Beyond Botox

On Halloween morning in 1975, Martha Murphy, then a 23-year-old newlywed, woke up with a stiff neck. “I thought I just slept wrong, no big deal,” she recounts. But the pain and stiffness did not go away over the days and weeks that followed. Eventually, she had trouble turning her head to the right. Then she had trouble looking down.

Over a 12-year period, as Martha’s symptoms worsened, she saw primary care doctors, chiropractors, neurologists, orthopedists, and even a rheumatologist, none of whom knew what was wrong. Toward the end of those 12 years, her head began jerking uncontrollably from side to side, interfering with even the most basic daily activities.

Finally, Martha found a new neurologist who supplied the correct diagnosis: cervical dystonia, a neurological disorder that causes muscles in the neck to contract involuntarily. “I was so happy to have a diagnosis that I didn’t really listen to the part where he said that it’s difficult to treat,” says Martha.

A string of oral medications helped reduce the symptoms, but it also made her feel drugged and dazed. Fi­nally, in 1994, another neurologist recommend­ed something different: injecting the affected muscles with a protein called botulinum neuro­toxin, best known in the United States as one of its brand names, Botox®. The treatment of­fered Martha relief, and she continued with the therapy until 1997, when it became less effective. At that point she enrolled in a clinical trial of a new botulinum toxin, now known as Myobloc® (rimabotulinumtoxinB), which provided benefit and which she continues to receive today. Al­though the injections are not a cure, “I get relief from the pain and the pulling without the side effects of other drugs,” she says.

From Poison to Treatment

Scientists and doctors have known about botulinum neurotoxin since the nineteenth century, though originally because it presented a serious health risk, not a treatment. Produced by a type of bacteria found naturally in soil, the toxin became notorious for causing outbreaks of a fatal food poisoning called *botulism.*1

When swallowed, the toxin pro­duced by the bacteria slowly shuts down normal communication be­tween nerves and muscles in the body. This can lead to difficulty seeing, speaking, and swallowing, and, if not treated promptly, trou­ble breathing and even death. Today botulism is rare.2

Now, as scientists have come to understand how it works and how to safely use it,3 the toxin has actu­ally become widely adopted in med­icine to treat a range of conditions.

“It’s a product that’s currently be­ing used from head to toe,” explains David Charles, MD, a neurologist at Vanderbilt University who special­izes in treating conditions involving muscle overactivity, such as cervical dystonia and spasticity.

Nerves direct muscles to con­tract by way of chemicals called neurotransmitters. Botulinum neu­rotoxin blocks the mechanism that nerves use to release these neu­rotransmitters, cutting off the mes­sage telling muscles to contract.4 The toxin can similarly cut off nerve signals to sweat, tear, and sal­ivary glands, making it useful for treating conditions characterized by excessive sweat, tear, or saliva production.5

Its effects also wear off over time, usually over the course of several months. Though this means that patients must return for repeat treatments, it also means that peo­ple who experience an unwanted side effect, such as excessive muscle weakness, can expect it to resolve over time, explains Dr. Charles: “There’s no lasting effect.”

Blocking the Pain Message

Since the late 1960s until recently, the toxin has primarily been used to treat conditions involving invol­untary and often painful muscle contractions. But as researchers teased out the details of how the toxin works, they realized that it may also be able to interfere with the transmission of pain signals in the body, which are also sent by neurotransmitters.6

Sheena Aurora, MD, an associate professor of neurology at Stanford University, became interested in the toxin’s potential effects on pain while treating patients diagnosed, as Martha was, with cervical dys­tonia. “I noticed that their neck pain got better before their mus­cle function improved,” suggesting that it wasn’t just muscle relaxation causing a reduction in pain, she ex­plains.

Dr. Aurora and her colleagues decided to test whether the toxin could be helpful for chronic migraine, an excruciating neuro­logical condition characterized by a wide range of symptoms, which can include nausea, vomiting, neck pain, aphasia, and headache, expe­rienced at least half the days of every month. In their double-blind, placebo-controlled study—in which more than 85 percent of participants were women—people who received botulinum toxin injections had an average of more than eight fewer migraine days per month, along with reductions in headache severity and length.7

Somewhat frustratingly, Dr. Au­rora says, “There are some people who respond a whole lot better than others, but it’s difficult for us to tease out who is going to re­spond.” This means that doctors don’t have a way to know if injec­tions will help someone with chron­ic migraine without trying it.

Teri Robert is one of the lucky patients. She began experiencing migraines when she was six years old, and they became chronic in her thirties. Now 61, she had tried the gamut of medications prescribed to prevent migraine onset. Many worked—some very well—for a while, but over time they all stopped working or had to be stopped for other medical reasons.

“By November 2012 I was back up to 25 [migraine] days a month” and basically bedridden, Teri says. Her doctor suggested she try botu­linum toxin injections.

Although she saw only a small improvement with the first round of injections, she went back 90 days later because the toxin often takes several rounds to be effective for chronic migraine and other condi­tions. Her persistence paid off: she now gets only about six migraines per month, and a dose of another medication usually eliminates them within an hour.

As an advocate for people with chronic migraine, Teri advises oth­ers to be patient when trying the in­jections. She remembers her doctor telling her, “Don’t be upset if you don’t get superb results the first time around; some people don’t get any results at first, but the results tend to be cumulative.” She also stresses the importance of seeing a specialist trained in treating chron­ic migraine because the injection protocol is complicated and spe­cific. “You want to make sure that the person who’s doing it has been trained, has lots of experience, and knows exactly what they’re doing because if it’s not done right, it’s not going to help,” she adds.

Martha Murphy gives the same advice to patients with dystonia. The first time she tried the injec­tions, the doctor she saw had used the treatment only in patients with eyelid spasticity. The resulting misdi­rected injections in her neck actually made her dystonia worse for a while.

She now strongly encourages dys­tonia patients seeking a physician to see a movement disorder special­ist or a neurologist with experience and training in treating dystonia (she keeps a list of qualified specialists to whom to refer other patients). And, like Teri tells people with chronic mi­graine, she advises people with dys­tonia that “it could take a few rounds of getting injections before they start really noticing a difference.”

Although other clinical trials have shown the toxin to be ineffective in treating episodic migraine and chronic tension headaches, doctors are testing it in clinical trials for the treatment of other types of pain, including back, joint, and post-sur­gery pain. “It’s an exciting, emerging field,” says Dr. Charles.

Disrupting a Negative Feedback Loop

Botulinum toxin is also now being tested for what at first may seem like a surprising application: treating de­pression. Eric Finzi, MD, PhD, a der­matologist and biochemist at George Washington University in Washing­ton, DC, was familiar with the toxin for its cosmetic uses. He had also watched his mother struggle with major depression for her entire life. Then he came across a theory called the facial feed­back hypothesis, which states that communica­tion between the brain and the nerves that control the muscles in the face is a “two-way street.”

Scientists know how the brain sends messag­es to the facial nerves to contract, producing the facial expressions we identify with com­mon emotions. The facial feedback hypoth­esis suggests that infor­mation can also flow from the facial nerves back to the brain, even when the muscles are inert, potentially rein­forcing both positive and negative emotions.8

When Dr. Finzi published pre­liminary results9 describing how blocking specific facial nerves with botulinum toxin might reduce de­pression, the response was skepti­cal: “Being a dermatologist, nobody believed me,” he recalls.

In 2010 Dr. Finzi teamed up with a psychiatrist at Georgetown Uni­versity, Normal Rosenthal, MD, to test the concept in a double-blind, placebo-controlled trial: partici­pants randomly assigned to the con­trol group received sham injections and therefore could not be influ­enced by knowing whether they ac­tually received the toxin.

The results were better than an­ticipated: more than 50 percent of patients receiving the toxin reported a reduction of their depressive symp­toms by more than half compared with only 15 percent of those who received the placebo injections.10

“And we put almost a third of the patients [who received the tox­in] into remission,” says Dr. Finzi. “Most were people who had tried other treatments—they had been suffering on and off with depression for years.” Two additional small tri­als, from Germany11 and Texas,12 have since shown similar results.

The toxin is now being tested in larger Phase II trials, which Dr. Finzi hopes will eventually lead to approval by the US Food and Drug Administration (FDA) for the treat­ment of depression. “I’m not saying botulinum toxin is a panacea for de­pression, but our current treatments help only some people, and we need all the help we can get to treat this very stubborn illness,” he says.

A Word on Safety

Understandably, for some, the idea of injecting a toxin associated with serious illness is a scary proposition. Rare cases of medical uses of the toxin causing botulism-like symptoms have been reported in patients, mostly after so-called off-label uses—medical uses that, while sometimes common, are not approved by the FDA. In 2009 the FDA published standard warning language about this risk and also highlighted that the four different botulinum toxin products avail­able in the United States cannot be used interchangeably. More information on the FDA warning is available at fda.gov/NewsEvents/Newsroom/PressAn­nouncements/ucm175013.htm.

In The Pipeline

Botulinum neurotoxin is under investigation for treatment of a wide range of diseases and dis­orders that involve signaling by neurotransmitters. Examples cur­rently in clinical trials include the following:13

Myofascial Pelvic Pain Syndrome
ClinicalTrials.gov Identifier: NCT02173405

Chronic Low Back Pain
ClinicalTrials.gov Identifier: NCT02221648

Temporomandibular Joint Disorders
ClinicalTrials.gov Identifier: NCT02202070

Trigeminal Neuralgia
ClinicalTrials.gov Identifier: NCT02088632

Carpal Tunnel Syndrome
ClinicalTrials.gov Identifier: NCT02070302

Urinary Incontinence
ClinicalTrials.gov Identifier: NCT01945489

Stomach Cancer
ClinicalTrials.gov Identifier: NCT01822210

References

1. Ney JP, Joseph KR. Neurologic uses of botu­linum neurotoxin type A.Neuropsychiatric Dis­ease and Treatment. 2007;3(6):785-98. doi.
2. Botulism: Epidemiological Overview for Clini­cians, Centers for Disease Control and Prevention website. Available here. Ac­cessed July 2, 2015.
3. Dressler D. Clinical applications of bot­ulinum toxin. Current Opinion in Micro­biology. 2012;15(3):325-36. doi: 10.1016/j. mib.2012.05.012.
4. Ting PT, Freiman A. The story of Clostridium botulinum: From food poisoning to Botox. Clin­ical Medicine. 2004;4(3):258-61. doi: 10.7861/ clinmedicine.4-3-258.
5. Charles PD. Botulinum neurotoxin serotype A: A clinical update on non-cosmetic uses. American Journal of Health-System Pharmacy. 2004;61(22 Suppl 6):S11-23.
6. Whitcup SM, Turkel CC, DeGryse RE, Brin MF. Development of onabotulinumtoxinA for chronic migraine.Annals of the New York Acad­emy of Sciences. 2014;1329:67-80. doi: 10.1111/ nyas.12488.
7. Aurora SK, Winner P, Freeman MC, et al. On­abotulinumtoxinA for treatment of chronic mi­graine: Pooled analyses of the 56-week PREEMPT clinical program. Headache. 2011;51(9):1358-73. doi: 10.1111/j.1526-4610.2011.01990.x.
8. Finzi E. The Face of Emotion. New York: Pal­grave Macmillan Trade; 2014.
9. Finzi E, Wasserman E. Treatment of depression with botulinum toxin A: A case series. Dermato­logic Surgery. 2006;32(5):645-50.
10. Finzi E, Rosenthal NE. Treatment of depres­sion with onabotulinumtoxinA: A randomized, double-blind, placebo controlled trial. Journal of Psychiatric Research. 2014;52:1-6. doi: 10.1016/j. jpsychires.2013.11.006.
11. Wollmer MA, de Boer C, Kalak N, et al. Facing depression with botulinum toxin: A ran­domized controlled trial.Journal of Psychiatric Research. 2012;46(5):574-81. doi: 10.1016/j.jpsy­chires.2012.01.027.
12. Magid M, Reichenberg JS, Poth PE, et al. Treatment of major depressive disorder using botulinum toxin A: A 24-week randomized, double-blind, placebo-controlled study. Journal of Clinical Psychiatry. 2014;75(8):837-44. doi: 10.4088/JCP.13m08845.
13. ClinicalTrials.gov website. Available here. Accessed July 2, 2015.