Headache: The Journal of Head and Face Pain

© 2014 American Headache Society

Headache Toolbox

Onabotulinum A
(Botox)

At least 2% of the population suffers from chronic migraine, who received placebo, although the number of hours of
a disorder that can be very disabling in terms of pain, quality of headache per month was decreased by about 1/3. However,
life, missed workdays, and interruption of usual activities people who had received onabot in the studies were found to
throughout the month. In October 2010, Onabotulinumtoxin A be better able to function and perform their usual activities even
(onabot) brand name Botox (Allergan, Irvine, CA, USA) was when they did have headache.
approved by the US Food and Drug Administration (FDA) as a The 2 clinical trials that led to FDA approval used a
preventive strategy for patients having headaches most days of standardized set of injections called the PHASE III Research
the month, lasting at least 4 hours per day. This approval was Evaluating Migraine Prophylaxis Therapy (PREEMPT) protocol.
based upon 2 randomized, placebo-controlled trials conducted With this protocol, developed and tested extensively, 31 small
at 122 sites across North America and Europe that injections of 5 units each are placed at prescribed locations over
demonstrated decreased number of headache days, decreased the forehead, sides of the head, and back of the head and
hours of headache, and improved function with administration of neck. The injections are just under the skin, creating a small
onabot. bubble or wheal at the site that is usually not visible beyond a
Chronic migraine, per the latest edition of the International few hours. The PREEMPT injection sites are illustrated in the
Classification of Headache Disorders (ICHD-3 beta), is defined Figure.
as headache at least 15 days per month, with a least 8 of those The amount of medicine approved by the FDA for chronic
days meeting criteria for migraine, in this pattern for more than 3 migraine prevention, and administered in the PREEMPT
months. This means that for at least 8 headache days, light protocol, is 155 units. However, onabot only comes in vials of
sensitivity and noise sensitivity, or nausea, must be present, and 100 or 200 units. Rather than throw out the remaining 45 units
the pain should be moderate to severe in intensity. However, the in the bottle, many practitioners will offer to administer the
prescribing information for onabot approved by the FDA did not remainder in areas in which patients particularly have pain. This
put all these criteria in place. Instead, chronic migraine, for the additional treatment strategy is called “follow the pain,” and it
purposes of approved use of onabot, is described simply as was also used by many of the PREEMPT testing sites before
headache (with any characteristics) at least 15 days per month FDA approval. Unfortunately, although “follow the pain” injections
lasting 4 hours per day. Onabot is not approved, nor has it been are frequently administered, it is not fully established whether
proven to work, in individuals with headaches fewer than 15 they provide additional benefit.
days per month. The PREEMPT protocol for onabot injections is the only
Onabot is an injectable protein produced by a bacterium FDA-approved injection pattern for chronic migraine, and
(Clostridium botulinum) that paralyzes muscles into which it is practitioners are specially trained in its administration. Although
injected. The precise location and quantity of each injection has cosmetic onabot is chemically identical to that used for chronic
been tested extensively for safety and effectiveness in treating a migraine, the amounts and locations tested and approved for
wide variety of disorders. Onabot is believed to work for migraine headache treatment are very different from that used for other
by blocking pain-signaling transmission between the head and indications.
neck and the central brain where migraine is generated. Onabot in general is well tolerated and usually is without
Onabot is not a cure for migraine. In fact, in the trials systemic side effects. However, about 9% of people report neck
leading to its approval, there were only about 2 fewer headache pain, 5% headaches, and 4% may have a temporary drooping
days per month in those who received it compared with those of the eyelid called ptosis. About 3% will experience muscle

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Figure.—Injection sites for onabot using the PREEMPT protocol for chronic migraine.

pains, and 2% will have some facial muscle paralysis, eyebrow Onabot works as an effective preventive intervention in
elevation, or muscle spasms. All of these are temporary should many migraineurs. When it works for chronic migraine, the
they occur. results can be dramatic, not just in reducing headache days, but
Patients typically notice they cannot wrinkle their forehead reducing all disabling aspects of daily headache. For this reason,
after onabot injections, and when they resume being able to do it is important to keep a diary of headache days, intensity, and
this, it can be a sign that the drug is wearing off. The duration both prior to and after receiving the drug. Patients may
effectiveness of onabot tapers off at 3 months, sometimes take 4 weeks after injection to notice benefit, although many see
sooner. If there are side effects, they typically are much shorter improvement sooner. There is good evidence that when it
in duration than the 3 months of effect on headache. works, onabot has a cumulative effect, with better and better
There are some people who have neurologic muscular response with each cycle administered every 3 months across a
diseases who need to be observed closely for more severe side year. Therefore, patience is a virtue and trying onabot for 2–3
effects if onabot is administered. Allergies to onabot are cycles may yield benefit not seen with just one set of injections.
uncommon, but as with any medicine, they are possible, and However, after 2–3 sets of injections, if no improvement is
range from a local reaction to one case of severe allergy and noticed, onabot should probably be discontinued. For those
death, thought to be possibly related to another medicine that who do respond, injections are continued every 3 months. To
was mixed with the onabot. Other isolated reports of trouble test whether it can be discontinued, the injections are spaced
breathing, speaking, and swallowing have been reported, but further apart and if the headaches do not increase, the onabot
these events seemed to occur in patients being injected with may be stopped. After stopping onabot a headache diary
onabot in larger amounts for different problems and were not should be continued to assure that there is no increase in
reported in the large studies for chronic migraine. migraine frequency, intensity, or duration without the drug.
Onabot has not been tested in pregnancy and therefore Chronic migraine is an important problem for at least 2% of
should not be administered to pregnant women or in women the population, having an adverse impact upon an individual’s
who may become pregnant in the 3 months after it is quality of life, as well as that of their families. Onabot is the first
administered. It was not tested in those under 18 years of age approved intervention found to result in a significant
for chronic migraine and therefore is not indicated for this improvement in this disorder. While it does not result in cure, it
younger group. represents a breakthrough in effective treatment.
The entire injection process takes about 10-15 minutes,
and afterwards, patients are able to drive home and resume Deborah Tepper, MD
normal activities. Vigorous neck exercises, hair dyes, and Cleveland Clinic Headache Center
permanents are discouraged for 24 hours after the procedure. Cleveland, OH, USA

To find more resources, please visit the American Migraine Foundation