Botox for Migraines?

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Botox for Migraines?



■ Anyone who has ever seen Nicole Kidman’s face frozen in permanent surprise or Meg Ryan’s unusually pouty lips is familiar with Botox, the trade name for one of the seven serotypes of protein produced by the bacterium Clostridium botulinum.
But Botox (onabotulinumtoxinA) is now being touted as a prophylactic treatment for chronic migraine pain.
So far, Botox has received approval from the Food and Drug Administration for use in several medical and cosmetic capacities, including strabismus (improperly aligned eyes), blepharospasm (eyelid twitch), certain muscle spasms, hyperhidrosis (excessive sweating) and, of course, the prevention of wrinkles and frown lines.
Although Botox has been used off-label for quite some time in the treatment of various disorders, it was only in October 2010 that Allergan, the company that manufactures Botox, received FDA clearance in using it for preventive treatment of chronic migraine. This treatment was not without its detractors, because only one month prior Allergan had settled an illegal-marketing-practice suit for $600 million; the company was accused of pushing Botox for off-label uses, including migraine.
Doctors first discovered Botox’s effects on headeaches from patients who reported serendipitous decreases in both immediate and long-term migraine symptoms after Botox treatment. This link spurred research—and the off-label uses of Botox.
Today, the FDA endorsement for Botox is specific. According to Dr. Mark W. Green, director of the Center for Headache and Pain Medicine and professor of neurology and anesthesiology at the Mount Sinai School of Medicine, “It is only approved and only used for preventive treatment of chronic migraine [CM], migraines that occur at least 15 days per month, with headaches lasting more than four hours. Other agents are approved for migraine prevention, but they often exclude those with CM, since they are hard to treat.”
Chronic migraine is an under-diagnosed and highly debilitating disorder that, unlike regular headaches, can render the individual extremely nauseous, dizzy and hypersensitive to light and sound. “Chronic migraine is one of the most disabling forms of headache,” says Dr. Russell Katz, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. Affecting approximately 1.3% to 5.1% of the global population, CM exacts large economic, social and familial tolls on the sufferer; thus, Katz says, “It is important to have a variety of effective treatment options available.”
Current treatments with drugs like triptans are used primarily in eliminating pain after the migraine has begun, and have little preventive value. Well-studied preventive drugs like Topomax are not specifically endorsed for CM, and, according to Dr. Alexander Mauskop, director and founder of the New York Headache Center, “also have many potential side effects which can be disabling and dangerous, while Botox has very few side effects and is almost never dangerous.”

Other lesser-known preventive treatments such as memantine and tizanidine are only mildly effective, have never been subjected to large controlled trials, and also have more side effects than Botox, Mauskop added.
Dr. Green agrees but notes: “What has been scary is the finding that Botox travels down the neuron and appears in the brain, but the significance of this is unknown and likely minimal.”
While the mechanisms of Botox in cosmetic and medical treatments of muscular disorders are well understood, its mechanisms of action in CM are less so. In traditional treatments, onabotulinumtoxinA relaxes muscles by inhibiting acetylcholine release, eliminating the nerve-to-muscle communication necessary for contraction.
“It clearly has nothing to do with muscle relaxation, as the onset of improvement does not match the onset of muscle relaxation,” Dr. Green explains.
In CM, according to Dr. Mauskop, “We think that Botox prevents headaches by inhibiting other neurotransmitters, such as CGRP, substance P and others, thus reducing the sensory input from the periphery into the CNS. It seems that the activation of the brain centers requires feedback from the periphery in order for the migraine process to get going.”
Botox treatment costs are higher compared to other therapies. Treatment for CM typically involves 31 injections in seven areas around the head, neck and shoulder areas, lasting for approximately 12 weeks, at which point patients will typically need another treatment. Furthermore, because the mechanisms of action remain unclear and not enough time has yet passed to understand how and who best to treat, Dr. Green believes that “the locations and doses of Botox that are approved are not yet close to optimal.”
The fuzziness of Botox’s mechanistic action is not the only controversy. Both the FDA and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) based their regulatory decisions on data from two multi-institutional studies named PREEMPT 1 and PREEMPT 2—both of which were funded by Allergan and have been the objects of criticism from healthcare and other professionals around the world. The PREEMPT studies were the largest controlled trials of their kind, and sought to determine the efficacy of preventive Botox treatments for CM by comparing a treated group to placebo group.
“You have to look not at the difference between treatment and placebo,” Dr. Mauskop says of the PREEMPT studies, “but at the number of days reduced from the baseline—this is very impressive. If you take the entire body of evidence for Botox, including clinical experience, the evidence is overwhelming.”
Not everyone agrees, and further criticisms include that over half of the study population was potentially misdiagnosed due to medication overuse which can cause headaches; and that results were potentially skewed by absence of blinding in study subjects, as injections of either Botox or the placebo cause noticeable alterations in facial appearance. Overall, according to Dr. Green, the data is underwhelming, and he further notes that altering the primary outcome in the second PREEMPT study was “sketchy. If CM was not so refractory to current therapies and so disabling, this agent would never have made it.”
It remains too early to see how the treatment will be embraced by patients, providers and insurance companies. However, aside from the current controversy, Botox may be enough to provide some sufferers a ray of hope—especially considering the lack of treatments available for CM.
“Botox is another tool in an area that we really need tools,” notes Dr. Green. “As negative as I am about the data, I have a fair number of patients who do really well on it.”
While the cost may be high, even the slightest potential in staving off CM episodes will be worth it to some.
“It is not the last resort,” Dr. Mauskop explains, “but first choice if money is not an object, as it is more effective and safer than any preventive drug.”


Source: www.brainworldmagazine.com