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 theoptimal 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 oralmost daily headaches that we used to call chronic daily headache. Now we diagnose them aschronic 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?
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The two types ofdaily or almost daily headache are usually the result of medications taken for pain and will be discussed in a future Short Notes onHeadache 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 migraineaura 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 thedisabling 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 benefitof 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-the-shelf 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 therecent 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 ofmoderate intensityfrequentlyseek 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 ofaspirin, 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 ofchronic 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 completelystop 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 ergotaminetartrate and dihydroergotamine(DHE). Ergotamine isthe 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®. Ergotconstrictsarteries. 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 agonistand thus wasa 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 authorfeels that it should be taken off the market.
In1943dihydroergotamine (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 bean effective 5HT1B/1Dreceptoragonist. 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 thetriptans are rapid acting, namely sumatriptan (Imitrex®), zolmitriptan (Zomig®),rizatriptan (Maxalt®),almotriptan(Axert®) andeletriptan (Relpax®). The onset of action in other two,naratriptan(Amerge®)andfrovatriptan (Frova®) is slower but their duration of headache relief may belonger. These two have advantages which will be discussed later.
In the double blind trials each triptan when compared to placeboshowed 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 anddifficulty 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 $5per 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 triptansor when there isnausea 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 injectorof 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 havebeen and probably never will be tested inpatients who are pregnant. Therefore pregnancy and attempting to become pregnant are listed as contraindications. Each of the authors has seennumerous patientswho 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 andworksbest if taken on an empty stomach. The most common immediate side effect is stomach pain or dyspepsia. If at the end of oneto two hoursrelief has not occurred,then either another dose of the NSAID can be given ora 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 becomedisabled anddehydrated 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 Londonshow that there is no benefit from these injections. A few studies show that steroids help in medication-overuse syndromes.
The patient with status migrainosus should be given intravenous fluids to correct the dehydration. An excellent agent to terminate the headache is prochlorperazine10 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.