Scientists weigh in on the safety of Botox injections like this one. [Credit: Eddie Codel, flickr.com]
The muscle-relaxing power of Botox has been wielded for so many different treatments—from frown lines and forehead wrinkles to neck spasms—that the drug has been touted as the aspirin of the 21st century. But when it comes to the safety of the versatile botulinum toxin, the class of drugs to which Botox belongs, the lower the dose, the better.
Those who swear by Botox as the Fountain of Youth in a needle can take comfort in knowing that the trace amounts dermatologists inject in the fine muscles of the face carry a low risk of complications. The same is true for medical treatments of the face that relieve droopy eyelid or excess sweating. Only about one percent of 1,000 botulinum toxin injections—primarily in the face and neck—led to serious side effects, according to a German study published in The Laryngoscope in May 2008. While undesirable, the most common risks of cosmetic treatments—bruising, swelling and facial asymmetry—are usually temporary and local.
The other face of Botox use, as a medicine to alleviate muscle spasms and tension in larger muscles such as those in the arms and legs, requires higher doses of drug. Recently, the U.S. Food and Drug Administration, or FDA, announced that a handful of child patients who received high doses of the toxin in their limbs suffered alarming side effects far from the site of injection, including difficulty breathing and loss of neck control. These long-distance effects could be the result of toxin circulating in the blood or, as doctors have long been aware, diffusion through muscles. And, as a study from Italy showed, the toxin can even hitch a ride along nerve cells in rats, opening up the possibility that the drug could travel from the injection site to the brain in humans.
Underlying the different uses of Botox is the important fact that it is “extremely poisonous and long lasting,” according to Dr. Daniel Drachman, a neurologist at The Johns Hopkins University, who has been studying botulinum toxin for the past five decades. The toxin can remain active in the body for up to several months. While these properties make the drug effective at low doses, he cautions that, “especially with rather large doses, you’ve got to be very careful.”
The myriad treatments involving Botox all depend on its ability to weaken muscle. Botulinum toxin, which comes from the soil bacterium Clostridium botulinum, can gain entry inside nerve cells in its vicinity. By injecting it into a muscle, doctors feed the toxin into the motor neurons that connect to and control the muscle. Inside the motor neurons, the toxin chops up and destroys a protein called SNAP-25, which is responsible for releasing a compound from the cells called acetylcholine that stimulates connecting muscles. Without acetylcholine, the muscles become weakened or paralyzed.
In February 2008, the FDA reported some wrinkles in the safety of certain botulinum toxin treatments. The most serious cases involved children who received large doses of toxin at multiple sites in their leg muscles for spasticity associated with cerebral palsy, a disorder that limits muscle control. Following the injections in their legs, they suffered distant side effects, like throat swelling, that made breathing difficult. A handful of children were hospitalized, according to the FDA announcement. One child even died.
In response to their clinical reports, the FDA launched a safety review of all botulinum toxin uses, clinical and cosmetic, approved and unapproved. Currently, the treatment of cerebral palsy-associated limb spasticity represents one of the many uses of botunlinum toxin that are not approved by the FDA. The toxin is also not approved for any treatments in children under 12 years of age.
As the FDA carries out its safety review, the administration heeds a general warning to doctors to confirm the concentration of drug before use because the potency could vary between different manufacturers. Even the correct dose could be more powerful in one patient than another as sensitivity varies, stated Dr. Russell Katz, FDA’s neurology director, in a press conference in February 2008.
With the exception of the widespread side effects announced by the FDA, scientists generally believe that the action of the poison is limited to the injected muscles and, at higher doses, its neighbors. But, at least in rats, the drug can travel along the highway of nerve cells to the brain, according to a recent study led by Matteo Caleo at the Institute of Neuroscience in Pisa, Italy, and published in the Journal of Neuroscience in April 2008. Three days after the researchers injected the toxin into the rats’ whisker muscles, they were surprised to find evidence of the toxin’s activity in the brains of dissected rats.
So do these findings in rats warn of another way in which high levels of botulinum toxin might be dangerous in humans? Allergan, the California-based manufacturer of Botox, does not believe so. “The authors used a laboratory preparation of botulinum toxin and did not use [registered] Botox,” wrote Allergan spokesperson Crystal Cienfuegos in an email. “Data suggest that different preparations of [the] toxin react differently in both the laboratory and in clinical practice,” she added.
Caleo, on the other hand, takes his findings to mean that scientists do not understand well enough how the drug works. Dermatologists and neurologists inject different amounts of drug in different muscles for different treatments. Caleo believes that, “for each specific system, the fate of the toxin might be different.” He advises that doctors need to know everything about how the drug works before they give it as a treatment.
Indeed, it remains unclear if the toxin triggers harmful side effects by traveling between neurons, as it can by spreading diffusely in muscles. The Italian study convincingly shows botulinum toxin can travel between nerve cells in rats, similar to the related tetanus toxin, according to Drachman, the neurologist at The Johns Hopkins University. He was not involved in the study.
But nobody knows if the toxin has the same effect in humans. As Caleo points out, the dose injected into rats was up to 10 times greater than what humans would typically receive. And it is clear that, in the experiments with rats, the dose given dictates the potency of the drug—increasing the dose means heightened Botox activity in the nerve cells of the brain. So, for travel between neurons, like diffusion in muscles, the drug might spread farther at higher doses.
Greater understanding about the spread of botulinum toxin could bring greater benefits of the drug. In some cases, the diffusion in muscles could improve treatments. “If the entire limb is spastic, and you inject one muscle, then you like the idea of diffusion through that muscle,” says Dr. David Simpson, who researches and administers botulinum toxin for neurological disorders at Mount Sinai School of Medicine in New York City.
Similar benefits may come if researchers find that botulinum toxin does travel between human nerve cells. Drachman speculates that its use to treat conditions like epilepsy where acetylcholine signaling in the muscles is disrupted “may be conceivable at some time in the future.”
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