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GOAL

The goal of this monograph is to educate pharmacists, physician assistants, and nurse practitioners on the symptomatology, pathophysiology, and presentations of migraine headache.

OBJECTIVES

Upon completion, the reader should be able to:

Discuss the classic presentation of migraine and the diagnostic features as outlined by the International Headache Society;
Recognize the possibility of migraine in clinical presentations felt to be more typical of “sinus” or “tension” headaches;
Explain the basic elements of migraine pathogenesis;
Identify the etiology of referred pain, muscle tension, and “sinus” symptoms within migraine; and
Describe the mechanism of action of the “triptan” therapies in the truncation of the migraine process.

Current estimates indicate that some 28 million people in the United States alone suffer from migraine, almost 1 patient in every 4 households.¹ The introduction of effective serotonin (5-hydroxytryptamine [5-HT])_1B/1D receptor agonists and improved prophylactic strategies offer more viable treatment options for migraine than previously available. Despite these advances, uncertainty persists regarding not only proper management, but accurate diagnosis of migraine, particularly when attempting to differentiate between migraine, tension-type headache, and sinus headache.

This point of confusion is reflected by recent clinical studies that demonstrate rampant underdiagnosis and undertreatment of migraine, which only implies the burden associated with migraine, both on the individual patient and the healthcare system. Migraine can significantly impair quality of life and functional ability, as demonstrated by the American Migraine Study II (AMS-II) that showed 51% of migraine sufferers reporting a 50% reduction in work or school productivity during an attack, and 76% reporting inability to cope with usual household chores.

Effective migraine management thus first depends upon accurate diagnosis, which provides the patient with reassurance that structural pathology and psychopathology have been ruled out.² In spite of major progress toward understanding and treating migraine over the past few decades, migraine remains underdiagnosed. AMS-II also showed in 1999 that 52% of headache patients meeting criteria for migraine established by the International Headache Society (IHS) had not been diagnosed with migraine.³ About 25% (5.6 million) of adult patients in the United States meeting IHS criteria for migraine (Table 1) have received the single diagnosis of migraine, while 9.9 million have been diagnosed with migraine complicated by sinus or tension headache. Of those undiagnosed migraineurs in AMS-II, 32% were diagnosed with tension-type headache and 42% with sinus headache.

Migraine is characterized by episodic headache pain, either presenting upon awakening or evolving over minutes to hours while awake, and lasting from a few hours to several days. Up to 98% of migraine sufferers experience moderate to severe pain during attacks, of a quality that may vary from steady aching to violent throbbing. The pain is typically exacerbated by physical exertion and is often complicated by nausea, vomiting, and sensitivities to light, sound, and even odors.⁴

New insights into the pathophysiology of migraine reveal how symptoms that resemble “sinus headache” or tension-type headache can all arise from the activation of one nerve pathway. The data suggest that migraine consists of (1) direct pain—the unilateral throbbing pain from direct stimulation of the trigeminal nociceptive fibers surrounding the meningeal vessels; (2) referred pain arising from activation of the trigeminal nucleus caudalis which can be perceived in the face, sinuses, nares, and neck; and (3) autonomic sinus symptoms that occur via recruitment of the reflexively-connected autonomic nerves from the superior salivatory nucleus.

The early vascular hypothesis of migraine pathogenesis suggested that the primary dysfunction originates at the cerebral blood vessels, but current theory recognizes that the primary dysfunction arises in the brain itself, specifically in brain stem centers important in regulating vascular tone and pain sensation. Migraine is a neurovascular disorder characterized by vasodilation of intracranial extracerebral blood vessels and the resulting stimulation of surrounding trigeminal nerve pain pathways.⁵ The trigeminal nerve is comprised of three main divisions that carry pain information: the ophthalmic division (V1), the maxillary division (V2), and the mandibular division (V3) (Figure 1). The trigeminal nerve thus innervates widespread areas of the head, face, and neck. The trigeminal nucleus caudalis (TNC), which is located in the brain stem, is important in processing and relaying pain signals to higher-order neurons in the thalamus and cortex. Activation of the TNC also heightens sensory input from all branches of the trigeminal nerve (face and sinus areas) and from upper cervical sensory branches. These connections may explain the referral of pain during a migraine to various regions of the head, face, and neck.

According to the neurovascular hypothesis, migraine results from activation of the “trigeminovascular system” (Figure 2).⁵

Cranial parasympathetic nerves that innervate the sinus cavities and tear ducts are directly connected to the TNC at the superior salivatory nucleus (SSN), and activation of the TNC causes reflex parasympathetic activation of the mucosa of the sinuses, nasal passages, and tear glands. Activation of the cranial parasympathetic nerves causes sinus-like symptoms such as lacrimation, rhinorrhea, and nasal congestion (Figure 3). Activation of the sensory nerves of the neck (C2, C3), which are also anatomically connected with the TNC, can result in posterior head and neck pain (Figure 4). The specific symptoms that occur depend on the degree to which the various portions of the neurovascular network are activated, but these connections help explain the referral of pain during a migraine to various regions of the head, face, and neck.

Symptoms widely considered atypical of migraine are the major source of misdiagnosis, specifically those perceived as more typical for sinus and tension-type headaches (Figure 5). Studies have demonstrated that among migraine sufferers, the following symptoms are experienced with migraine:

With this information in mind, it seems obvious that such symptoms may actually be multiple presentations of migraine and should prompt careful evaluation of the patient for migraine. Further, the patient whose headache symptoms are pigeonholed as sinus or tension headache has a high probability of being not only underdiagnosed, but undertreated or inappropriately treated, with commensurate waste of the clinician's time, the patient's money, and considerable pain and deterioration of quality of life.

According to the IHS diagnostic criteria (Table 2), all five of the findings listed must be present for a clear diagnosis of acute “sinus headache” (diagnosis code 11.5.1). The current high prevalence of this diagnosis is largely contested by both allergists and neurologists, who generally concur that sinus headache is rare even among patients with sinusitis.^10,11 This skepticism is supported by results of AMS-II, which reported that 42% of previously undiagnosed migraineurs were originally diagnosed with “sinus headache.”³ One explanation of such widespread misdiagnosis is a widespread misconception among clinicians that the association of headache with weather, frontal or maxillary pain or pressure, and autonomic features, such as tearing and rhinorrhea, are typical in sinus headache but not in migraine.

Widespread direct-to-consumer advertisement of various sinus headache remedies has made self-diagnosis with sinus headache popular, but often erroneous. Patients usually assume that since the sinuses are close to the eyes, headaches involving the frontal, supraorbital, or infraorbital region are sinus headaches. Such self-diagnosed sinus headaches are ultimately determined to be migraine in up to 98% of cases, as they often are:

While many headache features typically described in association with sinus, such as location and character of pain and associated symptoms like photophobia, may be indistinguishable between migraine headache and “sinus headache,” complaints commonly interpreted as “sinus” symptoms often occur as part of the phenotypic expression of migraine. One study diagnosing according to IHS criteria for migraine reported autonomic symptoms (nasal and/or ocular symptoms) in 45% of headache patients. Among that 45%, almost 50% reported both nasal and ocular symptoms (watery eyes, nasal congestion, and runny nose) with their migraine; 21% reported only nasal symptoms; and 34% reported only ocular symptoms.⁸

Another study designed to evaluate the frequency of self-misdiagnosis as sinus headache concluded that 98% of patients with self-described “sinus headache” but no previous diagnosis of migraine or past-year radiographic evidence of sinus infection experienced the following symptoms fulfilling IHS criteria for migraine or migrainous headache (Table 1). More than 90% of patients reported at least one symptom commonly associated with sinus headache¹³; 73% reported nasal stuffiness; 67% reported runny nose; and over 50% reported weather-associated headaches. Though 53% of these patients had previously consulted physicians about their headaches, none had been diagnosed with migraine or even evaluated for sinus pathology, but were commonly prescribed oral antihistamines and corticosteroid nasal sprays.¹²

Sumatriptan is migraine-specific therapy that selectively targets 5HT_1B/1Dreceptors of the cranial vasculature and trigeminal nerve fibers. Seventy-four percent of the patients in this group treating two of their “sinus headaches” with 50 mg of oral sumatriptan successfully reduced moderate or severe pain to mild or no pain 2 hours following administration. Sixty-two percent were “satisfied,” and 50% preferred the sumatriptan therapy to other tried therapeutic options. This favorable response rate is comparable to that reported in clinical trials involving patients meeting IHS criteria for migraine.¹²

Another study involving 2524 patients presenting to a primary care physician with self-described or physician-diagnosed sinus headache adds credence to the prevalence of misdiagnosis. Over 80% of these patients reported substantial to very severe levels of disability, with 67% reporting dissatisfaction with their current treatment. Only four of these patients actually showed signs of infection, but fully 90% fulfilled IHS criteria for migraine headaches.¹³

Patients' and healthcare providers' failure to recognize migraine may have arisen from these symptom patterns. Both historic and new data show that sinus symptoms frequently accompany migraine. The sinus symptoms that these patients experience are actually aspects of the multiple presentations of migraine. The following symptoms may be commonly associated with both migraine and “sinus headache” but in clinical practice may be commonly interpreted as being indicative only of “sinus headache”:

These data suggest that the occurrence of nasal symptoms should neither inevitably trigger a diagnosis of sinus headache nor exclude a diagnosis of migraine. Narrowing the conceptualization of migraine to that suggested by IHS diagnostic criteria eliminates consideration of nasal or ocular autonomic symptoms as possible manifestations of migraine and potentially results in misdiagnosis.

Neither the IHS nor the American Academy of Otolaryngology—Head and Neck Surgery currently recognizes headache arising from nonpurulent or noninfectious sinus pathology.¹⁵ These new data suggest the majority of patients labeled with sinus headache truly experience attacks consistent with migraine. The entity of sinus headache appears diagnostically and behaves therapeutically like migraine, essentially because it usually represents one phenotypic expression of migraine.

Migraine is also commonly misdiagnosed as episodic tension-type headache. Among respondents in the AMS-II who met IHS criteria for migraine but who lacked a physician diagnosis of migraine, 32% reported a physician diagnosis of tension-type headache.³

Moreover, in a recently reported post hoc analysis of data from the Spectrum Study, 37% of patients initially diagnosed with tension-type headache were later diagnosed with migraine or migrainous headache on the basis of a neurologist's evaluation of headache diaries.¹⁶ Like the “sinus headache” described in the previous section, tension-type headache is often one of the phenotypic expressions of migraine. The misdiagnosis of migraine as tension-type headache has potentially significant consequences in that it may preclude patients with disabling headaches from receiving appropriate treatment.

Episodic tension-type headache is the most frequent, but least distinct, of all primary headache disorders. A diagnosis of tension-type headache by IHS criteria is based chiefly on negative characteristics (Table 3).⁹ Whereas migraine is characterized primarily by the presence of “positive” features of photophonophobia, nausea, and pain worsening with activity, the IHS classifies tension-type headache by the absence of these elements. As opposed to the unilateral, throbbing, moderate-to-severe pain of migraine, tension-type headache is characterized by pain that is generally described as bilateral, steady, and mild-to-moderate in intensity. The lack of distinctive features of tension-type headache possibly contributes to its overdiagnosis: healthcare providers confronted with a patient meeting some but not all the diagnostic criteria for more distinct, specifically-defined headache types such as migraine may fall back on the less specific tension-type headache diagnosis. The extremely high prevalence of tension-type headache, which ranges from 30% to 66% in population-based studies,^14,15is consistent with the possibility that tension-type headache is overdiagnosed.

Clinically, a diagnosis of tension-type headache is likely whenever bilateral, nonpulsating head pain is present, if the patient reports that the headache is triggered by stress or muscle tension, or when neck pain is present. Additional evidence from the AMS-II suggests the presence of depression in conjunction with headache as a variable linked to the misdiagnosis of migraine as tension headache, despite epidemiological data that associates migraine and depression as comorbid illnesses.¹⁶

The extensive diagnostic overlap between migraine and tension-type headache may lead to the potential misdiagnosis of migraine.

In this study, approximately two-thirds of patients (69%) described their neck pain as “tightness”; 17% and 9% described it as “stiffness” and “throbbing,” respectively; and the remaining 5% described it in other (miscellaneous) terms.⁷ The neck pain was unilateral among 57% of patients—98% of whom reported pain ipsilateral to headache—and bilateral among 43%. Ninety-two percent (92%) of patients with neck pain reported that they experienced it during the headache phase of migraine, but neck pain was also common during the prodrome and the postdrome (Figure 6). In fact, more than 60% of patients reported neck pain during the migraine prodrome—that is, very early in the course of a migraine episode. These data show that the presence of neck pain should not automatically trigger a diagnosis of tension-type headache—migraine should be considered among the possible diagnoses for recurrent, episodic headaches accompanied by neck pain.

In the study described above, 5HT_1B/1Dagonist therapy was effective for the tension-type-headache-like symptom of neck pain when it occurred as a feature of migraine in IHS-diagnosed migraineurs.⁷ A subset of 30 patients treated 278 headaches, 231 of which were accompanied by neck pain, with a triptan. The percentage of mild, moderate, or severe headaches with a pain-free response 2 hours postdose was 68% for head pain and 73% for neck pain (Figure 7).

The similarities between migraine and tension-type headache in clinical manifestations and pharmacologic response have led to speculation that they may actually be the same, a question debated among the headache community for years.^24-26 Proponents of the continuum-severity theory contend that tension-type headache and migraine constitute the same entity distinguished only by severity, with tension-type headache lying on the mild end of the severity continuum and migraine lying on the severe end. Proponents of the view that migraine and tension-type headache are separate disorders contend that they are distinct entities, tension-type arising from abnormal muscle activity and the migraine arising from neurovascular causes.

Data show that many migraines are accompanied by tension-headache symptoms like neck pain and bilateral head pain. Thus, symptoms like neck pain, bilateral head pain, nonthrobbing pain, and the patient's report of stress or tension as a headache precipitant do not necessarily indicate the presence of tension-type headache. Rather, these features may also suggest the presence of migraine, in which case the “tension-type headache” is actually one of multiple presentations of migraine. Neck pain associated with a migraine is responsive to 5HT_1B/1Dagonist therapy.

The triptans are a group of novel anti-migraine agents hypothesized to be effective at alleviating migraine by virtue of their activity at 5HT_1B and 5HT_1D receptors. They stimulate the 5HT_1B receptor on the cranial blood vessels to reduce the pain-inducing vasodilation that may be responsible for migraine.⁵ They also stimulate the 5HT_1D receptor on trigeminal pain fibers that innervate the cranial vasculature, blocking the release of vasoactive peptides that cause neurogenic inflammation (Figure 2).⁵ Triptans have virtually no affinity for nonserotonergic receptor types.¹⁸

While it has been challenging to distinguish among “migraine,” “tension headache,” and “sinus headache,” new data show that many symptoms previously linked to tension or sinus headaches are actually common in migraine. Still, data from the AMS-II illustrate that migraine continues to be underdiagnosed both because of failure to recognize it and because of misdiagnosis of migraine as another headache type.³

Another recent study established an extraordinarily high prevalence of migraine among subjects presenting to primary care clinicians with a chief complaint of headache.¹⁹Among the 504 subjects completing the screening phase of the study, 88% were diagnosed with migraine, a diagnosis confirmed by an expert panel in over 90% of cases. Among those initially diagnosed as nonmigraine headache, migraine was still detected by the expert panel in 79% of document reviews. Thus, the overwhelming majority of patients presenting to primary care clinicians with headache will meet criteria for migraine.

Rigid adherence to IHS criteria in diagnosing migraine may result in underdiagnosis of migraine, as they do not include all symptoms that migraineurs frequently experience. Symptoms commonly interpreted as representing sinus headache or tension-type headache are often actually multiple presentations of migraine and should prompt a careful evaluation of the patient for migraine as well as other headache types. With greater awareness of these diagnostic pitfalls and greater attention to diagnosing migraine and other headache types, healthcare providers can improve the management of headache and help patients to receive appropriate therapy.