Introduction

Headache has been known to be a common and aggravating affliction since ancient times. Greek legend has it that Zeus from suffered from severe recurrent headaches which were relieved only after Vulcan opened his skull with an ax, from the cleft Athena goddess of wisdom was born. It seems oddly appropriate that our women patients are prone to suffer more frequent headaches than their male counter parts. In this chapter we will examine headache and the particular problems which arise in the diagnosis and treatment of women.

Classification

The International Headache Society has developed a classification system for headaches. This permits us to communicate with more confidence that we actually mean the same thing. There are two general groupings: primary and secondary headaches. Primary headaches are felt to be intrinsic to the brain. Secondary headaches are due to extrinsic factors.

Primary headaches include: migraine, tension, cluster and chronic paroxysmal hemicrania, and miscellaneous unassociated with structural lesions.

Secondary headaches are associated with: trauma; vascular disorders TIA, stroke, etc.); non vascular disorders (increased intracranial pressure; infection, neoplasm); withdrawal (nitrates, monosodium glutamate, analgesics); non cephalic infection; metabolic disorders (hypoxia, hypoglycemia); disorders of the cranium, neck, eye, ear, nose or throat; cranial neuralgias (trigeminal neuralgia, glossopharyngeal neuralgia); and unclassified.

Our focus will be on the primary headaches.

Epidemiology

The prevalence of headache depends upon the time intervasl of interest. Since almost every human being has had a headache at one time or other it is not surprising that those studies which ask about the presence of headache during one's lifetime have prevalence figures of 94 - 95 %. Yet even here women have a higher prevalence than men, with males having lifetime prevalences of 69 and 91 % respectively ( Crisp et al. 1977, Linet et al. 1989). Women consistently have a greater prevalence of headache than men for both migraine and tension headache types. They also complain of more frequent headaches irrespective of the time interval. If asked if one is having a headache at present 22 % of women and only 11 % of men will respond affirmatively (Rasmussen et al. 1991).

Migraine

Approximately 25 million Americans suffer from severe disabling headache with pain and focal neurological signs in 40 %. Migraine which is defined clinically as episodic unlateral headache associated with: nausea, a pulsating pain with photophobia and autonomic dysfunction is further divided into categories. Classic migraine is preceded by an aura usually a visual disturbance but other sensory abnormalities can also occur. Its prevalence is approximately 4%. Common migraine is a severe headache without visual, sensory or motor disturbances. Its prevalence is approximately 10%. In basilar migraine the headache is preceded by brainstem and cerebellar dysfunction such as dipolpia or ataxia. Hemiplegic migraine is associated with transient hemiparesis.

The overall prevalence of migraine appears to be 10 - 15 % of the population (Breslau et al. 1991). It is clearly more prevalent in premenopausal women, in a variety of studies the ratio of migraine in women is 2 - 3 times that of age matched males (Stewart et al. 1992). In children however the gender difference in prevalence is equal rising from 1% at age 6 to 5% at age 15. It is not until around the age of 11 years that the female preponderance appears reaching a 3:1 ratio of women to men by age 40 (Waters et al. 1971).

Pathophysiology

The pathophysiology of migraine is as yet undetermined. We do understand some what happens during an attack. There is a drop in ipsilateral regional blood flow with dilitation of the ipsilateral middle cerebral artery (Oleson et al. 1981, Frigerg et al 1991). There are alterations in platelet serotonin which falls during attacks of common but not classic migraine. Migraineurs have higher concentrations of excitatory amino acids glutamate and aspartic acid as well as decreased concentrations of magnesium. What remains unclear is what actually precipitates an attack.

Menstrual Migraine

In women an association of migraine and menstrual cycles has been well established, but the lack of a universally accepted definition has resulted in prevalence figures that vary widely averaging 60% (Edelson 1985). The International Headache Society has suggested a definition of menstrual migraine where over 90% of attacjs occur within 2 days before and the end of the menstrual period. Given this more restrictive definition 2 - 14% of women suffer from menstrual migraine (Headache Classification Committee 1988, Epstein et al. 1975).

It might be helpful in understanding menstrual migrain and attempts to treat it to review briefly the events of the menstrual cycle. The cycle is under the control of pulsatile secretions of sex hormones.. The frequency with which gonadotrophin releasing hormone (GRH) is released in turn effects the release of lutenizing hormone (LH) and follicle stimulating hormone (FSH). Rapid pulses (greater than one per hour) reduce LH and FSH. Slower frequencies increase FSH but further reduce LH. It is the LH pulse which in turn modulates the fluctuation of estrogen and progesterone. Estrogen concentrations rise just prior to ovulation. Progesterone concentrations are low in this follicular phase but rise dramatically with a secondary estrogen surge during the luteal phase. They both fall in the late luteal phase triggering menstrual flow.

It is this estrogen withdrawal in the late luteal phase which precipitates menstrual migraine (Welch et al. 1984.). This hypothesis has been verified by Somerville (1972) who demonstrated that sustained estrogen levels prevented menstrual migraine. Work which has been validated by other subsequent researchers ( Ligniers et al. 1986). In the post menopausal period menstrual migraine not surprisingly tends to abate.

This has lead to the use of hormonal therapy in menstrual migraine. Percutaneous estrogen patches have been used several days prior to menstruation to reduce the decline in estrogen levels. Conversely antiestrogen agents like tamoxifen or synthetic androgens like danazol have been used successfully to prevent the estrogen rise in the luteal phase (O'dea & Davis 1990, Calton & Burnett 1984). This hormonal intervention may have potentially undesirable effects on menstrual cycling. Most therapy in menstrual migraine is directed at either aborting individual attacks by using non steroidal anti-inflammatory drugs (NSAID) a few days before the menstrual flow, or sumatriptan. Prophylactic agents such as beta blockers, calcium channel blockers and valproic acid may also be effective.

Migraine and Oral Contraceptives

In most women oral or hormonal contraceptives to not appear to effect migraine headaches. A variety of responses have been described. Lundberg (1986) reported that between 18 - 50% of women have an increase in the severity and frequency of attacks. They also were more likely to occur during the drug free interval of oraql contraceptive use. Others report an improvement in migraine frequency and severity in 35 % of women (Larsson-Cohn & Lundberg 1970). Double blind placebo controlled trials have however found no difference in migraine frequency between those taking and those not using oral contraceptives, (Culberg 1972, Nilsson & Solwell 1967).

Migraine and Pregnancy

Migraine has no deleterious effects on pregnancy. Most pregnant women 62%, have a reduction in frequency and severity of migraine. Seventeen percent have complete alleviation of their headache (Chen & Leviton 1994). Medical management during pregnancy is complicated by the potential adverse effects of medication on fetal development. Given the fact that the majority of women will improve many physicians recommend discontinuation of prophylaxsis (Ratinahirana et al. 1990)..

The Federal Register has organized medications into 5 categories of relative safety for use in pregnancy.

Categories of Drugs in Pregnancy

Category A
Medications in this category have failed to demonstrate risk to the fetus in controlled studies.

Category B
Medications in this category have not demonstrated a fetal risk in animal studies, but lack controlled studies in pregnant women.

Category C
Medications in this category have produced adverse effects in animal studies but lack studies in women.

Category D
Medications in this category have demonstrated evidence of fetal risk but the benefits may be acceptable despite such a risk.

Category X
Medications in this category have demonstrated an association with fetal abnormalities and the risk of adverse outcome outweigh the benefits.

Aspirin and NSAIDs are category C and B respectively. They may increase the risk of bleeding and inhibit labor if used late in pregnancy. Ergots and sumatriptan are category X and C respectively and are contraindicated in pregnancy (Wilkinson et al. 1995). Amytriptyline and valproic acid are both category D, but may be considered for prophylaxsis if used after the first trimester. Beta blockers have been reported to increase fetal and neonatal toxicity, and are designated category C. Calcium channel blockers are category C and have not been well studied in pregnancy.

Acute attacks can be managed with rest for many patients will recover from the pain of migraine headache after awakening from sleep. Acetaminophen or acetaminophen and codeine are often effective in acute attacks. Antiemetics emetrol or phosphorlated carbohydrate solution or prochlorperatine act directly on the GI tract and are thought to be safe in pregnancy (Callaghan 1968).

Migraine and Menopause

As with many medical problems little study has been directed at the effects of menopause on migraine. Generally the prevalence of headache declines with aging in both sexes. Migraine prevalence peaks at a female to male ratio of 3.3 : 1 between the ages of 40 - 45 decreasing after menopause women still have significantly more migraine than men the ratio never falling below 2:1 (Stewart et al. 1992). In some series the frequency of migraine attacks does not change with the advent of menopause. It may actually worsen during the early phases when there are marked fluctuations in hormone concentration (Whitty & Hockaday 1968).

Estrogen replacement has been used to treat menopausal migraine with mixed results. Dose adjustment either downward or changing from continuous to pulse dosing and/or switching to another formulation of estrogen may improve effectiveness (Silberstein & Merriam 1991). In general however, treatment of menopausal or post menopausal migraine differs little from that of migraine during other life epochs.

Medical Management of Migraine

The management of migraine can be thought of as having 3 phases. Prophylaxis hence prevention of attacks; abortion of attacks early before the onset of severe headache; and treatment of severe headache itself. The choice of approach is dictated in large measure by the patient's presentation. If the attacks are infrequent and have an aura then abortive therapy is appropriate. Rare attack do not require daily medication, and the presence of an aura provides an opportunity for medication to prevent the severe headache pain. The three products used primarily in abortive therapy are: ergotamine, dihydroergotamine, and sumatriptan.

Abortive Therapy

Ergotamine has rather poor oral bioavailability with less than 1% of the oral or sublingual dose being absorbed. When given as a rectal suppository or inhalant the rate increases to 1-3%. Never the less it has been used orally for prophylaxis. Its contraindication in pregnancy and relative lack of bioavailability has resulted in it being supplanted by dihydroergotamine and sumatriptan.

Dihydroergotamine 0.75-1.0 mg IV over 2-3 minutes usually preceded by prochlorperazine 5mg. is very effective in aborting a migraine attack. In a controlled trial 85% of patients presenting to an emergency room for migraine treatment were successfully managed with this method (Callaham & Raskin 1986). The most common side effect is nausea hence the use of Prochlorperazine. Angina and ergotism have rarely been reported (Raskin 1968). A nasal inhalant form is considerably more convenient for patients one "puff" being equivalent to 1 mg. It is however less effective with success rates of 20-37%. The nasal form is not as universally available as the parenteral formulation (Bousser & Loria 1985).

Sumatriptan is an analog of serotonin and acts as an agonist on a subtype of serotonin like receptors. It is effective orally, nasally and subcutaneously in aborting migraine attacks. Two thirds of patients respond within 2 hours to oral dosing of 100-200 mg. (Oral sumatriptan dose defining study group 1991). Nasal sumatriptan 20 mg. is effective in 64% of subjects after 1 hour and 75% after 2 hours, and is clearly more easily tolerated in a nauseated patient (Finnish Sumatriptan Group 1991). Subcutaneous sumatriptan is the most popular formulation here in the United States. It is more rapidly available and can be utilized even by a nauseated patient. Seventy three percent of patients given 6 mg. sc respond within one hour (Ensink 1991). There are potential side effects of a subjective feeling of chest and neck heaviness, tingling and warmth. Its vasoconstrictive properties contraindicate its use in pregnancy.

Prophylactic Therapy

When attacks are relatively frequent or there is little clear aura to provide an opportunity to abort the headache, prophylaxsis provides a more effective approach. Beta adrenergic blocking drugs are the most frequently used for this purpose. Propranolol was found serendipitously to reduce the frequency of migraine by Rabin et al. (1966) while studying its effects on angina pectoris. There are 2 classes of beta receptors beta 1 subserving the myocardium, and beta 2 subserving skeletal muscle, the bronchi and vasodilatation and bronchiodilitation. The mechanism of action of these drugs in migraine is unclear and is felt to effect cerebral spreading depression and not simply vascular diameter (Schoenen et al. 1986). Five beta blockers have been studied in migraine.

Propranolol is effective but has great interindividual variation in plasma concentration after oral dosing hence the wide range of effective dosing from 80 - 240 mg. day. While its half life is approximately 4 hours its pharmacodynamic effects are longer and bid dosing is usually effective.

Nadolol 80 - 240 mg. a day has a long half life of 12-20 hours and can be given once a day.

Timolol has a greater bioavailability than either propranolol or nadolol. Its half life of 4 hours requires at least bid dosing. Doses of 10 mg. bid have been demonstrated to be more effective than placebo.

Atenolol in doses of 100 mg. day is more effective than palcebo. There is less interindividual variation in plasma concentrations and relatively high bioavailability. The half life is 5-8 hours.

Metoprolol has a short half life of less than 4 hours and wide individual variations in plasma concentrations. Dose is 50-100 mg. bid or with the long acting formulation 200 mg. a day.

NSAIDs are effective in prophylaxis by reducing platlet aggregation and the release of vasoactive products. In the 15% of women migraineurs who have menstrual migraine they can be used effectively by dosing for a few days prior to menses. Naproxen 550 mg. bid is more effective than placebo and also reduces premenstrual syndrome symptoms (Epstein et al. 1975).

Calcium antagonists appear to prevent migraine by blocking transmembrane influx of calcium with a subsequent vasodilating effect on cerebral vessels. Flunarizine 10 mg per day was not only better than placebo in 7 clinical trials but more effective than verapamil and nimodipine (Jansen et al. 1991). Verapamil 80 mg. tid or qid and nimodipine 40 mg. tid are also more effective than placebo.

The anticonvulsant sodium valproate has been demonstrated effective in migraine prophylaxis. Doses of 600 mg. bid resulted in 11/22 patients headache free, and 6 of the 22 markedly improved (Sorensen 1968, Hering & Kuritzky 1992). Recent studies currently underway suggest that gabapentine may also be an effective as a migraine prophylaxis.

The antidepressant amytriptyline appears to have antimigraine effects unrelated to its antidepressant action. Its proposed mechanism of action is the inhibition of noradrenaline and serontonin uptake. In 3 trials doses of 10-150 mg. a day only 62% of patients were able to complete the trials secondary to side effects (Couch et al. 1976).

Management of Acute Attack of Migraine

Raskin (1990) has outlined a protocol for the management of acute attacks of severe migraine or "status migrainosus".

1- metoclopramide 10 mg. IV for nausea.

2- DHE 0.5 mg. IV over 2-3 minutes

A- if there is no pain or nausea can follow up with DHE 0.5 mg. IV q8h, prn.

B- if there is pain but no nausea: repeat DHE 0.5 mg. IV in 1 hour. follow up with DHE 0.75 - 1.0 mg. q8h, prn.

C- if there is nausea but no pain: metoclopramide 10 mg. plus DHE 0.3-0.4 mg. q8h prn.

If pregnancy is a possibility then DHE needs to be avoided. Acetaminophen and codeine or a sedative to induce sleep may be effective.

Tension-Type Headache

The most prevalent type of headache and the most poorly defined. Characterized as pain in the head without associated symptoms, the International Headache Society classifies tension headache as: episodic, pressure or tightening pain of mild or moderate quality lasting minutes to days and without associated symptoms; chronic, headache present for at least 15 days per month for 6 months, nausea and photophobia may occur; and other. Prevalence data suggest that the episodic or infrequent tension headache is approximately 40 %. Most studies report a higher prevalence in women (Rasmussen 1993).

The pain is classically characterized as band-like and thought to arise from local as opposed to central intracranial structures. The principle causative factor is tension of muscles of the scalp, neck or jaw, however analgesic abuse with its rebound effect has been associated with approximately 50 % of tension headache (Baumgartner et al. 1989).

Therapy includes techniques to improve muscle relaxation and stress. Management of acute attacks is concentrates of aspirin, acetomenophen, NSAIDs and muscle relaxants. Muscle relaxants are usually used concurrently with analgesics. Lioresal 10 mg. tid; diazepam 10 mg. day; tizanidine 1 mg. day ; cyclobenzaprine 10 mg. day; and dantrolene sodium have all been found to be of benefit. Controlled trials are however rare and only tizanidine has been demonstrated useful prophylactically (Couch 1987). Combinations of sedatives, analgesics, and tranquilizers have been popular in the management of tension headache, and the combinations appear to have some synergistic effect.

Prophylactic therapy appears to be the only practical approach to chronic tension headache. Tricyclic antidepressants have been studied the most extensively and have had the greatest efficacy. Trials of muscle relaxants and NSAIDs have been shown to be as effective.

Cluster Headache

Defined as attacks of highly localized pain which occur in "clusters" followed by long periods of remission. It is an uncommon headache type more prevalent in men 0.4% than women 0.08% (Kudrow 1980, Manzoni et al. 1981). The attacks are severe unilateral and focused about the orbit or temporal regions. They last a relatively short period of time 15 minutes to 3 hours and occur repetitively over a varying interval. Associated symptoms are common, rhinnitis, tearing, and conjunctival injectionfacial sweating, miosis, ptosis, and edema of the eye lid.

Cluster headache can be triggered during cluster periods by vasodilating substances such as histamine, nitrogylcerin or alcohol. Interestingly enough there is often a latency of 20-30 minutes between the introduction of the precipitating substance and the occurrence of the attack.

Management of acute attacks has been revolutionized by sumatriptan. Six mg. subcutaneously produces prompt response in a majority of patients (Ekbom 1992). It has supplanted oxygen 100% at 7 liters per minute, and ergotamine and dihydroergotamine intravenously or nasally.

Prophylactic treatment appears most effective with sodium valproate (Hering & Kuritzky 1989). It has safety advantages over lithium and is more effective than ergotamine.

Chronic Paroxysmal Hemicrania

These unusual headaches are clinically similar to cluster headaches in their pain characteristics and types of associated symptoms. They are different however in that they have a strong female preponderance, 70% compared to 30% in men (Antonaci & Sjaastad 1989). They also tend to be shorter in duration but the attacks are more frequent. The number usually exceeds 15 per day and individual attacks last 2-25 minutes.

The onset is usually in midlife. As with migraine, attacks often lessen in frequency and severity during pregnancy. Menstruation and oral contraceptives do not appear to consistently influence paroxysmal hemicrania (Sjaastad et al. 1980).

In some patients attacks can be precipitated by bending or turning the head or by pressure against the transverse processes of C4, C5 or the greater occipital nerve. These attacks are exquisitely sensitive to indomethacin 150 mg. per day. So much so that a response is considered diagnostic.

-End-

Go to the Top of this Document

Mark S. Yerby M.D., M.P.H.
North Pacific Epilepsy Research
Mother Joseph Plaza
9427 SW Barnes Road - Suite 595
Phone: 503-291-5300
Fax: 503-291-5303

SEIZURES.NET | NPER HOME

©1997 Dr. Mark Yerby. All rights reserved. All material in this site is copywrited by Dr. Mark Yerby, North Pacific Epilepsy Research, and/or others. The information herein is to be used solely for the purposes of improving the treatment of epilepsy. Feel free to download this information and share with others. All unauthorized reproduction of these materials for commercial purposes or personal gain is strictly prohibited.