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A psychiatric patient recently asked his doctor for a change in medication, or some kind of assistance with his depression. He was entertaining suicidal thoughts, even though he was on antidepressants and always kept his appointments. As you might imagine, he was getting desperate.
An elderly gentleman was experiencing progressively worsening twitching of his eyelid. More than annoying, it was getting to the point where normal activities, like watching tv and reading the newspaper, were becoming painful since his left eye was terribly dry. None of the medications prescribed had helped at all.
Jane was a recently retired secretary who had long been looking forward to the next phase of life but had been developing symptoms of a subtle spasming of her jaw, causing difficulty with chewing. Her primary care doctor had prescribed a course of physical therapy, but she made minimal gains.
What do these individuals have in common? All these conditions, and many others, were treated with what is, quite simply, a poison. Because of its use as a wrinkle-smoother, and the subsequent discovery of its ability to treat a host of medical conditions, a toxin produced by the clostridium botulinum bacterium is being used to treat various medical maladies. This poisonous substance, known world-wide as Botox, has become a triumph of medicine, as well as a true cultural phenomenon.
Most of the uses of Botox are off-label. The off-label use of FDA-approved medicines, like Botox, is legal in the U.S. Once a drug has been approved by the FDA for a condition, licensed physicians are legally allowed to prescribe it for any medical issue they think it could benefit, regardless of whether it’s been proven to work for that condition. This is standard practice in American medicine.
Botox is increasingly being utilized for problems that go far beyond the cosmetic. The depression suffered by the previously mentioned patient is just one example on a list that includes everything from excessive sweating and neck spasms to leaky bladders, cold hands and even the dangerous cardiac condition of atrial fibrillation. The range of conditions for which doctors are using Botox is staggering.
Currently, the Food and Drug Administration has approved botulinum toxin A for several indications, including blepharospasm, strabismus, cervical dystonia, chronic migraines, axillary hyperhidrosis, upper limb spasticity, and urinary incontinence. But this may elicit a relevant question: are the many uses due to the drug’s unique characteristics, or the drug industry’s strategies for creating a blockbuster?
The botulinum toxin is one of the most poisonous substances known to man. Estimates claim a single gram could kill a million people and a couple of kilograms could kill every human on earth. In sufficient concentrations, the toxin can produce botulism, a severe, life-threatening illness. Botulism, left untreated, may result in respiratory failure, even death. Despite this substance being so toxic, Botox is in huge demand.
Botulinum toxin’s popularity continues to increase. In 2001, the year before Botox was approved for wrinkles, it generated about $310 million in sales. By 2013, the year it was approved for overactive bladder, the company owing the rights to Botox reported nearly $2 billion in revenue. From 2000 to 2015, use of the toxins for wrinkles increased 759 percent. Culturally, its success has spawned Botox parties, Simpsons jokes, even greeting cards. The global revenue generated by Botox is now up to $2.45 billion, with more than half of that figure coming from therapeutic uses and not cosmetic ones.
As more off-label uses are developed, these figures will only increase. Some uses now regarded as routine include the treatment of tension headaches, tilted neck, chronic back pain, eye lid twitches, limb spasticity after stroke, cerebral palsy, multiple sclerosis, hyperhidrosis and tremors.
Botox was discovered by accident when, in the '70s, an ophthalmologist started studying the toxin as a therapy for people with a medical condition that rendered them cross-eyed. He named the drug Oculinum and formed a company to investigate the commercial potential. In 1989, he received FDA approval for the treatment of strabismus and abnormal eyelid spasms.
Botulinum toxin is injected into humans in extremely small concentrations and works by preventing nerve cell signals from reaching muscles, therefore paralyzing them. In order for muscles to contract, nerves release a neurotransmitter, which is a chemical messenger, at the nerve-muscle junction. Botulinum toxin causes a reduction in abnormal muscle contraction, allowing the muscles to become relaxed. Paralyzing muscle activity is how Botox can steady a straying gaze, eliminate an eyelid spasm or stop signaling from nerves that stimulate sweat.
Clostridium botulinum, the bacterium from which Botox is derived, is found in many natural settings. When Clostridium botulinum bacteria occur naturally, they are generally harmless. Problems only arise when the spores transform, and the cell population increases. At a certain point, the bacteria begin producing botulinum toxin, the deadly neurotoxin responsible for botulism.
One of the most exciting new uses has been to prevent chronic migraines. As is so often the case, it’s unclear exactly why Botox works. Some physicians now are thinking that Botox may be accessing, and thus influencing, the central nervous system. Further evidence was provided by a study showing that when injected into the muscles of rats, there was evidence of the drug in the brain stem.
The use of Botox for migraines was, like many other new applications for the drug, a kind of happy accident. A plastic surgeon observed that people who got Botox for wrinkles were reporting fewer headaches, a finding which paved the way for further studies. Similarly, European physicians were intrigued when they noticed less sweating in their patients who got Botox for facial spasms. On a side note, since we are uncertain what causes these severe headaches in the first place, it's difficult to say how Botox works.
The company which owns the rights, Allergan, is hoping to obtain official approval for the drug as a depression treatment. That wouldn’t change anything for doctors, since they can already prescribe it off-label, but it would allow Allergan to begin marketing Botox for depression, a change that could dramatically increase its adoption, and sales.
Do you know when your physician is prescribing some therapy off-label, and do you care? They may have noticed that the drug works for a given condition but may not be sure why. We do not know the exact mechanism for many drugs and therapies. Physicians, seeking new treatments for their patients, frequently explore creative new uses for approved drugs. In essence, these are real-world experiments that take place beyond the reach of federal regulators. To many in health care, this raises questions about the risks of deploying medicines in ways that have not been fully vetted.
Even if the laws remain unchanged, as long as off-label uses are permitted by law, you can expect doctors to keep pushing the boundaries of Botox’s applications, sometimes in the name of medical progress and sometimes with remarkable results. It is impossible to say what new uses will be developed, but don't be surprised if a doctor recommends some type of off-label therapy for you.
Editor's note: Dr. Conway McLean is a physician practicing foot and ankle medicine in the Upper Peninsula, with a move of his Marquette office to the downtown area. McLean has lectured internationally on wound care and surgery, being double board certified in surgery, and also in wound care. He has a sub-specialty in foot-ankle orthotics. Dr. McLean welcomes questions or comments atdrcmclean@outlook.com.