EPIDEMIOLOGY OF MIGRAINES
Barriers to Migraine Management
The majority of migraine sufferers are not actively seeking medical care. Migraine is often under-diagnosed because it is misdiagnosed. Patients aid in this misdiagnosis by treating themselves with over-the-counter medications, while physicians often promote this misdiagnosis by prescribing analgesics rather than a specific migraine treatment.
Disorders associated with migraine include depression, anxiety disorders, personality disorders, strokes, sleep disturbances, and epilepsy. Many of these conditions share similar characteristics with migraine. Also, the same medications are often used to treat migraine with a comorbid disorder. These include comorbid migraine and epilepsy, which might be treated with an anticonvulsant, and comorbid migraine and depression, which could be treated with an antidepressant.
Special Populations – Women
Migraine is three times more common in women than in men. Researchers have established a link between migraine and fluctuations in the female sex hormones, estrogen and progesterone. Cyclic hormonal changes are probably the basis for menstrual migraine and as many as 60% of female migraineurs experience migraine associated with their menstrual cycles.
Pathophysiology of Migraine Anatomy
The pathophysiology of migraine is not understood. The aura is a cortical phenomenon, whereas the pain may be due to dysfunction of the trigeminal nerve and the blood vessels supplied by the nerve, including dural vessels. Migraine pain is thought to have three components:
Vasodilatation of the Intracranial VesselsInflammation within the perivascular space. Activation of the trigeminal nerve pathways within the brainstem (trigeminal nucleus caudalis). This nucleus receives input from the upper cervical nerves, which explains why neck pain is often a major part of the migraine process.
The Role of Serotonin
Many of the drugs used in the treatment of migraine are linked to serotonin metabolism. Sumatriptan, the first selective serotonin receptor agonist, was designed specifically as an anti- migraine medication.
The Clinical Phases of Migraine
The details of how migraines occur are not completely understood. There are four different phases of migraine. Not all of these phases occur in a given patient or in an individual attack.
Approximately 60% of migraine sufferers report symptoms 24 hours or more prior to the onset of the headache. These symptoms include mood shifts, abnormal food cravings, repetitive yawning, thirst, fluid retention, neck pain, anorexia, increased urination, constipation, and diarrhea. Neurological symptoms may also include photophobia, phonophobia, and hyperosmia.
This occurs in approximately 15% of the patients and develops slowly over 5 to 20 minutes and lasts up to one hour. Usually the aura is visual and includes such symptoms as flashing lights, shimmering waves, or zigzag or jagged lines. Neurological symptoms, such as marching paresthesias or a hemiparesis, may also occur. The presence of an aura preceding the headache is virtually diagnostic of migraine.
Usually unilateral, but the pain may travel from one side of the head to the other side. Bilateral headache does not exclude migraine; children often have bifrontal headaches. The pain is often described as pulsating or throbbing. Head pain is often aggravated by activities which may increase intracranial pressure, such as coughing, sneezing, bending over and climbing stairs. Associated symptoms that may occur are nausea, vomiting, dizziness, and heightened sensory perception including photophobia and phonophobia. Patients are often irritable and want to be left alone in a dark room.
In this stage the patients may have a feeling of exhaustion, are tired and irritable, and may have mood changes.
Diagnosis of Migraines and Migraine Types
The 1988 International Headache Society (IHS) classification provided descriptive names for two of the most important migraine types, namely migraine without aura, and migraine with aura.
Migraine Without Aura (Formerly known as Common Migraine)
Occurs in up to 75% of patients according to the IHS. The IHS defines migraine without aura as a recurring headache disorder which lasts anywhere from 4 to 72 hours. Before making the diagnosis a patient has to have a history of at least five attacks and at least two of the following pain features: unilateral location, pulsating quality, moderate or severe intensity, and aggravation of the headache with routine physical activity. One of the following needs to be present during a headache: nausea and/or vomiting, photophobia and phonophobia.
Migraine With Aura (Formerly known as Classic Migraine)
The basic features are similar to migraine without aura with the additional aura symptoms. Fifteen percent of patients with migraine present with an aura. The aura is a focal neurological symptom that occurs prior to the headache and lasts up to 60 minutes, as discussed previously. The typical aura is visual and migratory, spreading slowly over the visual fields. Such symptoms as jagged lights, flashing lights, or loss of vision are typical of the visual aura. Some individuals have a sensory aura such as paresthesias or numbness, beginning in an arm and moving to the leg on the same side.
Precipitating Factors for Migraine Attacks
Precipitating factors include hormonal changes, foods, stress, environment, and drugs. These are listed in Table 9.
Diagnostic Testing in Migraine
The diagnosis of migraine can be made based on a detailed history and examination. In general, neurodiagnostic studies are not indicated. However, in some instances it may be important to do a study such as:
Electroencephalogram (EEG). The EEG may be useful for evaluating patients who have both headaches and a seizure disorder. An MRI or CT scan of the brain is used to rule out a secondary headache disorder. A lumbar puncture may be performed in patients who complain of sudden onset of severe headaches to rule out the possibility of a subarachnoid hemorrhage or meningitis. Prior to doing the lumbar puncture, a CT scan or MRI of the brain is indicated to rule out signs of increased intracranial pressure.
MRI of the Brain in Migraine
MRI’s of the brain are being ordered with increasing frequency, and often, the primary care providers are concerned about reports which describe white matter abnormalities. White matter abnormalities are very common in patients with migraine, the prevalence ranging from 12% to 46%. The clinical significance of these abnormalities is unclear. The differential diagnosis of white matter lesions in the brain MRI is shown in TABLE 14.
Many that suffer from headaches and other disorders are actually migraine sufferers and candidates for migraine specific therapy.
Millions of patients remain undiagnosed, incorrectly diagnosed, or ineffectively treated. It takes an average of 3.5 years for a patient to find effective treatment. Patients try an average of nearly five different options before obtaining effective treatment for migraine. Migraine is often overlooked. It is overlooked in many patients who are diagnosed with sinus headaches. The typical history of a patient with a sinus headache is:
- A DULL ACHE LOCATED NEAR THE NOSE.
- PRESSURE OVER A SINUS CAVITY.
- THICK, COLORED NASAL DISCHARGE.
Over-the-Counter Medications May Relieve the Pain
While acute purulent sinusitis can cause a headache, the so-called sinus headache without the above nasal symptoms is likely a migraine headache. A triptan should be tried, unless there are contraindications to triptan use.
Tension-type headaches are also a frequent misdiagnosis. If the patient presents with throbbing neck pain associated with such symptoms as nausea and/or vomiting and disability, such as bed rest, or interferes with daily activities, one should consider the diagnosis of migraine. Again, the patient may respond to a triptan.
Treatment of Migraine
Migraine treatment is divided into non-pharmacologic and pharmacologic management.
Non-Pharmacologic: Behavioral Therapy
Non-pharmacologic techniques are useful in selected patients. This type of management requires:
Establishing a credible diagnosis and educating patients about their diagnosis.
Patient education to include pamphlets, various treatments, and support groups.
Specific behavioral interventions, including biofeedback therapy (both EMG and thermal), relaxation therapy, yoga, stress management training, and acupuncture.
Relaxation therapy and biofeedback therapy appear to reduce the sympathetic neuro-outflow and muscle activity in patients with migraine. Stress management and psychotherapy are largely directed at reducing stress which appears to precipitate or aggravate migraine.
- ACUTE (ABORTIVE) TREATMENT.
- PREVENTATIVE (PROPHYLACTIC) TREATMENT.
Acute treatment is used during an attack to minimize the impact, whereas preventative treatment is used on a daily basis whether or not a headache is present.
Guidelines For Acute Treatment
Patients desire complete pain relief, want rapid onset, relief of associated symptoms, no recurrence, and no side effects. The medications that patients use should restore the patients’ ability to function.
Medications for migraine are divided into:
NONSPECIFIC (SYMPTOMATIC) AGENTS/SPECIFIC AGENTS
Nonspecific (Symptomatic) Agents (Table 10)
These medications work for general pain and include nonsteroidal anti-inflammatory agents (NSAIDS) such as ibuprofen and naproxen, as well as aspirin associated with a combination of caffeine and acetaminophen. These medications are used to treat mild to moderate migraine attacks.
Specific Agents (Table 11)
These agents work for acute migraine, menstrual migraine, and cluster headaches.
The “step care strategy” in the past required that patients with acute attacks of migraine use medications at the bottom of the therapeutic pyramid such as a simple analgesic or an NSAID and then move in a stepwise fashion through a series of medications on a trial and error basis. The “step care strategy” has not worked well and “stratified care” is considered to have better outcomes than the “step care” approach. “Stratified care” is the state of the art approach for migraine management. “Stratified care” is one system which best accounts for the variability in the way headaches present and matches the treatment to the level of headache severity and disability. In “stratified care” a triptan is given as the first medication. All triptans are 5HT1B/1D agonists, which inhibit vasoactive peptide release, cause vasoconstriction, and inhibit pain fibers within the brainstem. The first triptan, sumatriptan, was introduced in the United States in 1993. Zolmitriptan and naratriptan were approved by the FDA in 1997, and rizatriptan was introduced in 1998, and almotriptan in 2001. Eletriptan (Relpax) is the latest drug in this class. Early intervention with triptans is important. For the majority of patients this means using the medication as soon as a migraine headache begins, while the pain is still mild. This will increase the pain-free efficacy and shorten the time to return to normal functioning.
Most patients with migraine prefer oral tablets, but sometimes nausea and vomiting are present, and oral tablets may not be tolerated. Slow gastric motility during migraine may delay absorption of oral medications. At one hour approximately 70% of patients have excellent pain relief and at two hours 82% have excellent pain relief with the various triptans. Triptans are indicated for migraine, with and without aura in adults. Sumatriptan is also indicated for cluster headaches.
The pharmacokinetics of the various triptans are different, but the clinical effects appear to be strikingly similar. There can be individual differences in the response to triptans. If a patient does not respond to one oral triptan after three attacks, then another triptan should be tried. All triptans help reduce the associated symptoms of migraine, including nausea, vomiting, photophobia, and phonophobia.
Sumatriptan was the first triptan introduced and is available in 25 mg, 50 mg, and 100 mg tablets. It is also available in nasal spray (5mg and 20 mg) and subcutaneous injection (6 mg). Being the first of its kind, sumatriptan is considered the gold standard. Subcutaneous administration of sumatriptan results in a 96% bioavailability of the drug and sumatriptan subcutaneously has an 82% efficacy at two hours, which is the most efficacious of any of the triptans. The major advantage of the injectable sumatriptan is that its onset of action is within ten minutes and is very useful for such peaking headaches as cluster headaches. The onset of action of oral sumatriptan is approximately 30 minutes. The nasal spray’s onset of action is approximately 15 minutes. The onset of action for the subcutaneous injection is approximately 10 minutes. Like all triptans, the subcutaneous injection of sumatriptan may be associated with transient triptan “sensations” which include heaviness of the chest and chest discomfort, throat discomfort, paresthesias of the head, neck, and extremities. These effects are less pronounced with oral and intranasal administration. It is important to explain to the patient that the symptoms are transient.
Zolmitriptan (Zomig)® and (ZMT)®
Zolmitriptan is available in 2.5 mg and 5 mg tablets, as well as orally disintegrating tablets. One of the clinically helpful features of zolmitriptan is its consistency, but a second dose of zolmitriptan may be useful for a headache recurrence. Onset of action is approximately 30 to 45 minutes.
Rizatriptan (Maxalt® and Maxalt MLT®)
Rizatriptan comes in 5 mg and 10 mg tablets and orally disintegrating tablets. Central side effects such as somnolence, dizziness, and asthenia occur more frequently with the 10 mg dose than with smaller doses. Onset of action of these oral forms is approximately 30 to 45 minutes.
Naratriptan is somewhat distinct from other triptans because of its longer half-life. It comes in 2.5 mg tablets. Its two-hour efficacy rate, however, is not as high as the shorter acting triptans. Naratriptan is most useful in patients with slow onset prolonged migraine or in menstrual migraine. Onset of action is approximately 60 minutes.
OTHER SPECIFIC MEDICATIONS
Ergot alkaloids and derivatives include Ergotamine in oral or rectal formulations associated with caffeine. Dihydroergotamine (DHE) can be given I.V. or by nasal spray (Migranal®). Ergotamine, either orally or rectally, with caffeine is also used in selected patients. However, the incidence of adverse effects is higher than with triptans or NSAIDS.
Isometheptene-Containing Compounds (Midrin®)
This fixed combination of a vasoconstrictor, analgesic, and mild sedative can relieve the pain of an acute migraine attack. It is well tolerated and can be useful in mild to moderate acute migraine headaches.
These combinations are also used in acute migraine, but they do have the side effects of sedation and increase the potential for opiate abuse. Medication overuse has been associated with chronic daily headaches.
Botulinum toxin is a protein produced by the rod bacterium Clostridium botulinum. There are seven distinct serotypes which produce unique forms of botulinum neurotoxin. Botulinum toxin A is commercially available as BOTOX® (Allergan,Inc.) and is the most widely used form in the United States. BOTOX® works at the neuromuscular junction where it blocks the release of acetylcholine. BOTOX® has been used effectively in a number of neurological diseases, including dystonia, blepharospasm, spasticity, hemifacial spasm and headache. It is very useful in preventing headaches and is usually injected in the muscles of the face and neck. After BOTOX® treatment some patients are headache free from ninety to one hundred and fifty days.
Guidelines for Preventative Treatment for Migraines
The goals of preventative treatment are to reduce the frequency, severity, and duration of migraine attacks and reduce disability. Migraine prophylaxis may include either pharmacologic or non- pharmacologic treatment. The non-pharmacologic treatment is similar to the treatment discussed above for acute treatment. Migraine prophylaxis should be initiated using medications with the highest level of efficacy. Care must be taken that medications given do not interact with other medications. There are several preventative medications and these are listed in Table 12.
- BETA BLOCKERS
- CALCIUM CHANNEL BLOCKERS
Treatment of Multiple Headache Disorders with Sumatriptan (Spectrum Study19)
It has been shown that some migraine patients experience a spectrum of primary headache disorders. These patients will often have some or all of the following headaches, (IHS classification, as noted).
- MIGRAINE (IHS 1.1, 1.2)
- MIGRAINOUS (IHS 1.7)
- EPISODIC TENSION-TYPE HEADACHES (IHS 2.1)
Although sumatriptan is not indicated for migrainous or episodic tension-type headaches, the drug effectively treated all three of the above headaches. Details of the spectrum study are published elsewhere. Sumatriptan has been shown to treat tension-type headaches in migraineurs, but will not relieve the headache in patients with pure tension-type headaches. That is, as long as the patient had migraine, as well as tension-type headaches and migrainous headaches, all three types of headaches would sometimes respond to the sumatriptan. In non-migraineurs, there was no difference in response between placebo and sumatriptan.
Triptan Side Effects
Triptan side effects are mild and usually include dizziness, somnolence, fatigue, asthenia, paresthesias, and chest symptoms.
Contraindications and Precautions for all Triptans
Because of their vasoconstrictive properties, the selective serotonin receptor agonists are contraindicated in patients with ischemic coronary artery disease and uncontrolled hypertension. The contraindications are listed in Table 13.
COMMON TRIGGERS FOR MIGRAINE
- ALCOHOL, NITRITE-LADEN MEAT, MONOSODIUM GLUTAMATE, ASPARTAME, CHOCOLATE, CAFFEINE AND CHEESE
- STRESS, ANXIETY, AND DEPRESSION
- MENSTRUAL, ORAL CONTRACEPTIVES, AND HORMONAL REPLACEMENT THERAPY
- NITROGLYCERIN, HISTAMINE, RESERPINE, ESTROGEN, HYDRALAZINE, AND RANITIDINE
- LACK OF SLEEP, CHANGE IN SLEEP/WAKE CYCLE
- FLASHING LIGHTS, VISUAL STIMULATION, WEATHER CHANGES, AND HIGH ALTITUDE
MIGRAINE TREATMENT: NONSPECIFIC AGENTS – ANALGESICS
- TYLENOL, ASPIRIN
- FIORINAL®, FIORINAL WITH CODEINE®
MIGRAINE TREATMENT: SPECIFIC AGENTS – TRIPTANS
- SUMATRIPTAN – ORAL, NASAL, INJECTION
- RIZATRIPTAN – ORAL AND DISINTEGRATING
- ZOLMITRIPTAN – ORAL AND DISINTEGRATING
- NARATRIPTAN – ORAL
- ALMOTRIPTAN – ORAL
- ELETRIPTAN – ORAL
- ERGOT DERIVATIVES
- ERGOTAMINE AND DIHYDROERGOTAMINE (DHE)
MIGRAINE TREATMENT:PREVENTATIVE TREATMENT
- Beta Blockers
a. Propranolol (Inderal®)
b. Atenolol (Tenormin®)
c. Timolol (Blocadren®)
a. Divalproex (Depakote®)
b. Valproic Acid (Depakene®
c. Topiramate (Topamax®)
d. Gabapentin (Neurontin®)
- Tricyclic Antidepressants
a. Nortriptyline (Pamelor®)
b. Amitriptyline (Elavil®)
- Calcium Channel Blockers – Verapamil (Calan®, Isoptin®)
- Selective Serotonin Reuptake Inhibitors (SSRI)
a. Fluoxetine (Prozac®)
b. Paroxetine (Paxil®)
c. Sertraline (Zoloft®)
- Serotonin Antagonists
a. Methysergide (Sansert®)
TRIPTAN USE CONTRAINDICATIONS AND PRECAUTIONS
- ISCHEMIC HEART DISEASE
- CEREBROVASCULAR DISEASE
- UNCONTROLLED HYPERTENSION
- HYPERSENSITIVITY TO ANY TRIPTAN
- THE USE WITHIN 24 HOURS OF OTHER 5HT AGONISTS/ERGOTS
- HEMIPLEGIC OR BASILAR MIGRAINE
- CAUTION SHOULD BE USED IN PATIENTS WITH RISK FACTORS FOR CORONARY ARTERY DISEASE
SSRI PRECAUTION. THERE ARE RARE CASES OF HYPERREFLEXIA AND INCOORDINATION IN PATIENTS TAKING AN SSRI AND 5HT AGONIST.