow fever (4, 5). Kerner freely admitted that all of these applications were merely suggestions and needed to be confirmed or disproved by experimental studies (3, 4).

As a result of his publications, Kerner was widely acclaimed as an expert on “sausage poisoning” and was commonly referred to as “Wurst-Kerner” (“sausage Kerner”). “Sausage poisoning” was sometimes called “Kerner’s disease” (3, 4, 6).

In 1869, H. Müller, a German physician, coined the term “botulism” to refer to the sausage poisoning syndrome. Müller derived the word from the Latin botulus, meaning sausage (4, 5, 7).

The Belgian Connection

In 1895, the Ellezelles coroner attributed the deaths of the three Belgian musicians to food poisoning. Their symptoms included dilated pupils, double vision, difficulty swallowing and breathing, inarticulate speech, dry mucous membranes, urine retention, constipation, and severe muscle weakness (2, 3). The illness was traced to a spoiled ham eaten at a post-funeral meal at Le Rustic (2).

The Ellezelles public prosecutor ordered a chemical analysis of the ham, and two of the victims were autopsied (2, 3). He also asked Professor Emile Pierre-Marie van Ermengem in Ghent to investigate. Van Ermengem was given the test results, along with samples of the spoiled ham and organs collected from the autopsies (1, 2).

Unlike Kerner, Autenrieth, and the other physicians who had reported cases of “sausage poisoning” in earlier years, Van Ermengem had a tremendous advantage. He had received his medical degree from the Catholic University of Leuven, Belgium, in 1875 and continued his clinical training in London, Edinburgh, and Vienna. In 1883, worked in the laboratories of Robert Koch (a pioneering microbe hunter) in Berlin. In 1888, Van Ermengem was appointed Professor of Microbiology at the University of Ghent (2)

Van Ermengem first reviewed the attending physicians’ clinical observations and autopsy reports. He found a clear correlation between the amount of spoiled ham consumed by the 34 victims (including the 3 who died)

Emile Pierre-Marie van Ermengem and the severity of the symptoms (2). In the histological sections of the spleen of one victim, Van Ermengem saw numerous anaerobic bacteria (2, 3)

He also saw considerable invasion of anaerobic bacteria in the spoiled ham (2, 3). After studying the process that had been used to prepare the Le Rustic ham, Van Ermengem concluded that it had been improperly cured (2).

Next, Van Ermengem injected tiny bits of contaminated ham subcutaneously into cats, pigeons, monkeys, guinea pigs, rabbits, and mice. The animals exhibited symptoms similar to the Ellezelles victims. Oral administration to monkeys, guinea pigs, and mice produced the same symptoms. In the rabbit, the lethal dose by subcutaneous injection was extremely low: only 0.0005 mg (2).

The anaerobic bacterium that Van Ermengem isolated from the ham and the organs of the Ellezelles victims had numerous villi. When grown in tissue culture, its spores produced a gas with a rancid odor (2, 5).

From his analysis, which he published in 1876, Van Ermengem concluded that the bacterium itself caused little harm. Rather, he confirmed Kerner’s deduction that the agent responsible for the clinical syndrome was a toxin, produced by the bacteria under anaerobic conditions (5, 7)

Van Ermengem named the bacterium Bacillus botulinus, because the clinical symptoms were similar to the “sausage poison” syndrome long known in southern Germany. The toxin is now called botulinum toxin, and as little as 0.1 microgram can be fatal to humans (2).

In 1917, the nomenclature committee of the Society of American Bacteriologists redefined two distinct genus groups of bacteria: Bacillus and Clostridium. Aerobic microorganisms were assigned to Bacillus, and anaerobic, rod-shaped, spore-forming bacteria were assigned to Clostridium. So, Van Ermengem’s tadpole-shaped Bacillus botulinus became Clostridium botulinum (5).

Grouping the Toxins

For a long time, based on Kerner’s and Van Ermengem’s results, health officials thought that only poorly stored meat and fish caused botulism. Examples included ham in barrels of brine in France, poorly dried and stored herring in the Baltic, fermented trout packed in willow baskets in Scandinavia, and liver sausages swinging from the rafters of Austrian huts (3, 5).

That view changed in 1904. In Darmstadt, Germany, 21 people ate canned white beans, and 11 of them died from botulism. Investigators isolated bacteria from the canned beans and compared it with the bacteria from the Ellezelles ham. It was, indeed, a case of botulinum toxicity. But interestingly, they found that the C. botulinum strains were different, and the two botulinum toxins were serologically distinct (3, 5).

In 1919, Georgina Burke at Stanford University examined 12 strains of C. botulinum, including 5 outbreaks of botulism from home-canned fruits and vegetables (5, 9). Based on her laboratory assay, which measured toxin-antitoxin reactions, Burke identified two biologically distinct botulinum toxins. She designated them Type A and Type B (9).

Microbiologists now recognize seven distinct antigenic types of botulinum toxin: A through G. Of those, botulinum toxin Types A, B, E, and F are responsible for human cases of botulism (5). Type A is by far the most potent and prevalent (7). It is 100 times more toxic than cyanide (10)

Achieving Purity

In 1928, P. Tessmer Snipe and H. Sommer at the University of California San Francisco first isolated botulinum toxin as a stable acid precipitate (11). During World War II, military authorities became interested in the isolated botulinum toxin because of its extremely high potency (10).

Edward Schantz, while serving in the US Army, helped produce and evaluate the toxin’s potential as a biological weapon (12, 13). But Schantz’s research team at Fort Detrick, MD, concluded that botulinum toxin had only limited battlefield applications (10, 12)

In 1946, Schantz, now an Army reserve officer, became head of the chemistry branch at Fort Detrick’s Biological Research Center (12, 13). Along with Carl Lamanna and others, Schantz developed methods for crystallizing pure botulinum toxin Type A (5, 13, 14). They also determined its chemical structure and developed a process for standardizing and stabilizing it (7, 13).

Schantz generously supplied his purified toxin to basic researchers and clinical investigators. He also provided advice on how to handle it, including his assay method, which was widely adopted (13).

The innovative studies of those researchers led to a better understanding of the toxin’s pharmacological actions (7). Using systemic administration as well as injecting individual muscles, academic researchers determined the toxin’s selectivity for various types of muscle, its duration of action, and its systemic potency.

In 1949, British physician and pharmacologist Sir Arnold Burgen and his colleagues at Middlesex Hospital Medical School in London conducted a comprehensive and convincing series of experiments using the isolated rat phrenic nerve-diaphragm preparation (15). They used the Type A toxin for most of their studies, because it was much more potent than Type B. Burgen definitively showed that botulinum toxin’s mechanism of action was blocking the release of acetylcholine from nerve terminals (15)

This discovery inspired other laboratory researchers to further characterize the toxin’s actions. Botulinum toxin does not cause nerve terminal degeneration, but the toxin-induced blockade of acetylcholine release is irreversible (16). Neurotransmission is restored by sprouting nerve terminals and the formation of new synaptic contacts, which usually takes 2-3 months (2, 16)

From Poison to Drug

In parallel with the laboratory studies, clinicians pursued therapeutic applications. Ophthalmologists had long been interested in non-surgical manipulation of ocular muscles to realign the eyes of patients with strabismus (cross-eyed). One of the first investigators was Conrad Berens, who injected alcohol into the eye muscles. Unfortunately, the effect either was inadequate or, occasionally, caused permanent paralysis. Other ophthalmologists tried to correct strabismus with a variety of drugs including local anesthetics but without much success (5, 17).

In the late 1960s, Alan Scott, an ophthalmologist in San Francisco, experimented with several substances on monkeys in which he had induced strabismus via a surgical procedure (1, 5). Although these early experiments were unsuccessful in correcting strabismus, Scott mastered a technique for drug injection into specific extraocular muscles using a custom-designed needle and developed criteria for evaluating the effects (5).

Then, Alfred Maumenee, a California colleague who had worked with Schantz at Fort Detrick, suggested that Scott might try botulinum toxin (5). Using Schantz’s highly purified botulinum toxin Type A, Scott conducted the first of his now-classic experiments.

In his experimental monkey model, botulinum toxin produced localized paralysis of the targeted eye muscles for a reasonable period of time and without side effects (10). Scott published the monkey results in 1973 (17).

In 1972, Edward Schantz retired from Fort Detrick and became a biochemist in the Food Research Institute at the University of Wisconsin (13). He continued his studies of neurotoxins and also continued to supply his purified botulinum toxin Type A to other researchers, including Scott (12, 17)

Oculinum

In 1977, the Food and Drug Administration (FDA) permitted Scott to begin clinical trials (10, 17). Drug companies were not interested in his ophthalmology treatment, which they considered an orphan indication. Scott took out a mortgage and asked for small donations from doctors, who then assisted with the trials (18). Scott renamed the toxin Oculinum (undoubtedly to conceal “botulinum toxin” from his patients) and formed a company, Oculinum, Inc., in Berkeley, CA, to distribute it (5, 16, 19).

In 1978, Scott injected his first patient with botulinum toxin (18). The patient had undergone three failed operations for double vision (10). One of his eyes pulled to the side. When Scott first injected botulinum toxin into the patient, he later told Scientific American, “I don’t know if he was more nervous or I was more nervous” (10)

Altogether, Scott injected 132 doses of botulinum toxin Type A into 42 patients with strabismus, and it was “uniformly beneficial” (17). Oculinum was effective and could be re-injected without allergy or loss of potency.

The effect lasted between 2 weeks and 8 months (depending on the dose), left the muscle normal after the toxin’s effects wore off, and induced no systemic effects. The only local complication was weakening of adjacent eye muscles. Scott published his clinical results in 1980 (17).

In December 1989, Scott received approval from the FDA for Oculinum (botulinum toxin Type A) to treat strabismus, blepharospasm, and hemifacial spasm (1, 5, 16, 18). Blepharospasm is a neurological condition in which the eyelids are involuntarily forced shut. Hemifacial spasm is involuntary contraction of facial muscles on one side of the face.

Until the FDA approved botulinum toxin, the options for patients with blepharospasm were either medication, which doesn’t always work, or surgery (10). Most experts now consider botulinum toxin the first line of treatment for both blepharospasm and hemifacial spasm (1)

Clinicians from around the world visited Scott to learn how to selectively inject the targeted eye muscles using his special needle apparatus. When they left, he gave them samples of Oculinum (5).

Enter: Botox

Although the drug was eagerly embraced by ophthalmologists, Scott had no desire to become a pharmaceutical manufacturer (10, 18). In 1991, he sold his Oculinum rights to Allergan in Irvine, CA, for $9 million (5, 19, 20).

Allergan had primarily been an eye care company with products like contact lens cleaners and prescription solutions for dry eyes (19). Sales of those products generated revenues of about $500 million annually. The company saw Scott’s drug as a niche product to treat strabismus, which affects about 4% of the US population. By the end of 1991, Allergan had collected about $13 million in botulinum toxin sales (19).

In 1992, Allergan rebranded the drug as Botox (5, 18, 20). Schantz’s lab in Wisconsin continued to produce and purify all the botulinum toxin Type A that was used commercially in the United States through 1998 (13).

Going off Script

Once Botox was approved by the FDA, doctors could legally prescribe it for any medical condition that they thought could benefit from it. And prescribe it, they did. The obvious targets were localized muscles and glands, where overactive cholinergic transmission caused unwanted muscle contractions and secretions, respectively.

Although drug companies cannot advertise a drug for unapproved indications, they are often the first to hear about off-label uses (19). Doctors share their experiences with sales representatives, who in turn pass along the news to the company’s researchers.

Allergan followed up on the reports from doctors and conducted clinical trials for some of these additional indications (20). Over the years, FDA approved Botox for excessive underarm sweating, cervical dystonia, overactive bladder, and upper limb spasticity (1, 19, 20). Botox is now a treatment of choice for limb spasticity resulting from stroke, multiple sclerosis, spinal cord trauma, and cerebral palsy (5).

As doctors became more comfortable handling botulinum toxin, they continued to experiment, injecting it into muscles and glands all over the body (20). And Allergan (now AbbVie) continues to sponsor clinical trials. More than 200 ongoing clinical trials with botulinum toxin are listed in clinicaltrials.gov.

These experimental therapeutic uses include treatment of chewing problems, swallowing problems, pelvic muscle spasms, drooling, anal fissures, phantom limb pain, and atrial fibrillation after heart surgery (20) The more exotic uses include treatments for premature ejaculation, hair loss, and cold hands (19).

AbbVie owns or has applied for patents on more than 90 Botox indications. These include sinus headache, fibromyalgia, pain, ulcers, inner ear disorders, uterine problems, and buttock deformity (20). Although some of these novel indications may be overly ambitious, botulinum toxin has, in fact, become an essential treatment for many conditions that are otherwise difficult to treat medically or surgically (2).

Sharing Anecdotes

It wasn’t long before Scott and other ophthalmologists began receiving anecdotal reports from their patients, who said their facial wrinkles had faded after receiving botulinum toxin injections for blepharospasm or hemifacial spasm (5, 20). Although Scott continued research on innovative ophthalmology treatments for the rest of his life, he wasn’t interested in pursuing cosmetic indications, saying, “I think that’s a charming, slightly frivolous use” (10, 18). But other physicians did follow up.

In 1989, plastic surgeons Richard Clark and Craig Berris at the University of California Davis treated a 52-year-old woman (5). She had undergone two face lifts and surgery to eliminate crow’s feet.

Unfortunately, the surgery caused one-sided facial muscle paralysis. Clark and Berris injected botulinum toxin Type A into the functioning facial muscle on the opposite side. The procedure relieved the unilateral forehead wrinkles and brow elevation and restored the symmetry of her face (5)

Following this, many reports regarding cosmetic uses of Botox were published by other clinical investigators, including Jean and Alastair Carruthers in Vancouver, Canada (21).

Alastair’s dermatology practice encompassed cosmetic procedures and surgery for skin cancer (21). He shared an office with his wife, Jean, an ophthalmologist who treated pediatric disorders, as well as adult conditions like blepharospasm. The blepharospasm procedure involved injecting Botox into the skin around the eyes, to temporarily paralyze the spasmodic eyelid muscles.

One day, a patient became irate because Jean was not injecting her forehead. The patient’s forehead was not spasmodic and required no treatment, but she insisted, “When you inject my forehead, my wrinkles go away” (21)

At dinner, Jean mentioned the incident to Alastair. Coincidently, some of his dermatology patients had been frustrated by his failed attempts to erase the vertical frown lines between their eyebrows (21) The injected fillers available at that time were short-lived and could be painful. The next day, the Carruthers’ receptionist volunteered to be their first test subject. When Alistair saw the cosmetic results after Botox injection, he was immediately convinced (21)

The Carruthers began conducting clinical trials, which now have resulted in more than 100 papers in peerreviewed dermatology journals. They also presented their findings at dermatology conferences. Initially, their colleagues were skeptical, but patient satisfaction drove demand.

Jean qualified as a cosmetic surgeon, and the couple altered their practice to concentrate on cosmetic medicine. Through their practice and extensive research, they have sought to make cosmetic medicine “academically respectable” (21).

Commercializing Anecdotes

Not surprisingly, Allergan was also receiving anecdotal reports from physicians about the cosmetic effects of Botox (20). In 1998, the incoming CEO, David E. I. Pyott, pushed the company to begin clinical trials and explore Botox’s wrinkle-reducing potential (19, 20). Allergan conducted a series of randomized, double-blind, placebo-controlled trials in thousands of patients. Botox was effective in reducing or eliminating crow’s feet, wrinkles between the eyebrows, and forehead lines. In 2002, Botox Cosmetic received FDA approval (5). It was the first time a therapeutic drug was granted approval for a strictly cosmetic purpose (19)

Originally, Botox Cosmetic injections targeted the upper third of the face. But now, it is used to correct lines, creases, and wrinkles all over the face, chin, neck, and chest (16). Botox is North America’s No. 1 cosmetic procedure (21).

Similar to the discovery of Botox’s cosmetic efficacy, patient feedback triggered another unanticipated indication. A plastic surgeon in Beverly Hills, CA, was getting reports from his patients who said they experienced fewer migraines after their Botox injections for wrinkles (19). He passed the anecdote to Allergan researchers, who must have been somewhat skeptical.

But they followed up with two randomized, placebocontrolled, double-blind clinical trials. The results confirmed the anecdotal reports and demonstrated that Botox induced statistically significant and clinically meaningful relief from migraines.

Unlike most of the other applications of botulinum toxin, which logically result from inhibition of acetylcholine release, the mechanism of action of the anti-migraine effect remains unclear (7, 19). Nevertheless, FDA approved Botox for chronic migraines in 2010 (7). The migraine treatment consists of injecting Botox into seven specific head and neck muscle areas.

The Downside

For therapeutic and cosmetic use, physicians inject only a tiny amount of a dilute botulinum toxin solution into the target tissue, and most experts consider it safe (19). The controlled local pharmacological effect (that is, muscle paralysis or glandular secretion inhibition) typically lasts 3-6 months.

Botulinum toxin injections are generally well tolerated, and side effects are few, mild, and transient. There may be mild injection pain and local edema, redness, transient numbness, or headache. If nearby muscles are unintentionally weakened/paralyzed, they usually recover in weeks to a few months, depending on the site, dosage strength, and type of muscle (16).

Life-threatening complications of Botox are rare (16, 20). But if the toxin spreads from the injection site and enters the bloodstream, other parts of the body will be affected. This can cause serious swallowing and breathing problems. Larger intravenous injections of the toxin, of course, mimic the symptoms of botulism.

Off-label prescribing, though legal, raises questions about the risks of using a drug in ways that have not been fully vetted. Some critics worry that doctors are adopting novel uses of Botox without regulatory oversight or rigorous clinical trials to establish safety and efficacy for those indications. “It’s trial and error with a nerve poison” (20)

The adverse reports accumulated, and in 2009, the FDA required Allergan to add a black-box warning to Botox’s label, cautioning about the drug’s side effects (19). The reported adverse effects included muscle weakness, double vision, drooping eyelids, difficulty swallowing, urinary incontinence, and breathing difficulties. Most cases of serious side effects involved off-label uses, injecting excessive amounts of the toxin, and/or treating spasticity in children (19).

“Wonderful Medical Results”

In addition to Botox, there are now four other commercially available botulinum toxin Type A products (Dysport, Xeomin, Jeuveau, and Daxxify), and one botulinum toxin Type B product (Myobloc). But Botox holds the largest market share by far. In 2021, AbbVie reported $4.7 billion in net Botox revenues, with slightly more revenues from Botox Therapeutic than Botox Cosmetic.

Botox is used by almost every sub-specialty of medicine (16). And because physicians continue experimenting with an ever-expanding list of off-label indications, it is likely that the market for therapeutic uses of Botox will continue to grow. The New York Times calls it “medicine’s answer to duct tape” (20).

Alan Scott never regretted selling his rights to Botox. “I had my house paid for, my kids were educated, and I had the satisfaction of seeing absolutely wonderful medical results” (18).

References:

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13. University of Wisconsin (May 5, 2005) UW-Madison biochemist Edward Schantz dead at 96. UW CALS News; available from: https://news.cals.wisc. edu/2005/05/05/uw-madison-biochemist-edward-schantz-dead-at-96/

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17. Scott AB (1981) Botulinum toxin injection of eye muscles to correct strabismus. Trans Am Ophthalmol Sci 79: 734-770.

18. Green P (January 12, 2022) Alan Scott, doctor behind the medical use of Botox, dies at 89. New York Times; available from: https://www.nytimes. com/2022/01/12/health/alan-scott-dead.html

19. Sifferlin A (January 5, 2017) Botox: the drug that’s treating everything. Time 189(3); available from: https://time.com/4623409/botox-drug-treating-everything/

20. Singer N (April 11, 2009) So Botox isn’t just skin deep. New York Times; available from: https://www.nytimes.com/2009/04/12/business/12botox.html

21. Asenburg K (October 4, 2018) The real history behind the birth of Botox. Readers Digest; available from: https://www.readersdigest.ca/health/beauty/birth-botox/.

Biosketch:

Rebecca J. Anderson holds a bachelor’s in chemistry from Coe College and earned her doctorate in pharmacology from Georgetown University. She has 25 years of experience in pharmaceutical research and development and now works as a technical writer. Her most recent book is Nevirapine and the Quest to End Pediatric AIDS. Email rebeccanderson@msn.com

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