headache therapy florida

Headache Stephen E. Nadeau, M.D. Geriatric Research, Education and Clinical Center, Malcom Randall Department of Veterans Affairs Medical Center, and the Department of Neurology, University of Florida College of Medicine, Gainesville, FL Headache is one of the leading causes of doctor visits. Serious causes of headache are unusual but are commonly missed, and yet the average patient frequently undergoes excessive diagnostic evaluation. Headache is a major cause of suffering, leads to large numbers of lost workdays and yet it is commonly inadequately treated. Abortive treatment carefully tailored to the particular pattern of the individual patient's headaches can substantially eliminate 90% of headaches in 90% of patients, and represents the mainstay of effective headache management. Headache is so common that generalists must assume substantial responsibility for its treatment. DIFFERENTIAL DIAGNOSIS AND CHARACTERISTIC IDENTIFYING FEATURES The first task of the physician in dealing with the headache patient is to distinguish benign headaches from headaches that are indicative of serious underlying disease (Table 1). Headache Symptomatic of Serious Underlying Disease There are three major types of serious headache: 1) headache due to subarachnoid hemorrhage or acute meningitis; 2) headache due to a structural process involving the head or chronic meningitis; and 3) headache due to focal invasion, ischemia or inflammation of the dura or extracranial soft tissues. Subarachnoid hemorrhage, most often due to aneurysmal rupture, typically produces a severe pancranial headache of paroxysmal onset, often with syncope, nausea and vomiting, and neck/back pain, sometimes with focal neurological symptoms and signs. The patient usually states that it is "the worst headache of my life." Meningitis, whether of infectious (viral, bacterial, fungal, or amebic) or chemical origin (e.g. ibuprofen-induced), may produce a headache of similar quality but more gradual onset. Headache due to structural processes involving the head or to chronic meningitis need not be particularly severe but it is typically fairly persistent and usually has a duration of weeks to months. There are often no focal neurologic symptoms or signs but there may be nausea, vomiting, malaise or confusion. Characteristically the headache is markedly worsened by cough, Valsalva maneuver, lifting, bending over, or driving over bumps in the road, even when it is quite mild. In contrast, in migraineurs these "traction" symptoms are noted only during the most severe phases of the headache. Patients with structural processes or chronic meningitis typically do not awake with the headache (as do migraineurs) but rather develop the headache after they have been up on their feet for a few minutes. The structural processes causing such headaches include brain tumors and abscesses, intracerebral, subdural or epidural hemorrhage, obstructive hydrocephalus, pseudotumor cerebri, impaction of the cerebellar tonsils in association with an Arnold Chiari malformation, and sinus obstruction or mucocoele. In patients with chronic meningitis, headache may be obscured by associated confusion. Headache due to focal invasion, inflammation or ischemia of the pachymeninges or of the extracranial soft tissues is typically very persistent, localized, severe, unassociated with convincing migrainous symptoms, and not significantly affected by cough, Valsalva maneuver or positional change. The most common cause is tumor (metastasis or meningioma) involving the cavernous sinus or the floor of the middle cranial fossa, in which case pain is usually referred to the temple, less often to the frontal or retro-orbital regions. The pain of a pituitary tumor may be referred to the vertex. The pain of posterior fossa Table 1 Features of Headaches Caused by Serious Underlying Disease Cause Acute meningeal irritation Aneurysmal subarachnoid hemorrhage Acute meningitis (infectious, chemical) Structural process involving brain (e.g., tumor, hydrocephalus); chronic meningitis Invasion, inflammation, or ischemia of pachymeninges or extracranial soft tissues (e.g., tumor of cavernous sinus, middle cranial fossa; temporal arteritis) tumors may be nuchal/occipital or it may be referred to the temporal or frontal regions. Squamous cell carcinoma of the face occasionally migrates backward along cranial nerves, causing associated palsies and great pain, sometimes trigeminal neuralgia. Steady, unilateral, boring facial pain may be caused by the pre-trigeminal syndrome, usually a precursor to trigeminal neuralgia. One of the most common posterior circulation strokes, lateral medullary infarction, is usually associated with vertebral thrombosis and commonly accompanied by ipsilateral nuchal/occipital pain because the vertebral artery commonly supplies a portion of the meninges. Temporal arteritis may present with persistent, localized headache without clearcut aggravating factors. Vascular dissections, either carotid or vertebral, may be associated with persistent unilateral pain in the neck or head. The notion that elevated blood pressure causes headache is probably incorrect. It is fair to say that all headaches that do not have the features discussed above are benign as long as the neurologic examination is completely normal. However, the characteristic features of benign headache syndromes may be of considerable value in discriminating them from serious headaches and headaches that do not conform to a known benign pattern should be investigated. Features Apoplectic onset of very severe pancranial headache Rapid onset of severe pancranial headache Pancranial or predominantly unilateral headache, at times mild, aggravated by cough, sneeze or Valsalva Persistent, non-fluctuating, usually severe, unilateral boring pain without precipitating or aggravating factors. Benign Headache Syndromes Six benign headache syndromes will be discussed: migraine, cluster, tension headache, chronic daily headache, cervicogenic headache, and medication overuse headache. The single most characteristic feature of most benign headache syndromes is the intermittence of the headache. It is mainly the persistent benign headache disorders, chronic daily headache and headache of cervical spondylosis, that sometimes raise diagnostic issues. Migraine The most important and common benign headache is migraine. Migraine may be divided into common migraine (migraine without aura) and classical migraine (migraine with aura). Common migraine typically is associated with scant neurologic symptoms before headache supervenes. The most common include vague confusion or "spaciness," difficulty focusing or blurring of vision, mild photophobia, a change in emotional tone, usually sudden unexplained sadness, nausea, and neck tightness. These symptoms then give way to headache, more severe nausea, vomiting, phonophobia, photophobia, at times exquisite scalp tenderness, and malaise. Of all these symptoms, malaise is the most consistent, and it is an unusual migraineur who does not prefer to lie down, particularly when the headache is severe. Classical migraine is characterized by clear-cut, focal neurologic symptoms and signs that typically persist for 5 to 30 minutes, but occasionally for Nadeau 3 hours or even days, before they give way to headache. These symptoms occasionally last for days after resolution of the headache. The most characteristic symptoms are visual or sensory and very commonly there is dizziness of either a vertiginous or presyncopal character. Visual symptoms may include various active phenomena, such as scintillating scotomas; jiggling lines, circles or ovals in central vision; jagged, often multicolored shapes; or floating opaque blobs, sometimes drifting slowly across the visual field, sometimes progressing to the point of complete obscuration of half or full visual fields (cortical blindness). Often these patients will have preserved islands of vision. Because the brain tends to fill in the intervening spaces, they may have the sensation of looking through shattered glass or a stained-glass window, or they may sense that their vision is unreliable and that objects appear to leap from one portion of the visual field to another as they move, rather than traveling smoothly. Sensory symptoms characteristically consist of numbness and tingling paresthesias that may affect the entire hemibody and face all at once, but more classically expand in a sensory march from one part of the body to another over the course of one to 20 minutes. Both sides of the body are occasionally affected. However, exquisite splitting of the midline mouth and lips is very characteristic, as is exquisite localization to part of an extremity. Migraineurs, in strong contrast to patients with transient ischemic attacks (TIAs), will commonly describe numbness confined to a single finger, a foot, or a patch on the arm, usually in a non-anatomic distribution. Also unlike numbness in TIAs, numbness in migraine is characteristically extreme, comparable to that achieved with local anesthesia, or it is characterized by prominent tingling paresthesias, as after inadvertent sciatic compression ("leg going to sleep"). Less common migraine features include agitation, lethargy, aphasia, olfactory hallucinations, hemiparesis, quadraparesis, ataxia, ophthalmoplegia, more generalized brain stem symptoms and signs, Horner's syndrome, prolonged episodes of confusion, syncope, seizure like behavior, tremor, chorea, sharp pains throughout the body, deep aching/colicky abdominal pain, diarrhea, nasal stuffiness and rhinorrhea. Rare features include focal (especially face) or generalized edema, subconjunctival hemorrhage, petechiae, epistaxis, and orbital echymosis. Considerable caution is in order before attributing such symptoms to migraine. In general, only when atypical symptoms occur in the context of typical symptoms (e.g., visual or somatosensory) can one be reasonably confident of the diagnosis of migraine. Diagnostic confidence is markedly enhanced by a history of repeated, stereotyped attacks, a migraine hallmark. The headache of classical migraine may be mild or even non-existent, particularly in the elderly. However, most patients, even those without headache, will develop sufficient malaise to want to lie down as their aura subsides. Contrary to popular belief, both common and classical migraines may develop de novo at any age (1). The headache of migraine may be throbbing, aching or boring, and some patients experience excruciating stabs of pain lasting a minute or two. The latter are referred to as "icepick" headaches and while they are overwhelmingly associated with migraine, they may occasionally occur in isolation. Migraine may involve all or any part of the cranium, face or neck, and it may be unilateral or bilateral. Headaches may last as little as ten minutes or as long as weeks. Mechanism of Migraine. In the early 1940s, an experimental psychologist, Karl Lashley, published a paper describing his own migraine headaches (2). These headaches were heralded, as in many migraineurs, by a visual "aura" characterized by a pulsing figure in the center of his vision that slowly expanded from pinpoint size until it encompassed the entirety of a visual field (Figure 1). Lashley reasoned correctly that this reflected something happening in his visual cortex. Since he knew the dimensions of the calcarine cortex, by plotting the extent of the jiggling figure over time, he was able to compute the rate of progression of this process along the calcarine fissure. He estimated 3 mm/minute. Three years later, a Brazilian neurophysiologist, Aristides Leao, then also working at Harvard, reported an annoying but interesting phenomenon he had encountered in his experimental work with animals (3). Sometimes the application of small amounts of ionic solution to the cortex of cats elicited a sudden temporary but profound depression of cortical neuronal activity that slowly expanded across the cortex like a ripple caused by a stone thrown into a pond. The rate of expansion was 3 mm/minute. This phenomenon has since been known as "spreading depression of Leao." Leao actually speculated that it might be the mechanism underlying migrainous aura. In the early 1970's, investigators in Scandinavia perfected a means to measure cerebral blood flow by injecting radioactive xenon into a carotid artery and measuring the ultimate distribution of radioactivity over the hemisphere, using a large number of scintillation counters mounted in a helmet placed over the head. Because cerebral blood flow is determined by synaptic activity, this promised to be a means for defining the 12/21/07 Nadeau 4 particular regions of the brain engaged by specific tasks. Hundreds of laboratories are now involved in this type of research. These Scandinavian investigators quickly discovered that inserting a needle into a carotid artery of a migraineur was a very effective way of precipitating a migraine. They found that the aura phase of migraine began with a profound reduction of cerebral blood flow in the occipital regions of the brain that slowly expanded anteriorly until it encompassed the entire hemisphere. The rate of forward expansion was 3 mm/minute (4, 5). Figure. The development of Karl Lashley's migrainous visual aura over time (2)). It is now generally accepted that migrainous aura is caused by spreading depression of Leao. Further research has shown that the transient profound depression of neural activity is caused by massive glutamate release that depolarizes cortical neurons and temporarily renders them incapable of repolarizing sufficiently to resume firing. Furthermore, when spreading depression is induced in animals, it triggers activity in the spinal nucleus of cranial nerve V, strongly suggesting that these animals are experiencing headache. The mechanism by which this occurs is not known. The headache of migraine is thought to be primarily of meningeal origin, although pain from structures outside the skull, most notably the galea, is clearly contributory in many patients. It is thought that headache begins with slow firing of trigeminal endings in the meninges. This is associated with the release of a number of vasoactive substances from these endings, including substance P, neurokinin A, and calcitonin gene related peptide. These substances lead to local microvascular vasodilation, increased vascular permeability, and local edema. These events are thought to stimulate the trigeminal endings, increasing their firing rate, and thereby, initiating a vicious cycle. Triptans, the prototypic agents used to abort migraine, are agonists at the 5-HT1B/1D receptors on trigeminal endings. They act to inhibit the release of the vasoactive proteins, thereby breaking the vicious cycle. Ergots are thought to act in the same way. The molecular mechanisms that predispose people to migraine in general and to migraine associated with certain kinds of auras are unknown. The high prevalence of a familial history in migraineurs strongly suggests genetic causes. Molecular genetic studies in a particular form of migraine, familial hemiplegic migraine, have established that it is due to a missense mutations in genes coding for a voltage sensitive sodium channel, a voltage sensitive calcium channel, or a sodium-potassium ATPase. It is not known whether migraine in general is caused by "channelopathies" but such a mechanism would not be at all surprising. 12/21/07 Nadeau 5 Cluster Cluster headache is characterized by severe, often excruciating, unilateral boring pain in the frontal, temporal, or retroocular regions. The pain may be so severe that some patients are literally tempted to shoot themselves in the head to end it. Cluster headache may be very sharply localized, e.g. to an area the size of a quarter. Its most characteristic feature is its brevity: the headaches typically develop precipitously, last for 30 minutes to two hours, and then end quite abruptly. Classically there is associated ipsilateral tearing, nasal stuffiness, and rhinorrhea. A transient Horner's syndrome may be observed in many patients and occasionally it becomes permanent. Classically, cluster headache patients pace with their headaches but many prefer, like migraineurs, to lie down. Many cluster headache patients also experience nausea, vomiting, phonophobia and photophobia. Classically, cluster headaches occur one or more times daily for weeks or months and then remit for varying periods of time, hence the name. However, many patients have headaches that seem to persist indefinitely. Tension Headache It has been traditional to distinguish tension or muscle-contraction headaches from migraine. However, the consensus among headache investigators after years of research is that there is presently no principled basis for making such a distinction. Tension headaches are generally pancranial and not sufficiently severe to interfere with activity. When they become more severe, they typically have features of common migraine. Tension headaches may respond to migraine specific drugs such as ergotamine or sumatriptan. Thus, for the time being at least, it seems reasonable to view them as mild and more easily treatable common migraines. Chronic Daily Headache Chronic daily headache, one of the most common headache syndromes, consists of a steady, usually pancranial headache that is present from the moment the patient wakes up to the moment s/he goes to bed and generally is not associated with other symptoms such as nausea, photophobia or malaise unless it is punctuated by more typical migraine (which is quite often).1 It may persist for weeks, months or years. Chronic daily headache does not have the traction features that distinguish the headache of intracranial masses and chronic meningitis but there are occasional cases in which differential diagnosis is difficult and further evaluation is warranted. Chronic daily headache probably represents a migraine variant. Many patients have significant psychiatric disease, or meet diagnostic criteria for fibromyalgia or chronic fatigue syndrome. Cervicogenic Headache In people who are susceptible to the development of headache, presumably for genetic reasons, any source of head or neck pain may serve to precipitate or aggravate headache. Chronic neck pain, whether idiopathic or due to cervical spondylosis, is extraordinarily common among headache patients and is very often a major contributor to the genesis of headaches. Often the history is telling in that the onset or worsening of headaches occurred in the wake of a motor vehicle accident, most often with associated whiplash injury. Headache pain often begins or is maximal in the nuchal and occipital regions. However, when migraine supervenes, pain may become hemicranial or pancranial. Other symptoms may include neck pain radiating into the shoulder, shoulder pain, and evanescent paresthesias radiating down the arm. Although many patients will deny neck pain, vigorous palpation of posterior cervical paraspinous muscles will often reveal considerable tenderness and may elicit severe pain that startles the patient. Neck pain triggering headache provides a major treatment opportunity and should be looked for in every patient. Only if the neurologic exam is abnormal (or in the immediate aftermath of trauma) is diagnostic evaluation indicated. Cervical MRIs obtained in the context of a normal neurologic exam serve only to confirm the presence of degenerative disease or muscle spasm (revealed as straightening of the cervical lordotic curvature). 1 The international Headache Society (HIS) defines chronic daily headache as headaches occurring chronically more than 20 days a month. However, so long as headaches are occurring intermittently, they have a beginning and an end and can be treated like any other migraine. Since chronic daily headache, as I have defined it here, has no beginning or end, it must be treated in a fundamentally different way (see below). 12/21/07 Nadeau 6 knowledge base regarding medication overuse headache or its treatment is supported by controlled trials. There is no agreed upon treatment. Despite the lack of clarity and scientific rigor in the medication overuse headache literature, several conclusions can be drawn: • Many cases of medication overuse headache reflect poorly adjusted abortive treatment for migraine. For example, a patient having 4 migraine headaches a month, each lasting 5 to 7 days, may be dosing multiple times daily with migraine specific drugs or analgesics in a vain attempt to achieve pain relief. With a welldesigned abortive regimen, this same patient may be able to virtually eliminate headaches using but 4 well-timed doses a month. • One major contributor to the implication of butalbital containing compounds in medication overuse headache is the fact that patients are often wont to consume excessive quantities of these drugs in a largely vain attempt to ameliorate headache that should be treated using a completely different drug strategy. • When a patient is doing well, even if frequently taking medication, it is hard to argue for a change that may, at least for a time, cause severe suffering, lost work, and a blighted social life. • There are no data whatsoever supporting the concept that restricting use of medication will prevent an increase in the frequency of headache or medication overuse headache. • Treatments for medication overuse headache proffered by experts are challenging, often cause great patient suffering, and their reliability is completely unknown. • Headache frequency fluctuates greatly in many patients and it is very easy for us to convince ourselves that we have effectively treated headaches when the improvement actually represented a spontaneous change. DIAGNOSTIC EVALUATION Headaches suggestive of serious underlying disease require urgent diagnostic evaluation and headache suggesting aneurysmal subarachnoid hemorrhage or acute meningitis should be treated as an emergency. The patient with suspected subarachnoid hemorrhage should immediately undergo a computed tomographic (CT) scan of the head. CT Medication Overuse Headache In the early 1980’s, it was recognized that some patients chronically using ergotamine multiple times daily developed a dull, unrelenting pancranial headache. In open clinical trials, it was demonstrated that in up to 80% of these patients, if medication could be eliminated for as long as 6 weeks, this headache improved markedly and patients could do well with only occasional use of medication, although there was a recidivism rate of up to 30%. Thus was born the concept of medication overuse headache, commonly also referred to as “rebound headache.” Similar reports have now linked medication overuse headache to essentially all commonly used analgesics, including over-the-counter drugs, and most particularly to butalbital containing compounds (e.g., Fioricet, Fiorinal, Esgic, Sedapap, etc.). The evidentiary basis for these conclusions is not robust and there is disagreement even among experts as to which drugs might cause the syndrome. In the early 2000’s, several centers reported a medication overuse phenomenon in patients frequently using triptans for treatment of migraine. However, in this case, the overuse headache was characterized by increased migraine frequency. Favorable results were reported with drug withdrawal in open trials involving this type of patient as well. With these publications, and strong endorsement of the concept of medication overuse headache by leaders in migraine research, the concept has become widely known and enthusiastically endorsed, and it is now a common reason given for restricting medical treatment of headache patients, at considerable cost to these patients in suffering and disability. Medication overuse headache is actually an uncommon problem, involving approximately 10% of patients referred to major headache centers. In epidemiologic studies, only one third of patients with daily headache meet the definition of medication overuse headache. The mechanisms underlying medication overuse headache are various, complex, and poorly understood. Medication overuse headache actually represents a variety of syndromes, none of which has been clearly defined in the literature. Recommended treatments may involve prolonged hospitalization and may subject patients to intense suffering during the withdrawal period. None of the present 12/21/07 Nadeau 7 is preferable to magnetic resonance imaging (MRI) because it has greater sensitivity for blood in the basal cisterns during the 2 to 3 days immediately following the event. If no blood is detected, the patient should immediately undergo a lumbar puncture. If the lumbar puncture is traumatic, the cerebrospinal fluid (CSF) should immediately be spun down. A xanthochromic supernatant is evidence of subarachnoid hemorrhage. The CSF may remain abnormal and suggestive of subarachnoid hemorrhage for a week or more, although as time passes, the chemical meningitis elicited by the blood may lead to a substantial pleocytosis and fall in glucose that can lead to confusion with bacterial meningitis. If either the CT or the lumbar puncture provides evidence of hemorrhage, the patient should immediately be transferred to the care of a neurosurgeon knowledgeable about current management of subarachnoid hemorrhage. The mortality of aneurysmal subarachnoid hemorrhage is approximately 50%. Therefore, even the slightest suspicion should lead to the diagnostic evaluation indicated. Research carried out over the last 10 years suggests that intervention initiated within hours of hemorrhage may have a significant impact on survival and quality of outcome. The patient with headache suggestive of acute meningitis should also be treated as an emergency. In the absence of focal neurologic signs, lumbar puncture can be performed safely, although it has become nearly universal practice to obtain a CT scan first. In any event, antibiotics should be started immediately. This may lead to negative CSF cultures but it may also save the patient's life. The patient with headache suggestive of a structural process or chronic meningitis should undergo on the day of presentation a CT or MRI scan of the head before and following contrast administration. MRI, particularly following gadolinium administration, will provide better detail in the posterior fossa, and coronal cuts will be more sensitive for the presence of a basilar meningitis. However, a CT scan is perfectly suitable for emergently ruling out a large mass or a herniation syndrome. Care should be taken to include the sinuses in the imaging procedure. If no mass or shift of intracranial contents is evident, the patient should undergo lumbar puncture on the same day. In the patient with headache suspected to be due to focal invasion, inflammation or ischemia of the dura or extracranial soft tissues, the major items in the differential diagnosis are temporal arteritis and cancer metastatic to the middle cranial fossa or cavernous sinus region. Temporal arteritis is typically characterized by headache and a history of generalized but particularly limb girdle arthralgias, malaise, depression, and systemic symptoms. Some patients will experience transient diplopia, unilateral visual loss, or jaw claudication. A sedimentation rate should always be obtained promptly. Temporal arteritis is unlikely in patients less than 60 years of age and it is less likely in Afro-Americans than in whites. If the patient is likely on a clinical basis to have temporal arteritis, then temporal artery biopsy is not necessary. However, if temporal arteritis is but one of several diagnostic considerations, biopsy should be undertaken. The greater the risk of steroid complications, the more strongly biopsy is indicated [Nadeau, 1988 #1259]. All patients with headaches characteristic of focal tumor, inflammation or ischemia should undergo an MRI scan of the head, including coronal cuts, before and after gadolinium administration, with particular attention to the cavernous sinus region, the sella turcica, the floor of the middle cranial fossa, and the posterior fossa. The typical axial CT scan routinely obtained in headache patients is quite likely to miss the structural processes of concern with this type of headache. Magnetic resonance imaging is the procedure of choice to rule out cerebrovascular dissection because it can demonstrate the characteristic ellipse of blood in the cross section of the vessel wall. Magnetic resonance angiography may effectively demonstrate the characteristic long, tapering stenosis, but it is less specific. Benign headache syndromes do not generally require any diagnostic evaluation unless the patient's symptoms do not clearly identify the type of headache or there are focal abnormalities on the neurologic exam. Conventional wisdom has it that migraines are commonly due to arteriovenous malformations (AVMs). This association is probably specious and related to ascertainment bias: asymptomatic AVMs are not rare, and if one routinely gets cerebral imaging studies in any particular group of patients, he is likely to pick up some of these AVMs and conclude that there is an 12/21/07 Nadeau 8 association with the criterion for patient selection, in this case, migraine headache. However, there may be some indications for specific studies in certain benign headache patients. The possibility of a triggering central nervous system event such as a stroke should be considered in patients with late onset classical migraine or in any patient with a major change in the character of her migraines. Patients with cluster headaches who have any persistent neurologic abnormalities other than a Horner's syndrome, e.g. ophthalmoplegia or an impaired corneal reflex, should undergo MRI with a particular focus on the cavernous sinus/superior orbital fissure region. Patients with headache consistent with cervical spondylosis with radicular impingement should undergo MRI of the neck if there is evidence of significant myelopathy (urinary incontinence, lower extremity spasticity, proximal lower extremity weakness). TREATMENT Headaches symptomatic of serious underlying disease should be treated primarily to the extent possible. The treatment of benign headache syndromes depends on the particular syndrome and the particular patient. There are as many different headache patterns as there are people with headache and treatment must be precisely individualized. Migraine Non-Pharmacological Approaches Nonpharmacological approaches should be considered, even though they generally have limited applicability. They may comprise the only completely acceptable management technique in certain circumstances such as pregnancy. Anyone of a variety of foods and beverages may precipitate headache in some people and patients should be encouraged to maintain some vigilance. The most common offenders are alcoholic beverages of any type in any amount, but particularly red wine, chocolate, and hot dogs. Other foods to be considered include nearly any type of cheese except cream cheese or cottage cheese, any type of preserved meat or fish (e.g. delicatessen meat), nuts, monosodium glutamate, and any very cold food or beverage. Patients should be alerted to these possibilities and advised to keep a diary as a mnemonic aid. There is no particular advantage to placing a patient on a diet free of these substances. Caffeine is frequently proscribed by physicians, despite the lack of scientific evidence of a link to migrainogenesis (except possibly with caffeine withdrawal), and the fact that caffeine is therapeutic for many migraineurs. Migraines may be precipitated by certain smells, e.g. perfume, hair spray, solvent fumes, or automobile exhaust, although this tends to be more characteristic of cluster headaches. Migraines may be aggravated by inescapable stress, and measures likely to dispel tension and improve sleep, such as exercise, may provide some benefit. Migraines are fairly commonly aggravated by irregularities in sleeping and eating habits; patients need to be counseled to rise and retire at exactly the same time, seven days a week, and to eat three meals every day, always at the appropriate times. Meals need not be large: even 150 calories may suffice. Regular betweenmeal snacks may be of value in preventing migraine in some patients, especially if they frequently experience a vague feeling of hunger and malaise, often characterized as "hypoglycemia," before migraines. Patients with migraine who smoke should be strongly encouraged to quit because of the increased stroke risk. Pharmacological Approaches The key to successful pharmacological management of migraine is to tailor therapy to the nuances of the individual's headache pattern. Critical data include percentage of headaches that awake the patient at night as opposed to developing during the day; the mode of headache development (abrupt or insidiously progressive over hours); warning symptoms of impending headache; predictable times or circumstances of headache onset; frequency of disabling headaches (as opposed to headaches of any type); and associated sleep and affective disorders. Sleep and affective disorders, which are almost ubiquitous among migraineurs, should always be treated aggressively. There are three major pharmacological approaches to migraine: abortive, prophylactic and symptomatic. Abortive. For most migraineurs, abortive therapy offers by far the best chance of success, particularly if headaches have a reasonably well-defined onset and typically begin while the patient is awake. Complete elimination of 90% of headaches 12/21/07 Nadeau 9 Table 2 The Generalist's Guide to Headache Therapy Prophylaxis: Lorazepam at bedtime (any headache syndrome associated with cervical tenderness) Methysergide for cluster headache Bedtime Cafergot or a titrated dose of a long-acting opiate for patients who awake with incapacitating headache more than twice a week Fioricet + Ibuprofen (± Lorazepam 0.5mg, especially for chronic daily headache) Sumatriptan/Zolmitriptan/Rizatriptan/Almotriptan/Eletriptan Midrin Cafergot Short acting opiates Oxygen (cluster) 4% intranasal lidocaine (cluster) DHE-45 nasal spray/injection Sumatriptan/zolmitriptan nasal spray/sumatriptan injection Titrated short acting opiates Anti-emetics DHE-45 1mg IM/0.5mgIV q8h + long acting opiates as needed Abortive treatment: Rescue treatment: Symptomatic treatment(including ER treatment): Refractory can be achieved in 90% of patients using properly adjusted abortive therapy. Five abortive regimens provide a reasonable first approach for the generalist. The combination of Fioricet (1-2 tabs) and ibuprofen (400mg) is quite effective for many patients and represents a maximally benign regimen. It is most likely to be effective if headaches are usually not disabling and tend to develop gradually. Any one of a variety of triptans may be used (sumatriptan (Imitrex) 50-100 mg, zolmitriptan (Zomig) 5-10 mg, rizatriptan (Maxalt) 10 mg, almotriptan (Axert) 12.5 mg, or eletriptan (Relpax) 40-80 mg). Placebo controlled trials suggest that rizatriptan, almotriptan and eletriptan may be slightly more effective, but patient preferences are variable. Zolmitriptan and rizatriptan come in a wafer form that dissolves in the mouth; this is a particularly convenient application. Triptans, on average, provide the most reliable and side-effect free abortive treatment of migraine and will work in nearly all patients if taken correctly (see below). However, their great expense ($15-20/tablet) and monthly quotas imposed by insurance companies provide considerable incentive to try Cafergot, Midrin or opiates in many patients. Finally, for the many patients who do not achieve adequate results with migraine-specific medications (Midrin, Cafergot or triptans) (6), the few who do not respond at all, and for patients who absolutely cannot take any of these drugs (e.g., those with symptomatic coronary artery or peripheral vascular disease; pregnant women) short acting opiates, used alone or in combination with migraine-specific drugs, can be highly effective and the only means to complete success in aborting migraines. Fioricet #3 (Fioricet + codeine 30 mg), 1-2 tabs, hydrocodone 5-10 mg + acetaminophen (Lortab, Vicodin, Narco) are 12/21/07 Nadeau 10 reasonable drugs to begin with. If these prove ineffective or are poorly tolerated, then titrated doses of oxycodone, morphine sulfate, hydromorphone, or meperidine can be employed. Very high doses may be required and are safe as long as they have been achieved through a careful titration process. The goal is to reliably abort headache with a single dose of medication without producing any cognitive or neurological side effects. Physicians inevitably worry about the potential for abuse of opiates. However, even in the patient with daily migraines, requiring seven doses/week of an opiate, the probability of dependence or tolerance is nil. Abortive medications should always be administered instantly when migraine symptoms, however subtle, first appear. This applies to over the counter medications as well as to prescription drugs. This approach is key to effective therapy and also helps to minimize the side effects of medications. Unfortunately, it is extraordinarily difficult to elicit adequate patient compliance in this regard. Even when told to take drugs within 60 seconds of symptom onset, patients commonly tarry 30 minutes or more. Patients often fail to carry their drugs with them at all times. If the timing of headache is predictable (most often the case with cluster headache), it may be useful for the patient to simply take his/her abortive "cocktail" an hour before anticipated onset. A form of this strategy may be beneficial for patients who frequently awake with migraine (also often the case with cluster) — a bedtime dose of Cafergot or a long acting opiate (methadone, Oxycontin, MS Contin) may be 100% effective in preventing morning headache. Lorazepam can be co-administered with Cafergot in patients who are sensitive to caffeine. There is seldom any value in taking repeated doses of a migraine specific drug for persistent headache. If headaches frequently persist or rebound, a better abortive strategy should be developed. The goal is to invariably achieve complete abortive relief with a single dose of drug. Many patients experience severe nausea with migraines. Promethazine (Phenergan) 25 mg q4 h, metoclopramide (Reglan), 10 mg q4h, or ondansetrone (Zofran) 8 mg q4h can be used to treat this. Usually a pre-emptive approach is the best: the patient should take the first dose of the anti-emetic in combination with the drugs used to abort migraine. The major adverse effect of these drugs is sedation. The sedative effects vary from person to person. Only ondansetron is almost never sedative, but unfortunately, it is extremely expensive. A number of pharmacological approaches should be considered as second line abortive treatment. As we have noted, 40% or more of patients who initially respond to a migraine specific drug either experience rebound or fail to achieve definitive relief, in which case they often end up "chasing" their headache for hours or days with repeated doses of migraine specific drugs or various analgesics. Chasing migraines is never good therapy, as it leaves patients with hours of pain if not disability, and it compounds headache with drug side effects. Nearly all patients who respond only partially to migraine specific drugs can achieve nearly 100% reliable abortive relief by combining the best dose of their best migraine specific drug with a titrated dose of a short acting opiate (e.g., hydrocodone, morphine sulfate, oxycodone, or hydromorphone). Butorphanol (Stadol), a µ-opiate receptor antagonist, κ-receptor agonist, available as a nasal spray, has advantages of rapidly achieved blood levels, and almost magical efficacy in some patients. Unfortunately, many patients experience prominent side effects of lassitude and nausea, in which case the drug may be usable only for symptomatic treatment of headaches that awake the patient at night or that have failed abortive treatment during the day. Patients who tolerate butorphanol can often effectively abort the migraine and prevent rebound by simultaneously taking a dose of a longer acting opiate (e.g., oxycodone), thereby also avoiding a pattern of butorphanol "abuse" characterized by frequent dosing. Patients who exhibit rebound despite optimal doses of abortive therapy will often benefit by the addition of a titrated dose of a longacting opiate to their abortive cocktail. If these approaches fail, migraines are particularly severe, or migraines have a particularly abrupt onset, parenteral therapy with dihydroergotamine mesylate (DHE-45), sumatriptan, or ketorolac should be considered. DHE-45 comes in 1 ml ampules and can be intramuscularly administered hourly up to 3 doses per headache and every eight hours thereafter. Metoclopramide 10 mg provides effective relief of nausea and may be synergistic in providing headache relief. Both drugs are given intramuscularly and nearly all patients can handle the procedure if instructed properly. Sumatriptan is provided as a single dose of 6 mg in an autoinjector and is given subcutaneously. In some patients rebound can be prevented by taking an oral dose of a triptan at the same time as the parenteral dose of sumatriptan. Triptans should never be administered when the patient has already received ergots. Both DHE45 and sumatriptan are optimally administered at the first sign of headache but both may be quite effective even when headache is well underway. Ketorolac 30-60 mg IM may be highly effective in aborting migraine and may provide substantial symptomatic relief in some patients. The patient should always be observed when the first dose is given because of the possibility of anaphylaxis. 12/21/07 Nadeau 11 Prophylactic Therapy. Prophylactic therapy consists of administration of a drug on a daily basis in order to reduce the frequency and severity of headaches. Randomized controlled trials of a large number of drugs, including beta-blockers, tricyclic antidepressants, nonsteroidal anti-inflammatory drugs, calcium channel blockers, and anticonvulsants (valproate, topiramate, gabapentin) have shown statistically significant benefit relative to placebo. The results have been remarkably similar in these trials. Typically, placebo produces a 20% reduction in migraine frequency and drug a 40% reduction. In trials in which the impact of drug dose was systematically explored, there was no dose effect beyond a minimum threshold. Thus, valproate 1000 mg/day was not more effective than valproate 500 mg/day and topirimate 200 mg/day was not better than 100 mg/day. Recently reports of randomized trials of botulinum toxin injections for migraine have shown a smaller margin of benefit relative to placebo. In 20 years of systematic and aggressive trials of prophylactic therapy, I have seldom achieved a 20% reduction in migraine frequency and in most apparent successes, this benefit was not sustained over time. In those few patients who did appear to experience sustained benefit, headaches did not worsen when the drug was stopped. Instead, they expressed gratitude for being freed of medication side effects. Side effects, sometime quite unpleasant, are quite common with drugs used for migraine prophylaxis. The reasons for the discrepancy between clinical trial experience and clinical practice are unclear. It may be that the greater response to drugs in clinical trials reflects an augmented placebo effect; patients are convinced that they will do better with the drug than with placebo may experience an enhanced placebo effect when they note drug side effects. If such placebo effects could reliably be achieved in clinical practice, producing as much as a 40% decrease in migraine frequency, this would be quite useful. Unfortunately, extensive personal clinical experience suggests that they cannot be achieved and sustained at the same time that side effects are very common. Thus, prophylactic therapy cannot generally be recommended for treatment of migraine. The one important exception is muscle relaxants, e.g., lorazepam, administered at bedtime, to headache patients wit6h neck tenderness. Migraine is not necessarily aggravated by birth control pills, and they may even help in certain patients. Birth control pills are not contra-indicated in common migraine, and even in classical migraine, are only contraindicated in the presence of other risk factors (age greater than 40, smoking, other risk factors for vascular disease, history of venous thrombosis, presence of antiphospholipid antibodies). Birth control pills containing estrogen in very tablet, 28 days a month (e.g., Seasonale)(interrupted every 3 months), may be effective in women with particularly severe and refractory headaches during menses. Treatment of Migrainous Aura. Presumably because migrainous aura is associated with spreading depression of Leao (see above) and not with events at trigeminal endings in the meninges, it cannot be aborted with migraine specific drugs. In fact, there is no proven abortive treatment for aura. Several prophylactic treatments have been described, including phenytoin plus amantadine, acetazolamide, and long-acting opiates. Of these, long-acting opiates provide the only reliable means of controlling aura. These drugs, as discussed, can be used safely and in a controlled fashion, but because of the effort and discipline required of both physician and patient in their use, they should only be considered in patients with frequent and disabling aura. Symptomatic Therapy. The long-term objective of any migraine treatment program should be to eliminate the need for symptomatic therapy, that is, to definitively abort 100% of migraines with a single appropriately titrated dose of the right combination of drugs. However, no regimen is perfect, and during drug discovery and titration phases of migraine treatment, patients will experience many headaches that persist despite abortive therapy, necessitating symptomatic therapy. There are a number of approaches to this problem. For patients with modest, non-disabling headache, Fioricet 1-2 tablets + ibuprofen 400 mg repeated at 4-hour intervals (up to 3 doses per day, on average) may be perfectly satisfactory. Fioricet is an extraordinarily safe drug, and problems arise in its use chiefly when patients with severe headaches are denied access to more effective medication, leading them to use excessive quantities of Fioricet. Several drugs may be used to rescue patients with disabling migraines. These include DHE-45 (1 cc IM q1h up to three doses, then q8h), sumatriptan injectible (6 mg SQ, repeated as needed in 2 hours), and short acting opiates (hydrocodone, oxycodone, morphine sulfate, hydromorphone). Parenteral DHE in conjunction with long acting opiates (e.g., Oxycontin) 12/21/07 Nadeau 12 administered q8h is probably the optimal therapy for status migrainosis. Many patients experience severe nausea, necessitating the use of anti-emetics as in the abortive treatment of migraine (see above), sometimes in parenteral form; sedative drugs may have an advantage in the setting of status migrainosis. Emergency Room Treatment. The optimal drug for emergency room treatment of migraine should be easily and quickly administered, 100% effective, and associated with minimal side effects other than sedation, which may be advantageous. Only parenteral opiates administered in an adequate dose meet these criteria. Most adults will require a minimum of 100 mg Demerol equivalent, some up to 200 mg, generally in combination with a parenteral anti-emetic. The likelihood of providing incentive for drug abuse or contributing to drug dependence with this approach is nil. Cluster Headache As for migraine, the possibility that foods, beverages or odors are triggering headache should be carefully explored. The clinical trial experience with prophylactic drugs for cluster headache has generally been comparable to that for migraine, with one notable exception, methysergide, which can be highly and reproducibly effective in those who can tolerate an adequate dose (up to 4 mg tid). For those intolerant of methysergide, bid long-acting opiate regimens can also be quite effective. Indomethacin has been recommended for a cluster variant, chronic paroxysmal hemicrania, which is characterized by a large number of daily headaches lasting 5-10 minutes. High doses of other NSAIDs may be equally effective and better tolerated. New clusters may be terminated at onset by a brief course of corticosteroids. Abortive/symptomatic therapy may be quite effective for cluster and overall offers the best strategy for management. Treatments include nasal oxygen inhalation at 3-8 liters/minute, unilateral intranasal injection of 1cc of 4% lidocaine solution, Cafergot, DHE45 intramuscularly (or intranasally where available), Stadol nasal spray, and triptans by any route. Lidocaine is most likely to be beneficial for patients with a significant retro-orbital component to their pain. Cafergot taken at bedtime or intranasal oxygen at 1-2 liters/minute may prevent nocturnal cluster headache. Failing these, an adequate dose of an opiate analgesic may be necessary. Because cluster headaches often occur at exactly the same times every day, abortive therapy can often be administered effectively an hour before expected headache onset. The major limitation of abortive therapy for cluster headache, a very common and serious one, is that it is not viable in patients experiencing multiple headaches per day. Tension Headache Tension headache, whether or not it comprises a mild form of migraine, can usually be treated successfully with over-the-counter analgesics, or Fioricet and ibuprofen in combination. When more severe, approaches used for migraine are in order. Chronic Daily Headache Chronic daily headache (as specifically defined in the foregoing) is notoriously unresponsive to treatment efforts, largely because the headache has no beginning, thus precluding abortive therapy. Potentially aggravating associated conditions such as depression or insomnia should be treated aggressively (e.g., SSRIs for depression, benzodiazepines for initial insomnia, trazodone for terminal insomnia/poorly sustained sleep, and dopaminergic agents for restless limb syndrome/periodic limb movements of sleep). For some patients, Fioricet + ibuprofen, occasionally supplemented with an appropriate dose of a short acting opiate, will suffice. Some will benefit from the addition of lorazepam 0.5-1.0 mg to this combination, provided this does not induce unacceptable sedation. Lorazepam initiated at a dose of 0.5 mg at bedtime and titrated upward to maximum tolerated dose (up to 6 mg), as defined by morning sedation, may be dramatically effective in some patients, particularly when there is a major component of neck tightness. Many patients waking with severe headache can be managed successfully with a single titrated dose of short-acting opiate on wakening, to reduce headache severity to the 12 range, followed by Fioricet for the remainder of the day to prevent headache build-up. Many patients with disabling chronic daily headache can be managed only with a chronic opiate analgesic regimen (e.g., Oxycontin, MS-Contin or Methadone in a titrated bid dosage, supplemented with up to two doses of a short acting opiate for flares of headache). The likelihood of clinically significant dependence or tolerance with this type of regimen is nil. Cervicogenic Headache Nearly all patients with symptomatic cervical spondylosis will respond favorably to the religious all-day use of a soft cervical collar for a week or so during flares of pain. The patient should be strongly encouraged to modify the collar (e.g. wear it backwards, or cut it down) until it maintains the head and neck in a comfortable position. Many patients with cervicogenic headache of any etiology may benefit from long-term use of a soft collar during periods of sustained neck tension, e.g., while driving long distances or working at a computer or crafts. Lorazepam, 1-4 mg at bedtime, may provide dramatic benefit. Contrary to common lore, patients can be maintained on a 12/21/07 Nadeau 13 constant dose of medication to good effect for years and withdrawal symptoms are minimal so long as drug discontinuation is preceded by dose tapering. Nonsteroidal anti-inflammatory drugs may be of modest benefit in some patients. Some will require chronic long acting opiate regimens. Decompressive surgery is only indicated when there is significant myelopathy or serious wasting and weakness of upper extremity musculature. Refractory pain is rarely if ever an indication for surgery. Drug Safety Issues In the course of nearly two decades of use, the triptans have proven extraordinarily safe, even with extremely frequent (e.g., daily) dosing. They may cause an alarming syndrome of chest and neck tightness in some patients. This has proven to be a benign phenomenon, dose related, most often observed with parenteral sumatriptan. Cafergot and Midrin are contraindicated in the context of symptomatic coronary artery disease. Triptans are proving safer than expected in this setting, but most experts would avoid prescribing. Ergots, including Cafergot and DHE-45, have the potential for causing vasospastic ischemia of the extremities (ergotism). Use of a no more than one dose of Cafergot per day is likely safe. Patients using excessive DHE-45 to treat status migrainosus will experience calf pain, which is a signal that dose frequency should be reduced. Methysergide, an ergot derivative, as been associated with a rare, largely unpredictable syndrome of retroperitoneal, mediastinal, and endocardial fibrosis. Use of opiates in the context of the strictly controlled regimens detailed above is safe. Gradual titration will prevent overdose and will enable the clinician to zero in on the regimen that will solve the headache problem without causing cognitive or neurologic side effects. Troublesome side effects constitute the single greatest problem with opiates and a substantial percentage of patients cannot tolerate any opiate. Concurrent use of alcohol should be absolutely proscribed, both because it narrows the therapeutic window and because it can accelerate release of drug from long acting formulations (e.g., Oxycontin). Nearly all of the drugs discussed in the foregoing are relatively or absolutely contraindicated in pregnancy. The notable exceptions are Fioricet, opiates, and metoclopramide. Even lorazepam is pregnancy class C; the only remotely similar drug that is class B is zolpidem (Ambien). CONCLUSION In over 95% of patients with headache, the cause is benign and no diagnostic evaluation is warranted. A careful history and neurologic exam will identify patients with headache potentially indicative of serious underlying pathology. Severe, sustained pancranial headache of paroxysmal or rapid onset suggests subarachnoid hemorrhage or acute meningitis and should be treated as a medical emergency. Other symptomatic headaches should be evaluated urgently. Many patients with benign headache syndromes will benefit to some degree from nonpharmacological measures designed to ameliorate precipitating or aggravating factors. Ninety percent of patients can abort over 90% of headaches with an appropriately titrated combination of drugs administered as soon as possible after onset of earliest warning symptoms of headache. Treatment must be individualized. Most benign headaches can and should be satisfactorily managed by the generalist. References 1. 2. 3. 4. 5. 6. Fisher CM. Late-life migraine accompaniments — further experience. Stroke 1986;17:1033-1042. Lashley KS. Patterns of cerebral integration indicated by the scotomas of migraine. Arch Neurol Psychiatry 1941;46:331-339. Leao AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol 1944;7:359-390. Skyhøj Olsen T, Friberg L, Lassen NA. Ischemia may be the primary cause of the neurologic deficits in classic migraine. Arch Neurol 1987;44:156-161. Woods RP, Iacoboni M, Massiotta JC. Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 1994;331:1689-1692. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: a metaanalysis of 53 trials. Lancet 2001;358:1668-1675. 12/21/07