Fear not: Botox safety concerns overstated, expert says

Vancouver, Canada

- Although some recent animal research and human case reports have spurred concerns regarding the safety of Botox Cosmetic (onabotulinumtoxinA, Allergan), one of the product's pioneers says that Botox remains safe when used as directed for cosmetic indications.

"Only if we really understand the bad things that could happen can we be very astute, caring physicians who make sure these negative outcomes don't happen in our own practices," says Jean D. Carruthers, M.D., clinical professor of ophthalmology, University of British Columbia, Vancouver, Canada.

Negative publicity

Among the most striking negative headlines involving cosmetic botulinum toxin were those reporting the 2004 South Florida case in which an unlicensed osteopath injected four people, including himself, with so much research-grade botulinum toxin that he and his patients suffered from life-threatening clinical cases of botulism, she says.

A subsequent investigation proved that the material injected was not Botox, Dr. Carruthers says. But as soon as media outlets began picking up this story, "The best product we’ve had for treating so many cosmetic issues was suddenly being tarred" in the popular press.

"This had a profound negative effect on the number of Botox treatments booked in Florida and adjacent states for some time afterwards,": Dr. Carruthers tells Dermatology Times.

Examples such as the Florida case underscore the importance of using products approved by the Food and Drug Administration (FDA), she says.

"We have no means in our offices to look at a vial and say how much botulinum toxin A is in it. We must be able to trust" that the vial’s contents match its label, she says.

More recently, an advocacy group called Public Citizen charged in January 2008 that Botox Cosmetic caused the death of a patient in 2004.

When authorities examined this case, Dr. Carruthers says, "They found that the woman had received a glabellar Botox injection seven weeks before she died of subsequent staphylococcal pneumonia."

Her physician attributed the patient’s demise to the pneumonia, Dr. Carruthers says.

Accordingly, she says, "Reporting of an adverse event doesn’t prove that the adverse event was caused by the drug the patient received."

Rare fatalities

Conversely, she says Botox"s label warns of very rare fatal outcomes in patients who suffer from significant debilitating conditions, such as juvenile cerebral palsy, who are treated with therapeutic doses of botulinum toxin.

While aesthetic physicians use one to three units of botulinum toxin per kilogram of body weight, "These patients are receiving 20 to 40 units per kilogram. These are children who are very sick, developmentally delayed and very spastic. Maybe they are too ill for their physicians to consider general anesthesia to try and relax the very tight musculature," Dr. Carruthers says.

This is an important area of future research, she says, "And much work needs to be done to find a better way to help these children.":

Murine model

Also in the past year, researchers published a study that showed hippocampal injections given to rats migrated to the opposite hippocampus (Antonucci F et al. J Neurosci. 2008 Apr 2;28(14):3689-3696).

Using injections in the whisker area, Dr. Carruthers says, "They also found that veterinary Botox cleaves SNAP25 in the brain, in the seventh nerve nucleus."

Somewhat similarly, researchers injected botulinum toxin in the brain and found that the toxin went retrograde to the retina, she says.

"This is fascinating, because it’s never been shown before that a neurotoxin can migrate towards and away from the brain," Dr. Carruthers says.

However, she emphasizes that these investigators were using a veterinary neurotoxin in enormous doses.

"Compared to our human dosing, it’s like a fire hose versus a drop. There hasn’t been any human data*#34; to support the claim that Botox migrates through the brain barrier, she says.

"Maybe there is something happening with neurotoxin going into the brain. After all, there have been published studies showing that glabellar Botox injections actually improve mood and help people cope with depression and anxiety," Dr. Carruthers says.

Nevertheless, she says that in 25 years of clinical experience with the product, "No studies have shown any intracranial neurological abnormalities. So there’s something going on here that requires different analysis and more study."

Cat model

University of Calgary investigators working on treatments for spastic cerebral palsy performed a similar experiment in a cat model, she says.

As in the rat study, "They used huge doses and huge dilutions and guess what? It migrated everywhere (Yaraskavitch M, Leonard T, Herzog W. J Biomech. 2008;41(4):897-902. Epub 2008 Jan 8)."

The study’s authors themselves have stated that due to the high doses used, one cannot draw any conclusions about Botox migration in human patients, Dr. Carruthers says.

Dysphagia

However, she says dysphagia is a rare but real complication from botulinum toxin treatments that recently prompted Health Canada to require the addition of a warning to Botox’s label.

The warning states that cosmetic spread is relevant only when the toxin is injected in the neck (in extremely large doses).

Fortunately, she says that in the case reported by her practice, "It was just a transient dysphagia."

To avoid this problem, she says that when working in the neck of a thin patient in particular, "Please go lightly - 25 to 30 units is enough."

If it’s not, "You can always get the patient to come back," she saysRare complications aside, Dr. Carruthers says scientific evidence overwhelmingly supports Botox’s safety in cosmetic indications.

Safety study

In the first long-term safety study in this regard, Dr. Carruthers and her husband Alastair Carruthers, M.D., retrospectively reviewed 851 treatment sessions in 50 subjects who’d been receiving Botox injections for at least five years.

In addition to the case of dysphagia mentioned above, they uncovered three instances of brow ptosis and one of eyelid ptosis, all of which were mild to moderate and transient (Carruthers A, Carruthers J. P03. Toxins 2005 (June 23-25, 2005; Denver). Neurotoxicity Research. 2006 Apr;9(2,3):225).

Moreover, physicians have used nearly 20,000,000 vials of genuine Botox safely, and medical literature documents nearly two decades of safe usage worldwide (Naumann M, Jankovic J. Curr Med Res Opin. 2004 Jul;20(7):981-990), she says.

"We’re used to seeing transient, local complications. That’s what we want to continue seeing" when complications do occur.

Overall, Dr. Carruthers says, "The message is that Botox is a very powerful drug that we should have great respect for. And when we see reports of adverse events, let’s find out if it was caused by Botox or some other unapproved product." DT

Disclosures: Dr. Carruthers is a consultant and investigator for Allergan and has received honoraria from the company. She also is a consultant and investigator for BioForm (in which she holds stock) and Merz Pharmaceuticals. Additionally, she is a shareholder in Aesthera and serves on advisory boards for several manufacturers of aesthetic treatments.