Download Abortive Therapy for Migraines

Short Notes on Headache
Number 4
Abortive Therapy for Migraines
Proper therapy to reduce or stop the pain and associate symptoms of the various
types of migraine has improved in recent years. Unfortunately recent surveys
have shown that over half of the Americans with migraine are not receiving the
optimal treatment for their particular migraine situation.
Like all other medical conditions, treatment of a patient with suspected migraine
should begin with a thorough medical history, review of systems and neurological
examination to establish the proper diagnosis. Occasionally appropriate tests
are needed. A major mistake that is frequently made is the failure to diagnose
the daily or almost daily headaches that we used to call chronic daily headache.
Now we diagnose them as chronic migraine and medication-overuse headache.
To avoid this mistake the examiner must always ask three questions: 1. On days
when there is no significant headache, is there some milder level of headache or
is the patient totally headache free? 2. What types of headaches are occurring
on the days when the patient is not having migraine? 3. How many days each
month does the patient note total absence of any headache pain?
.
The two types of daily or almost daily headache are usually the result of
medications taken for pain and will be discussed in a future Short Notes on
Headache describing the diagnosis and treatment of chronic daily headaches.
After making the correct diagnosis, the first and most important rule is to use the
simplest, safest, fastest acting, least expensive medications initially. Only if
these are not effective, one should progress to the medications with greater
strength, greater cost and greater risk of adverse events.
Not all the types of migraine require medications. The shortest and least
disabling presentation of migraine is the migraine aura without headache.
These attacks are painless and thus do not require any analgesic. Auras
typically last 20 minutes. They are so brief that spontaneous termination often
occurs before any oral medication could be absorbed from the intestine.
Perhaps the most disabling aura without headache would be the attack that
occurs when the person is driving an automobile or working with hazardous
machinery. That patient should stop what they are doing and wait for the
problem to spontaneously terminate. If the auras without headache occur
frequently, the patient might be considered a candidate for daily therapy to
prevent the attacks, an approach which will be covered in the discussion on
preventive therapy for migraine. Visual auras are the most common type, but
other auras can occur, including a slow spreading sensory disturbance on one
side of the body; speech arrest; and rarely a hemiparesis or hemiplegia.
The next problem to discuss is the therapy for mild migraine attacks in which the
pain is of only minimal intensity. These patients may have attacks with only
minimal nausea, or very low grade photophobia or phonophobia, but none of the
disabling features of classic or common migraine. They often obtain adequate
relief with a simple off-the-shelf medication such as aspirin, acetaminophen,
sodium naproxen or other NSAIDs. Some of the off-the-shelf analgesics are
combined with caffeine, an agent that is thought to enhance the pain relieving
potential of the analgesic. The addition of caffeine has been used for over fifty
years. The benefit of caffeine never has been and probably never will be proven
by carefully designed double blind studies. These milder migraines are often
confused with sinus headaches since both might have a clear nasal discharge
and pain in the forehead extending down over the face. They may both be
weather related. The patient often chooses an off-the-shelf sinus medication
containing an analgesic and an unnecessary decongestant. Studies have shown
that over 90% of patients who think they have sinus headaches turn out to have
migraine.
Patients with migraine pain of moderate intensity should initially try a simple
analgesic, such as 440 mg sodium naproxen (two tablets of Aleve ®) or other
NSAIDs. The simple analgesics are more effective if used at the very beginning
of a headache. If the simple analgesics fail to work, the next agent to try would
be the combination of a simple analgesic and caffeine. There are several off-theshelf tablets and powders which contain aspirin and caffeine, none of which have
Federal Drug Administration (FDA) approval for migraine.
In previous years an effective medication for treating the patient with moderate
pain was the combination of aspirin, caffeine and sodium salicylate sold under
the brand names of Excedrin ® and Excedrin Migraine ®. The latter had FDA
approval for treating migraine. Unfortunately some of the recent bottles of
Excedrin contained tablets of an opiate which prompted the FDA in late 2011 to
recall all bottles of Excedrin ® with an expiration date before December 2014.
Novartis has not said if or when they will resume production of these popular and
effective agents.
Patients with probable migraine pain of moderate intensity frequently seek
help from a primary care provider or neurologist when they fail to obtain
adequate relief with one of the off-the-shelf medications. After the diagnosis is
established, the physician should first advise the early use of a higher than usual
dose of sodium naproxen or prescribe a non-addicting, inexpensive analgesic
such as Fiorinal® (a combination of aspirin, caffeine and butalbital), Fioricet ® (a
combination of acetaminophen, caffeine and butalbital) or Esgic Plus ® (another
combination of acetaminophen, caffeine and butalbital). Butalbital is not highly
addicting. The long term user rarely develops an urge to increase the daily dose.
But like other barbiturates, butalbital is habituating and should be used
infrequently. Abrupt withdrawal of the drug after frequent use might cause
convulsions and the drug must be gradually tapered. Since analgesics combined
with butalbital are a frequent cause of chronic daily headache, they should be
prescribed in small quantities which cannot be refilled. Before 1993, these drugs
with butalbital were considered the drugs of choice for migraine, even though
they were approved only for tension-type headache and had never been proven
to work in migraine. Now that triptans are readily available, most headache
specialists prefer triptans to the butalbital containing medications. If the simple
analgesics containing caffeine and/or butalbital do not completely stop the
migraine process and prevent the attack from coming back later in the day, the
patient should be started on one of triptans which are more effective in
terminating a migraine. If less expensive analgesics work, we encourage
patients to use them. But if headaches sometimes worsen, we caution that the
right treatment the first time may ultimately be better.
Primary care physicians and some neurologists often prescribe an opiate for
moderately severe or severe migraine pain. There are two good reasons to avoid
them: 1. They do not work on the migraine process. They may reduce the level
of pain or put the patient to sleep but they do not stop the pain in most patients.
2. Opiates cause dependency and are addicting and are one of the causes of
medication-overuse headache or chronic migraine. The authors strongly feel that
since the advent of triptans, opiates should never be prescribed for recurrent
migraine pain of moderate or severe intensity. If sodium naproxen 1100 mg,
diclofenac potassium powder for solution 50 mg (Cambia®) or the analgesics
combined with butalbital fail to provide prompt and complete relief of moderately
intense migraine headache, triptans should be prescribed. Even though these
patients might not have all the requirements listed by the IHS for severe or
classic migraine, it would be better to use a triptan for these patients.
Next will be a discussion of the previous treatment of severe migraine
(migraine without aura) and classic migraine (typical aura with migraine
headache). Prior to 1988 the only migraine specific agents were ergotamine
tartrate and dihydroergotamine (DHE). Ergotamine is the principal alkaloid
produced by the ergot fungus. It was synthesized in 1918 and first used in 1925.
It was soon combined with caffeine and sold as Cafergot ®. Ergot constricts
arteries. It was used in the days when the throbbing pain of migraine was
erroneously thought to be exclusively the result of dilation of the superficial
extracranial arteries such as the superficial temporal artery. Serotonin was
discovered in the 1940’s and in the 1980’s ergotamine was shown to acts as a
selective 5 hydroxytryptamine / serotonin1B/1D receptor agonist and thus was a
specific antimigraine compound. Ergotamine can occasionally cause major side
effects including gangrene, increased nausea and ergotamine-overuse
headache. It was never extremely popular and in recent years it is seldom
prescribed in this country. The author feels that it should be taken off the market.
In1943 dihydroergotamine (DHE 45®) was synthesized by the addition of two
hydrogen atoms to the ergotamine molecule. The new compound has reduced
arterial constriction and increased venous constriction potential but it continues to
be an effective 5HT1B/1D receptor agonist. The resulting compound is poorly
adsorbed by the oral route. DHE is a useful antimigraine agent when
administered subcutaneously, intramuscularly or intravenously. It is one of the
agents of choice when migraine rapidly reaches peak intensity or when
nausea/vomiting occurs early in a headache. It most successful use is in
patients whose migraine has lasted more than 24 hours with poor triptan
response and when given intravenously or subcutaneously to patients with
medication-overuse headache or chronic migraine. The major problem with the
intravenous route is it usually causes nausea and often vomiting, necessitating
premedicating with metoclopramide. The cost of an injection is comparable to a
tablet of triptan. DHE has been approved as a nasal spray, but the spray has not
been highly effective in stopping a migraine attack. DHE should never be used
when there is a possibility of cortical venous thrombosis.
The major breakthrough in the search for better antimigraine therapy was the
synthesis of the first triptan, sumatriptan by Sir Patrick Humphrey in England
while working for Glaxo in the 1980s. He was looking for a compound that
worked as well as IV serotonin with fewer adverse events. He found that
combining the indole molecule of ergotamine with a large side chain worked in
migraine. As compared to ergotamine, sumatriptan and the newer triptan
molecules are 5HT1B/1D agonist but have greatly reduced arterial constriction.
Sumatriptan was marketed in 1993 and since then 6 additional triptans have
been approved by the FDA. Five of the triptans are rapid acting, namely
sumatriptan (Imitrex ®), zolmitriptan (Zomig ®), rizatriptan (Maxalt®), almotriptan
(Axert ®) and eletriptan (Relpax ®). The onset of action in other two, naratriptan
(Amerge®) and frovatriptan (Frova®) is slower but their duration of headache relief
may be longer. These two have advantages which will be discussed later.
In the double blind trials each triptan when compared to placebo showed
approximately 55% - 65% significant improvement in a migraine attack at two
hours. The injection of sumatriptan subcutaneously worked much better at 1
hour but had more side effects. Each triptan tablet has similar side effects,
namely neck pain, chest tightness or pressure and difficulty with swallowing.
These are often the result of esophageal spasm, but have led to the drugs being
contraindicated in patients with heart disease. When first introduced the cost of a
tablet of each triptan was comparable, about $25 - $30. Recently sumatriptan
has been approved by the FDA as a generic and the cost is about $5 per tablet.
Others generics will be available later
Both sumatriptan and zolmitriptan can be administered by nasal spray which is
an alternate route for the patient whose migraine has a rapid onset, when there is
poor absorption of oral triptans or when there is nausea or vomiting early in the
headaches. Sumatriptan nasal spray has a bad taste and is not consistently
absorbed as compared to zolmitriptan nasal spray. Sumatriptan can be given
self-administered subcutaneously by autoinjector, which provides rapid onset of
action but the injector of the generic cost over $150 per dose. The nasal sprays
are intermediate in cost between an injection and a tablet.
Each of the triptans has the same contraindications, namely coronary artery
disease, stroke, peripheral vascular disease, uncontrolled hypertension and
hemiplegic or basilar migraine. The triptans never have been and probably never
will be tested in patients who are pregnant. Therefore pregnancy and attempting
to become pregnant are listed as contraindications. Each of the authors has
seen numerous patients who used a triptan during pregnancy without
experiencing significant complications and it is used during pregnancy in Europe.
But we do not prescribe triptans for the pregnant patient. If a patient is trying to
become pregnant, we let them take triptans only after a full period and during the
first nine days of the cycle. Sumatriptan has been approved during breast
feeding.
A major problem with each of the triptans is recurrent headache. The initial
headache may markedly improve or cease, but about 20 - 40% of the time the
headache returns 6-18 hours later, necessitating a repeat triptan. The recurrent
headaches develop slowly and can be managed either a repeat of the original
triptan or with either of the slower acting naratriptan and frovatriptan. Note that it
is contraindicated to use 2 triptans within 24 hours, but many headache
specialists use a slower acting triptan for recurrent headache and there are
usually no problems.
Since there is no perfect triptan and each fails to provide relief in over 30% of
patients, there is no way to predict which triptan should be prescribed initially.
Chose one and have the patient take it 2 or 3 times early in the course of a
migraine. If it does not work well, change to another triptan or switch to a form
that bypasses the GI tract, like an injection or nasal spray.
Some patients who have an aura before their headaches or whose pain gradually
reaches peak intensity can take 440 mg - 1100 mg sodium naproxen (two - five
of the off-the-shelf tablets of Aleve ®) at the onset of a migraine and get relief
within one hour, thus eliminating the expense of a triptan tablet. Of the less
expensive NSAIDs sodium naproxen is the fastest in reaching a peak serum
level and works best if taken on an empty stomach. If at the end of one hour
relief has not occurred, a triptan can be used.
A recent advance has been the release of diclofenac potassium powder 50 mg
(Cambia®) dissolved in water. It works faster and better than the 50 mg tablets of
the same medication. It is the only NSAID approved for migraine and it is
approved only for that condition. As it is in buffered solution when it reaches the
stomach, it is reasonable to conclude that it will be absorbed from the small
intestine faster than any tablet. Cambia begins to relieve pain in 15 minutes and
works best if taken on an empty stomach. The most common immediate side
effect is stomach pain or dyspepsia. If at the end of one to two hours relief has
not occurred, then either another dose of the NSAID can be given or a triptan can
be used.
The patient must be told to keep their NSAID with them at all times and use it at
the first suspicion of developing a migraine, just like they should keep their triptan
with them. NSAIDs, unlike triptans, can be taken late in the migraine attack and
still be effective.
The treatment of status migrainosus is different than the treatment of all other
types of migraine. By the IHS definition status migrainosus is a severe migraine
which has lasted for more than 72 two hours. The attack is typical of the
patient’s previous attacks of migraine except for the duration. The patients
usually become disabled and dehydrated from repeated vomiting and seek
treatment at an emergency room.
This definition is not absolute. If a patient with a similar headache of 54 hours
duration comes to the emergency room, he should not be told to leave and come
back 18 hours later. The treatment is identical regardless of the duration. The
one treatment to absolutely avoid is the administration of any opiates. Opiates
are not specific antimigraine drugs and a may cause or perpetuate addiction.
Patients using opiates tend to have more trouble with other treatments for
migraine.
Starting in the 1970’s steroids were thought to be beneficial for status
migrainosus. However some recent studies from London show that there is no
benefit from these injections. A few studies show that steroids help in medicationoveruse syndromes.
The patient with status migrainosus should be given intravenous fluids to correct
the dehydration. An excellent agent to terminate the headache is
prochlorperazine 10 to 25 mg by slow intravenous push. This agent not only
stops the pain, but is an effective antiemetic and a sedative. Producing sleep in
the patient with status provides merciful relief. Another drug to consider is
intravenous DHE 0.5 – 1.0 mg by slow push. Many emergency rooms reflexively
give the patient with status intravenous sumatriptan, and agent that is much more
expensive than prochlorperazine or DHE and somewhat less likely to work.
Since the patient with status might be having chronic daily headaches or
medication-overuse headache, the physician administrating sumatriptan may be
unaware that triptans are a cause of the daily headaches. In the rare patient with
status and a previous reaction to chlorpromazine, an alternate approach would
be intravenous metochlopramide or droperidol, medications that are
antidopaminergic and antiemetic.
In summary with proper therapy most migraine attacks can be stopped.
Revised August 22, 2012
John S. Warner, M.D.
Professor, Emeritus
Department of Neurology
Vanderbilt University
Nashville, Tennessee