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Botox or Bust

Made from a deadly poison first developed for biological warfare, botox became the darling of the beauty business—a way to look young forever. Now doctors are using it for everything from back pain to stuttering. Is it really that good?

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Megan is not her real name, but we will call her that because otherwise we would not be able to watch. A 60-year-old blonde dressed expensively but casually in a black V-neck cardigan and slacks, she is reclined on a leather examining chair. An equally well dressed plastic surgeon with a robust Upper East Side Manhattan practice is seated to her right. He swabs her fine skin with alcohol. Megan closes her eyes and lifts her brows. He injects her forehead with a clear liquid made from a deadly poison, working intently, moving straight across the forehead, between the brows, and above the inner corners of her eyes. Five minutes later, the treatment is complete. She gathers her coat and thanks him enthusiastically.

"It's so wonderful, so natural," she exclaims on her way out. Ducking quickly before a mirror, she scrunches up her face into a frown. "The days following your appointment, you get up every morning and run to the mirror to check if those lines have disappeared, and they do in about five days," she says. Right now her forehead is still riddled with neat rows of little red bumps that look like tiny mosquito bites, but they will disappear within an hour, and she pays them no mind as she runs off to do errands. "It's the best thing. I just love it."

"It" is Botox, the poison-turned-blockbuster-antiaging-drug wielded so expertly by her physician, Darrick E. Antell, M.D. Botox, he says, can be a prelude to a face-lift or a tool for wrinkle prevention. "It's almost like good hygiene," he tells me from behind his big desk, just before Megan's procedure. "Like getting your teeth cleaned." Antell has undergone the injections himself. The effects last from about four to six months, and thus require retouching at least two or three times a year. He, too, then scrunches up his face into a frown, just like Megan did, to show me. There are no horizontal lines across his forehead or vertical ones on the inside of his brow. In fact, his face looks quite radiant and youthful for a 50-year-old with salt-and-pepper hair.

Antell then calls in one of his nurses, a bright-eyed brunette in blue scrubs. She is all of 26 years old, but also gets Botox injections. "I see patients who have these lines and I think, Gosh, I don't even want to get them in the first place. At 50, you can soften them, but you can't eliminate them if they're already really deep. I have an animated face and use my forehead a lot, so it's just very obvious to me to do it." And like Megan and Antell before her, she makes that face to demonstrate how superb the results are. I am by now convinced: Botox, when administered skillfully, does not stiffen the face—it merely transfers the expression of emotions from the wrinkles in the forehead to the eyes. These lines, especially the "11" that appears between the brows, result when our skin creases. Over the years, our skin becomes less supple; it doesn't bounce back to its smooth self, even long after we stop frowning or squinting. Botox disables the muscles from contracting in the first place so that, in a young adult user, the skin remains forever flat, like a crisp white shirt left interminably on the rack.

And so goes the latest chapter in the Botox craze. Doctors love Botox, patients love Botox, and now even people who don't need Botox love Botox. Not bad for a drug that isn't yet officially approved for cosmetic purposes by the Food and Drug Administration, not to mention one that is extracted from the toxin of the Clostridium botulinum bacterium, one of the culprits behind food poisoning.

Botox started out as an obscure drug, FDA-approved to treat strabismus (crossed eyes) and blepharospasm (uncontrollable blinking). But because doctors are allowed to use any FDA-approved drug "off-label" (for purposes other than the one approved), Botox has been able to take on a life of its own. A major turning point occurred in the early 1990s, when the ophthalmologist Jean Carruthers, M.D., realized that the substance she was injecting into ocularly challenged patients also smoothed out their wrinkles. Suddenly, Botox was as familiar a word as collagen or LASIK. In the last year alone, hundreds of thousands of wrinkle-obsessed people visited their plastic surgeon or dermatologist in search of it, often paying upwards of $600 a hit.

Allergan, its maker, has finally submitted Botox to the FDA for use for cosmetic purposes and expects it to be approved by the end of this year. Once that happens, Allergan will have carte blanche to advertise the drug as such (something not permitted for off-label usages) and drive up profits further. But Botox is poised to be so much more. Besides a recent FDA approval for the treatment of cervical dystonia (involuntary neck-muscle contractions), it is now used off-label and is undergoing clinical trials for such diverse disorders as hyperhydrosis (profuse sweating), migraines, back pain, anal fissures, spastic conditions related to Parkinson's disease, stroke and cerebral palsy, even stuttering. All told, $239.5 million worth of Botox was sold last year worldwide, a 36 percent increase over 1999. Mitchell F. Brin, M.D., the vice president of Allergan's Botox and neurology division, is hardly shy about his expectations: "Botox will join the ranks of drugs that have changed the nature of human suffering," he says, "and will go down in history as affecting mankind, similar to the impact of penicillin."

How did one of the deadliest poisons in the world spawn the latest "It" drug? And what are the repercussions when something clinical becomes fashionable? As the story of Botox suggests, sometimes chance and creativity are as significant as technology when it comes to medical progress.

In some ways the business of medicine is not that different from the business of selling cars or shoes: The best products fulfill a compelling consumer need or desire, and the wider the audience the bigger the profits. That is why drug companies, which invest millions of dollars in research and development, devote much of their energy to conditions that affect tens of millions of people, such as heart disease, arthritis, or diabetes. Botox also has the potential to attract a large audience, but not just because all of us are prone to wrinkles (after all, not everyone has the funds to pay out-of-pocket, as one must do for all vanity procedures). Rather, unlike the many drugs that tend to specialize in one specific disorder, Botox is amazingly versatile, addressing more than 90 conditions, many of which had no prior course of treatment.

This astonishing fact may not have been discovered if it weren't for some very serendipitous circumstances. Before its recent surge in popularity, clostridium, the bacteria from which Botox is derived, was most frequently found in contaminated home-canned foods. When swallowed, it can cause botulism, a form of poisoning that results in vomiting, throat constriction, and paralysis of the respiratory muscles. Without a speedy tracheotomy or a dose of antitoxin treatment, the victim often suffocates to death within 24 hours.

Scientists first began studying clostridium as a weapon for biological warfare, but although it was extremely potent—100,000 times stronger than nerve gas—they found it too volatile to be used efficiently. Microbiologists eventually distilled seven varieties of botulinum toxin from the bacteria: serotypes A, B, C, D, E, F, and G. Each type attaches to the neurotransmitter, blocking it from sending signals to the muscle and thus preventing involuntary contractions. Likewise, Botox—botulinum toxin type A—targets certain muscle cells and relaxes them.

This quality intrigued doctors. Alan B. Scott, M.D., now executive director of The Smith-Kettlewell Eye Research Institute in San Francisco, tested botulinum toxin A, as well as absolute alcohol, cobra venom, and nerve gas, on monkeys that had misaligned eyes. Some of the monkeys got very sick or died, but not those given the botulinum—their eye alignment improved and they stayed healthy.

Encouraged by his findings, Scott started clinical trials in the late 1970s using the botulinum on a variety of muscle problems, including strabismus (crossed eyes) and blepharospasm (uncontrollable blinking). He applied for FDA approval for the treatment of those two conditions in 1984, and passed five years later. In 1991, Allergan purchased the rights to Botox.

Soon after that, in Vancouver, Carruthers was using Botox around her patients' eyes when she noticed that their frown lines were smoothed out with each injection. She raised the issue with her husband, a dermatologist with whom she shared an office, and decided to try the drug out on her own wrinkles. Soon they convinced their receptionist to try it as well, then set out to enroll subjects in a trial. It took them three years (1987-90) to convince 30 patients to participate—evidently, perfectly healthy people did not embrace the idea of experimenting with poison as readily as those with an incurable disease.

"It was hard," Carruthers recalls. "People would say, 'You want to inject what?' They didn't realize that the amount involved in food poisoning is millions of times more potent than what's in the one vial used for treatment." By 1991, they finally reported their findings at a dermatology conference. "Our colleagues at that time weren't into the wrinkle world," says Jean, who likes to say she hasn't frowned since 1987. "People tend to see only what they know."

Meanwhile, other conversations were taking place, from doctor to doctor, and doctor to patient. Wrinkle patients noticed that their headaches vanished. Others noticed they didn't sweat as much. Gradually, scientists began to realize that this wonder poison had the power to relax hyperactive muscles in different parts of the body, thereby relieving a whole host of symptoms. This captured the imagination of medical specialists and their patients alike—hence the impressive range of Botox research taking place right now.

One of the reasons Botox is so successful is that it addresses conditions that have long been considered untreatable. Frown lines had dogged dermatologists and plastic surgeons for ages. Neurological diseases such as excessive blinking were so elusive to treat that exasperated doctors recommended psychiatric therapy and hypnosis. Then along came Botox—and all of a sudden, problem solved!—making doctors and patients downright giddy. "We thought it would take the situation from miserable to tolerable," says Richard Glogau, M.D., clinical professor of dermatology at the University of California at San Francisco, who treats at least four patients a week for sweating problems. "But it took it from miserable to gone." (He himself does not suffer from hyperhydrosis, but uses Botox anyway. "I haven't used antiperspirant since 1998," he says.)

What worries many doctors about Botox, however, is that patients are quick to rely on just this kind of anecdotal evidence and informal research. Good news gets puffed up into fantastic news. Possibilities become probabilities. Excellent drugs become miracle drugs. And therein lies the danger. Doctors can use a drug like Botox off-label at their own discretion. Even if the doctor writes a protocol, has it reviewed by his or her hospital board, then treats numerous patients and records their reactions, that is still a far cry in scientific rigor from FDA registration trials, which take years and cost millions of dollars.

Naturally, people have come to assume that Botox works every time on everyone. This, of course, is not true. For some people the effect is zero. For others, particularly with severe backache, migraine, and dystonia (movement disorder), the effect isn't perfect, though they are grateful for any benefits they reap. "I function more as a person now," says Mitchell Buchwalter, whose back pain from a job-related injury left him bedridden until he found Botox. "The intensity is different, but I'm still aware of the muscle spasms."

Pain management, critics report, is one of the stickier areas of research. Despite the scores of headache and backache patients who say they found relief in Botox after years of taking painkillers that destroyed their livers and barely worked, few studies have been published that actually prove the efficacy of Botox. One of the earlier studies released last year suggested that it's no more effective than a placebo.

Alexander Mauskop, M.D., director of the New York Headache Center in Manhattan and coauthor of What Your Doctor May Not Tell You About Migraines, knows both sides of the argument. He uses Botox on many patients, and acupuncture and conventional painkillers on others. He believes the right treatment depends on the person and the pain. The migraine study, he says, is flawed in that doctors were told to inject each patient 11 times in just one area of the forehead or around the temples, when in fact Botox works best when applied in several areas, including where the pain is. "In my migraine patients, that's usually the back of the head," says the bespectacled neurologist.

Back pain is another mystery. A recent study of 31 patients published in Neurology magazine by researchers at Walter Reed Army Medical Center in Washington found that Botox was effective in reducing lower back pain. While some specialists believe that Botox is effective in cases that are thought to be caused by muscle spasms squeezing the sciatic nerve, many orthopedic surgeons are still unfamiliar with the notion. But not Charles Argoff, director of Cohn Pain Management Center at North Shore University Hospital in Long Island, New York. With the help of a CAT scan, he says he can determine exactly where in the lower back and gluteal muscles he should inject the Botox. And while he says it works for about 70 percent of his back pain patients, it's difficult to tell whether a patient will be among that lucky majority.

"The problem with clinical trials is that you have different doctors in different centers looking at different people, and no matter how much you try to understand the results in a general sense, everyone is unique," says Argoff. "It's very much an art right now. Each patient is a clinical experiment."

So Botox is not perfect, but unlike the many slightly imperfect drugs out there it remains a standout, because it manages to be something that doctors and patients have been yearning for but never truly had: a life-enhancing medical procedure that is fast, noninvasive, and requires no downtime. Plastic surgeons have been plugging the "lunchtime facial" forever, but in reality this treatment takes a half-hour or so and you get back to the office with a suspicious red glow. LASIK takes roughly 12 minutes for each eye, but don't even attempt to leave the house, much less drive back to work after the procedure (unless you've rented a Seeing Eye dog and chauffeur for the next 24 hours).

Botox, in contrast, can be as quick as a few minutes for frown lines. And if you don't like it? No need to kick yourself. The effect of the neurotoxin on nerve endings will last no longer than three to six months, depending on the muscle group and patient. It's enough for one to sign up pronto—until one talks to Martha Murphy. "The doctor I went to just said 'where does it hurt?' and then he injected it," says Murphy, who suffers from cervical dystonia. "And I ended up with worse pain than before."

Because Botox looks so easy, it can end up in the wrong hands. Carruthers says she has noticed non-M.D.s attending courses on administering Botox. Worse, she says, "We get e-mails all the time. 'Just draw me a diagram,' they say. And then I tell them that this is a surgical injection. If you don't know what's underneath, how can you inject into it?"

In addition, because Botox comes freeze-dried and must be mixed into saline, and because the average efficacy rate has not yet been established, the patient must trust the doctor to provide the appropriate concentration. "I have lots of patients that come in and say they've tried Botox before and it doesn't work," says Steven Feldon, M.D., professor of ophthalmology and neurological surgery at the Keck School of Medicine of the University of Southern California, near Los Angeles. "But that is a result of the way it's given. There's still a diversity in terms of the skill and judgment of the doctor."

Reported side effects experienced after a dose that is overly concentrated or diluted include droopy musculature, numbness, and dry mouth. "If you see ads offering Botox for $33, you're probably paying for salt water," says Carruthers.

Megan, meanwhile, plans to make her semiannual pilgrimage to Antell's office for a long time to come. Ten days after her recent visit, she is happily tending to her granddaughter in her apartment on Madison Avenue. The red bumps on her forehead have long since vanished, leaving her face looking not taut but refreshed. "It's important to find a doctor you trust," she says. "Mine is a perfectionist."

Fortunately, as more clinical trials approach their final phases—finally producing hard data from thousands of subjects—protocols will be refined and implemented, and hopefully more Botox patients, including those with serious diseases, will share Megan's positive experience. In recent months, reports on ideal dosages for migraines and the surprisingly pleasing effects of long-term use for wrinkles (see What's Next? for details) have been presented at specialty meetings around the country.

As revolutionary as it is, Botox is not the only new neurotoxin that is derived from that nasty clostridium bacteria. Myobloc (botulinum toxin type B) was approved for cervical dystonia by the FDA just 16 days before Botox passed last December, and it has also begun to undergo tests for various conditions, ranging from frown lines to pain. Its manufacturer, Elan Pharmaceuticals, believes doctors will appreciate the convenience and consistency of Myobloc, which is sold in solution form and stable for up to nine months at room temperature and 21 months when refrigerated. (Botox must be stored at -5 degrees Celsius and reconstituted with saline before use.) They also believe that there are many more patients like dystonia sufferer Murphy, who had a second and improved run with Botox but then became resistant. "Myobloc is a godsend," Murphy says, adding that many members of her support group were desperate for it long before December.

Allergan says it isn't fazed by the competition. As Christine Cassiano, manager of public relations, explains, "The introduction of Myobloc will expand the market for neurotoxins in general." And this is a good thing for manufacturers, doctors, and the patients that depend upon them. More competition spurring more people to do thorough research in this area of therapy will only enhance quality and build credibility. And perhaps the success stories yet to come will inspire others to do as the earliest neurotoxin researchers did: look beyond their everyday surroundings and skillfully, gingerly cross the line between different medical specialties and academic disciplines. And between danger and discovery.


With doctors and patients trumpeting the effects of Botox, it's easy to forget that it's only FDA-approved for three rather obscure diseases: cervical dystonia (involuntary neck-muscle contractions), strabismus (crossed eyes), and blepharospasm (excessive blinking). All other conditions—the most common are listed below—are treated "off-label." That means: Buyer beware. Some guidelines:

COST: $400-$600 • TAKES EFFECT IN: 3-5 days • RESULTS LAST: 3-4 months • POSSIBLE SIDE EFFECTS: Droopy brows • SUCCESS RATE: Over 95% • RECENT FINDINGS: A double-blind Vancouver study on 535 patients by Alastair Carruthers, M.D., reports that the effects of Botox seem to last for longer increments of time with each successive treatment.

COST: $500-$750 • TAKES EFFECT IN: 1-2 weeks • RESULTS LAST: 2-4 months • POSSIBLE SIDE EFFECTS: Bruising, droopy eyelids • SUCCESS RATE: 70% • RECENT FINDINGS: According to a study published in the December 2000 Otolaryngology-Head & Neck Surgery journal, Botox seems to prevent the occurrence of acute migraine as well as treat it.

COST: $500-$1,000 • TAKES EFFECT IN: 7-10 days • RESULTS LAST: About 3-4 months • POSSIBLE SIDE EFFECTS: When very large concentrations are used, patients may experience weakness in the lower back muscles. • SUCCESS RATE: About 70% • RECENT FINDINGS: In the first double-blind randomized study published in Neurology by researchers at Walter Reed Army Medical Center in Washington, 73% of patients reported at least 50% improvement in pain after three weeks, with peak results occurring between ten days and two months.

COST: $1,000 for both underarms; $1,200- $1,600 per palm • TAKES EFFECT IN: About 12 hours; peaks in about a week • RESULTS LAST: 8-12 months (underarms); 2-12 months (palms) • POSSIBLE SIDE EFFECTS: Weakness in palms for about 2-3 weeks • SUCCESS RATE: Over 90% • RECENT FINDINGS: Doctors at Saint Louis University found that varying dilutions of Botox (100 units in 1.25 ml, in 2.5 ml, and in 1 ml) seem to produce the same effect.

Amy Young wrote about Jet Lag for the March/April issue of Departures.


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