Coastal Neurological
Medical Group, Inc.

Migraine

Migraine is a very common neurological disorder that impairs most patients' ability to interact daily in their normal lives and it gives them a significant amount of functional impairment. The primary care physician and the neurologist play an important role in the treatment of migraine. It has a significant health-related matters impairment and it is comparable in impairment as are other chronic medical conditions. It is important that we think about acute migraine therapy to improve the patient's quality of life and to do this we have to think about it from the patient's perspective that we need to have immediate onset of action in pain relief from the medication and relief of associated symptoms. One in four households in the United States has a migraine sufferer and the frequency varies, but it is between 8 and 10% in males and 15-20% in females. Importantly, most migraine sufferers are not diagnosed by physicians and they aren't treated with prescription medications that have been shown to be very effective. As a consequence to that, most migraines are important and frequent as impairing conditions in the patient's life.

The impact of migraine on the individual is significant in that it reduces their energy and their vitality, gives them physical discomfort, reduces their social function and also is a disease that can give them a significant amount of distress because of anticipated future attacks. It is certainly impairing on the family because it has a negative impact on the family and their interaction, and missed activities, not only work and social, are very important. Work function is reduced in many of the patients and it is said that 50% of the patients miss at least two work days a month and there is about six days of impaired ability to work. About 43% of the patients have significant reduced work effectiveness. Most patients feel that their headache is severe, probably between 40 and 50% and 40% feel that their headache is moderate in severity with pain and only 10-12% feel that it is mild. The economic burden of migraine is significant in that it is about $800-$1000 per year in cost and lost labor is as high as $15-17 billion annually. There is a great under-diagnosis of migraine and it is said that 59% of females are under-diagnosed and 70% of males are under-diagnosed.

The history is the most important in migraine and it usually makes the diagnosis in 90% of the cases. It is important to determine where the headache occurs, the circumstances and how suddenly it occurs as far as respect to its onset. It is important to determine the age of onset in the patient and the intensity, character and location of the pain. It is important to document duration, frequency and if the headache builds up and how long it lasts. Symptoms that occur prior to the migraine are important, essentially emphasizing the prodrome and the aura. It is also important to determine any aggravating, or provoking factors that occur. Oftentimes inducers will lower the threshold for migraine in a genetically predisposed patient. It is important to document the severity of impairment of the patient and how it affects not only their day to day life, but their economic aspects. It is important to determine if there is any factor that can reduce the migraine, or the migraine symptoms, and what past and present medications are being used. Comorbidity and medical history is important to document, as is the family history, especially if there is a positive family history of migraine. It is also important to review any psychosocial events or situations.

The classical clinical features of migraine are that is usually episodic, multifactorial. It is intermittent, occurs from 1-4 or more times a month on average. It is usually unilateral. It builds up, throbbing. It may start in the anterior or posterior part of the head and usually it is moderate to severe and increases with exertion. They last from a few hours, 3-4, up to 72 hours and often is associated with nausea, vomiting, photophobia, or sonophobia.

The pathogenesis of migraine is better understood now than it was numbers of years ago. The two prior theories were that of a neurogenic theory and a vascular theory. At the present time it is thought that there is a central sensitization that occurs. This is called the central sensitization theory. It is oftentimes supported clinically by the fact that patients have unusual sensitization events such as hypersensitive skin, hair, face, or other unusual hypersensitive phenomenon. It is felt that in some way there is a turning on of an area in the brain and then that area transfers some message or stimuli to the meningeal area via the fifth cranial nerves, mainly V I and C II. At this time there is a development of a pain generator in the peripheral area thought to be mainly in the vessels and in the meningeal region, but later is transferred after 20-60 minutes to a central area and there it lasts for some time. Brainstem neurons become hypersensitive after inflammation of the meningeal area and it is thought that this is progressive. The areas involved are located in the brain and it is associated with the spreading cortical depression (SCD). This is a phenomenon that occurs in the brain in the occipital area. It moves forward at a rate of 3-6 mm per minute and is associated with oligemia. It is not known for sure how the initiation of these stimuli or hypersensitivity occurs, but after this occurs the trigeminal nerve, mainly V I and C I or C II is activated. It is thought that activation of a primary nociceptor takes place in the periphery and then this is followed by central conduction through the peripheral trigeminal nerve to the trigeminal ganglion. Nerves from the trigeminal ganglion innervate large cerebral arteries and the meningeal area and the trigeminal nucleus complex, then sends fibers into pain processing areas of the brain such as the thalamus, the limbic system and other areas of the cortex. The exact site of initiation of this process is uncertain, but it is known that vessels in the meningeal area show a sterile inflammation and this sterile inflammation may allow for C-fiber activation which gives you a neurogenic inflammatory process and then primary afferent conduction takes place to the trigeminal nuclear complex and then that area sends to more central areas such as the thalamus.

It is known that genetics plays a significant role in migraine and that 70% of patients have a positive family history of migraine. It is known that migraine is a multifactorial disorder that is episodic and that gene mutations, or genetic aspects play a major role. It has been shown now by Joutel that there has been noted involvement in chromosome 19 in familial hemiplegic migraine. This chromosome 19 has a gene that codes for alpha 1A-subunit of the brain specific P/Q-type calcium channel. Other migraine types may later be found to have specific chromosome and gene involvement. At the present time it appears that the P/Q-type neuronal calcium channel has some effect on the modulation of neurotransmitter release, mainly the monoamines, the catecholamines and excitatory amino acids. Whatever the exact initiation and the mechanism, it is becoming more and more obvious that early treatment is a key component to effective therapy and to better quality of life for the patient.

The phases of migraine are prodrome, which oftentimes is associated with craving of food, yawning, heightened excitability and perception, fluid retention and irritability. Then there is oftentimes an aura, which is usually visual, or numbness, tingling, or some other type of aura. Then develops a progressive headache which is associated with an oftentimes unilateral pounding headache that crescendos and is associated with photophobia, sonophobia, anorexia, nausea and vomiting. Oftentimes the patient will then sleep and recover with a mild residual and then return to normal. The criteria for migraine without aura is that the patient needs to have two of the following; unilateral headache, pulsating throbbing headache, nausea, photophobia and sonophobia. And they have to have, to make the diagnosis of migraine without aura, similar pain or headache syndrome in the past and no evidence of any organic disease. Migraine with aura is diagnosed by headache pain preceded by at least one of the following neurological symptoms.

  1. Visual, either scintillating scotomata, fortification spectra, or photopsia.
  2. Sensory, with paresthesias, numbness, unilateral weakness, speech disturbances and no evidence of any organic disease.

Muscle tension headache is diagnosed by having head pain accompanied by two of the following symptoms: Pressure and tightness, nonpulsating; bilateral location and not aggravated by routine physical activity.

Muscle tension headache pain must be accompanied by both of the following symptoms: No nausea or vomiting, photophobia and sonophobia are absent, or only one is present.

Episodic tension headaches need to be fewer than 15 per month with headaches and there is no evidence of any organic disease. There is a category of chronic muscle tension headaches, or chronic daily muscle tension headaches.

The criteria for making the diagnosis of cluster headaches is as follows: Severe, unilateral, orbital, supraorbital and/or temporal pain lasting 15-180 minutes. There must be at least one of the following on the headache side: Conjunctival injection, facial sweating, lacrimation, myosis, nasal congestion, ptosis, rhinorrhea, or eyelid edema. There can be no evidence of organic disease.

The therapeutic options for migraine are as follows:

  1. Nonpharmacological approaches.
  2. Acute therapy or abortive therapy.
  3. Preventive therapy.
  4. Acute and preventive therapy combined.

Nonpharmacological treatment is associated with avoidance of any threshold lowering substances or events. This would be avoiding triggering mechanisms such as dietary, sleep excess or deprivation, or stress. Another nonpharmacological therapy is lifestyle changes, altering lifestyle so as to avoid headaches. Behavior therapies are also sometimes of benefit, such as relaxation exercises, stress management and conflict resolution.

Pharmacological agents indicated for the management of migraine are divided into two groups; acute prescriptions and preventive prescriptions. The acute prescriptions are NSAIDs, opioids, ergotamines, Stadol, Midrin and serotonin receptor agonists (triptans). Analgesics and opioids and other narcotics should be avoided on a regular basis in order to prevent rebound headache or transformed migraine. Prevention prescriptions oftentimes used are beta blockers, Depakote, Sansert, tricyclics, other antidepressants, and possibly Neurontin and Topamax. Over-the-counter medications are usually the NSAIDs, mainly Advil, Motrin and also Excedrin Migraine, Tylenol and aspirin.

Our biggest challenge at the present time is to improve our diagnosis of migraine and get more patients to come in to the physician and have their migraines diagnosed and effectively treated. It appears that only 45-50% of patients actually have their condition diagnosed and more than 50% are still untreated.

The pharmacological approaches to migraine, as mentioned, are broken down into acute and preventive. The acute therapeutic approach is used during the attack of migraine and used as soon as possible. It is hoped that the medication will limit the duration and severity of a headache and the symptoms and will restore the patient to normal function. Most patients can use acute or abortive therapy unless they have some contraindication to the triptans, or if there is a concern of pregnancy. Preventive therapy is done on a regular basis with daily medications. Its goal is to limit the frequency, severity and duration of the headaches and to allow the patient to have fewer headaches and have more effective control of their headaches when they use abortive medications. The most important medication for abortive therapy at the present time is the class of medication called triptans. These triptans are agonists at the serotonin receptor sites, mainly 5-HT1B and D. They have replaced much of the use of Cafergot, or ergotamines, and also have replaced DHE to a great extent, although DHE is still used. These drugs are effective and, if not given to a patient where there is a contraindication, they are quite safe. The key is for early treatment to allow early pain-free response, less recurrence, prevent progression of the attack, reduce disability and to reduce the need for multiple doses and rescue medication. The most important issue for monitoring clinical efficacy is 2-hour pain-free response. Pain response at two hours is also used, but the 2-hour pain-free response is probably the most important parameter. Next to that is a 24-hour sustained pain-free response where there is no pain at two hours, no recurrence from 2-24 hours and no rescue medications are needed.

When patient surveys are done to determine their most important significant concerns of migraine, most say they want complete pain relief, no recurrence and rapid onset as their most important features, basically in that order. They also do not want significant side effects and they want relief of associated symptoms. Route of administration is somewhat important also to most patients.

Triptans have varying pharmacological and clinical characteristics. They are all 5-HT1B/D agonists. Most of them have fairly good bioavailability and their T max is usually over several hours and their half-life is usually numbers of hours. The number of triptans available now are increasing and at the present time there will be seven oral triptans available in the United States. They are sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan and soon to be released eletriptan, and frovatriptan. These triptans have receptor affinities, as mentioned, mainly for 5-HT1B and 5-HT1D. They also have affinity for 5-HT1F, less so for 5-HT1A and for 5-HT2. They have little effect on the alpha adrenergic and the beta adrenergic and the muscarinic receptors.

The bioavailability of these drugs show that almotriptan has slightly more oral bioavailability and then next is naratriptan. Sumatriptans have probably the lowest oral bioavailability. T max in hours is highest for zolmitriptan, next naratriptan and then almotriptan with rizatriptan and sumatriptan being less. The half-life, or T 1/2, shows that naratriptan has the longest half-life, between 4.5 and 6.6 hours, then next is almotriptan, with zolmitriptan, rizatriptan and sumatriptan being less. The triptans vary in their metabolic and elimination pathways. This is important because it has an impact on whether the drug is reduced in patients who have renal or liver impairment. Almotriptan in the plasma is unchanged in 35-45% and about 75% is excreted in the urine. Forty-five percent is metabolized via two major pathways, the MAO type A, which is 27% and the CYP3A4 and 2D6, about 12%. Patients who have renal impairment will have higher triptan levels. Almotriptan has to be reduced in patients with renal and hepatic disease, but does not have to be reduced who are on propranolol, or SSRIs, or MAO type A inhibitors. Zolmitriptan does have active metabolites, as does rizatriptan. Naratriptan has some gender differences for bioavailability. Women have more bioavailability than men with that drug. Numerous studies have been carried out with all the triptans.

I will first use as an example almotriptan, or Axert, when compared to placebo. The clinical efficacy parameters were pain-free at two hours, pain response at two hours and no recurrence at 24 hours. It is shown that when comparing placebo to almotriptan at two hours, pain relief is 63% using 12.5 mg compared to pain relief with placebo at two hours 39%. At one hour almotriptan gave 35% pain relief and placebo gave 22% pain relief. Pain relief at two hours in all the triptans have shown consistency throughout various studies and in almotriptan the range was 57% to 65% pain relief at two hours in three different studies. Most of the triptans have shown consistency in therapeutic efficacy through numbers of attacks, so that the efficacy is as favorable on the first attack, second attack and the third attack. Most of the drugs will show an improvement in associated symptoms. Almotriptan reduces nausea over placebo indicating 30% of the patients reporting nausea at two hours after administration versus 45% with placebo. It reduced vomiting 55.9% at two hours compared to 11.1% for placebo and photophobia 26.9% versus 44.9% for placebo. Phonophobia 20.9% for almotriptan versus 38.9% for placebo. Adverse events with almotriptan were quite low and were lower than placebo for nausea, dry mouth and paresthesias and were 1%, 0.5% and 0.5% respectively. Noncardiac chest pain was also less common in almotriptan than was placebo.

A comparative study comparing Axert, or almotriptan, to sumatriptan 50 mg showed that 2-hour pain relief was 58% for Axert and 57% for sumatriptan. Adverse events were definitely less for Axert than they were for sumatriptan. Treatment emergent adverse events were 15.2% for Axert and 19.4% for sumatriptan 50 mg and drug-related adverse events were 9.1% for Axert and 15.5% for sumatriptan. At the present time Axert, outside the managed care system and in nonbidding situations, is the less expensive of the medications.

For using triptans it is important that the drug have rapid onset, give rapid relief of migraine associated symptoms, is well-tolerated with a low incidence of reported adverse events and has low potential for drug interactions and is competitively priced.

A meta-analysis of oral triptans was done by Ferrari et al and was reported in the Lancet 2001. The meta-analysis was done to compare oral triptans. Meta-analyses have strengths and weaknesses, but this meta-analysis has definite benefits. It was able to be done because the patient characteristics and preferences and patient responses are not predictable, but with the seven oral triptans and with the emphasis of evidence-based guidelines today, a meta-analysis to try to summarize efficacy and other characteristics of drugs should be of value. There have not been many head-to-head studies at the present time and there probably won't be a great number of them in the future. Meta-analysis has been shown to be a powerful tool for comparison of multiple treatments in multiple groups. Ferrari noted that many of the studies used the same characteristics and patient populations and the studies that were used to make the meta-analysis were randomized, double blind controlled studies in moderate to severe migraine attacks that fit the IHS criteria and the meta-analysis data has been summarized in the article. The differences between triptan and placebo were assessed and the results were present as absolute mean percent and 95% confidence interval. Since the study designs and eligibility criteria and endpoints were fairly similar, meta-analysis lent itself well in this situation. They used a sumatriptan 100 mg as a reference. The endpoints were pain relief at two hours, pain-free at two hours, sustained pain-free, recurrence rate, consistency across attacks and adverse events. No recurrence meant that there was no pain after 2-24 hours and no reason for rescue medication. Ferrari assessed 76 trials and chose 53 trials for the analysis involving 24,089 patients.

Response at two hours with the 95% confidence interval showed rizatriptan 10 mg and eletriptan 80 mg more effective than sumatriptan 100 mg. Naratriptan, frovatriptan and a lower dose eletriptan were less effective. Pain-free at two hours was measured and is thought to be a more desirable endpoint. Three triptans were significantly better than sumatriptan; rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg. Lower dose eletriptan, naratriptan and 25 mg sumatriptan were less efficacious. The placebo-subtracted pain-free at two hours to show therapeutic gain was used and it showed that rizatriptan at 10 mg, eletriptan at 80 mg were more efficacious, but almotriptan and zolmitriptan showed good efficacy. Recurrence of headaches at 2-24 hours showed lower efficacy for eletriptan at 40 and 80 mg, higher for rizatriptan and slightly lower for almotriptan. Sustained pain-free, meaning no pain and no rescue medication for 2-24 hours, showed that almotriptan was the most efficacious, with eletriptan at 80 mg being close as was rizatriptan at 10 mg. Lower dose eletriptan, naratriptan and lower doses of sumatriptan were less, as was zolmitriptan.

Pain relief at two hours, two or three attacks, showed that rizatriptan was most efficacious, but almotriptan, eletriptan, higher dose sumatriptan 100 mg, were all fairly efficacious. Pain-free at two hours showed that rizatriptan had more efficacy with over 45% pain-free in two or three attacks at two hours and almotriptan was 40%.

Adverse events were studied and it was documented that almotriptan and naratriptan had less adverse events and incidence of CNS events were less for almotriptan more than any other triptan. Incidence of chest adverse events were again less for almotriptan, with all others being about the same.

Throughout the meta-analysis there were comparisons and it appeared that rizatriptan was noted for consistency and rapid freedom from pain and eletriptan 80 mg was for high efficacy and low recurrence and eletriptan is noted for combining good efficacy and high tolerability.

The conclusions were that rizatriptan 10 mg and almotriptan 12.5 mg offer the most likely consistent success. The differences among the triptans were small, but it is important to remember there are differences in the drugs, as there are differences in the patient. It should be remembered that if a patient does not do well with one triptan they should be tried on another, and if they have side effects or poor response, another triptan should be definitely tried.

Pharmacologically maintained headaches, or transformed migraine, or rebound headaches are an important group of headaches that are commonly seen in the office practice. These are often associated with chronic usage of acute medications, especially opioids and narcotics. They are also associated with daily headaches that are on an ongoing basis and, importantly, these headaches require withdrawal of the excessively used medications in a very careful manner. Most patients will not get any better until these medications are withdrawn.

Migraine in the ER is an important group of patients. It is important in these cases to evaluate to make sure there is not some other cause of the headaches, especially subarachnoid hemorrhage, meningitis, or a mass lesion. If migraine is considered then triptans can be used, either orally, or even subcutaneous, or drugs such as IV Depakote can be considered. Narcotics should be used only as a last resort.

Prophylactic treatment of migraine is important and drugs used today are beta blockers, calcium channel blockers, 5-HT antagonists such as methysergide, or Sansert, NSAIDs, antidepressants and new drugs such as Depakote, Neurontin, Topamax and, of course, even Botox.

Depakote has been shown in one study to have a mean percentage reduction in migraine headache frequency by 45.7% for Depakote as compared to 10.9% for placebo. The percent of patients with 50% or greater reduction in migraine headache from baseline was shown to be 44% for Depakote and 21% for placebo. The mean percent reduction in migraine headache frequency for Depakote was 41% for Depakote and 26% for placebo. Adverse events for Depakote are nausea, weakness, somnolence, diarrhea, dizziness, vomiting, tremor, weight gain, alopecia and increased appetite.

Other safety considerations must be recalled in that patients with hepatic failure, or hepatic disease, should not be given Depakote. There have been cases of hepatic failure relating to Depakote, but most of these cases have been in younger patients. Liver function tests in all patients given Depakote should be monitored prior to therapy and at frequent intervals, especially during the first six months and intermittently then as indicated. Most importantly, patients with hepatic disease, or hepatic dysfunction should not get Depakote. Valproic acid has been shown to produce teratogenic effects on the fetus and it is said that 2% neural tube defect is the current known incidence. Patients should not be pregnant, or be able to get pregnant, when using this drug. Hence, Depakote should not be used in migraine prophylaxis in women of childbearing age unless they are using significant precautions. Depakote should be considered for effective migraine prevention on a prophylactic basis and it is generally well-tolerated in clinical trials. There are long term safety studies and it has a convenient multiple per day dosing versus a one dose at night.

New drugs will obviously be coming forth in the treatment of migraine and they will probably be based upon new scientific evidence of pathophysiology of migraine. Other AEDs will probably be explored for their efficacy for treating migraine on a prophylactic basis.

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Coastal Neurological Medical Group
9850 Genesee Avenue
Suite 860
La Jolla, CA 92037
Tel: 858.453.3842
Fax: 858.535.9390

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