A comprehensive approach to primary headaches

A systematic evaluation strategy that focuses on the impact headaches have on a patient’s quality of life can lead to more accurate diagnosis and more effective treatment.

Jill Smoldt, MPAS, PA-C

The author works in emergency medicine at Porter Hospitals, Denver, Colo. She has indicated no relationships to disclose relating to the content of this article.

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Headache is a condition that affects 90% of the population at some point in their lives. The disorder is the seventh most common chief complaint in primary care offices and costs society more than $13 billion annually.^1,2 Much of the pathophysiology of headache has remained unclear, but as additional research is compiled and the mechanisms underlying headache are identified, options for treating the disorder are improving. 

Pathophysiology

While much of the pathophysiology of primary headaches remains a mystery, recent research has provided clinicians with the knowledge to more accurately diagnose and treat these disorders. Current understanding has moved beyond earlier theories that headaches are strictly vascular (migraine) or muscular (tension) in origin.^3-6 

The cause: Trigeminovascular stimulation

Recent studies support the concept that stimulation of the trigeminovascular system causes most headaches (see Figure 1). Peripheral stimulus activates the nerves entering the trigeminal nucleus claudalis (TNC), altering the sensitivity and lowering the threshold of activation of the trigeminal circuit. This process is referred to as central sensitization. Serotonin (5-hydroxytriptamine, or 5-HT) mediates homeostasis of the trigeminal system.^3,4 Consequently, low levels of serotonin lead to central sensitization of the TNC, with several effects.

First, this stimulation causes activation of 5-HT1D receptors, causing a release of vasodilating neuropeptides such as substance P and calcitonin gene-related peptide (CGRP). Release of these vasopeptides results in the dilation of meningeal vessels via the 5-HT1B receptors.^5,7,8 Dilation of the meningeal vessels causes tension and stretch on the nerves surrounding the vessels, producing depolarization and thus activation of these nerves, which the patient experiences as pain. The lowered stimulation threshold of the TNC also can cause stimulation of the trigeminal nerve. This nerve has three branches: ophthalmic (V1), maxillary (V2), and mandibular (V3). Trigeminal nerve stimulation explains the symptoms that are often associated with headaches, such as auras (V1), sinus pain and pressure (V2), and temporomandibular joint (TMJ) pain (V3). Finally, the TNC has upper cervical spine dermatome neurons that, when stimulated, can be perceived as neck pain, another common symptom associated with primary headaches.^3,7

Convergence theory The mechanisms mentioned previously have been used specifically to describe the pathophysiology of migraine headaches, but many headache experts support the convergence theory, which hypothesizes that one underlying pathologic process exists for primary headache. This theory suggests that the difference in primary headache diagnosis depends on how far in the pathologic process the headache proceeds and to what degree the trigeminal system is activated before being stabilized by the brain’s homeostatic mechanisms. At this point the convergence theory is not supported by research.^2,3  

Other etiologies

Other factors have also been associated with headache etiology, including estrogen, genetics, and environmental and behavioral factors. Experts think that estrogen is associated with headaches, specifically migraines, because observational studies show that the intensity and frequency of headaches in women typically increase after puberty and diminish after menopause. Additionally, the occurrence of headache is equal among males and females until puberty, after which women are about three times more likely to have migraine headaches than are men.⁴ As a result of these two observations, along with the ability of estrogen to affect serotonin-producing neurons, estrogen has been speculated to play a role in the etiology of headache.^2,4

Genetics Children of parents who both suffer from migraine headaches are at a 75% greater risk of having migraines as compared to children whose parents do not have migraines. Even those persons with a distant relative who suffers from migraines have a 20% increased migraine risk.⁴

Finally, environmental and behavioral factors can trigger headaches (see Table 1). Triggers are not always obvious to the patient, and asking the person to keep a headache diary may be useful in identifying what they are.⁴   

Classification of primary headaches

The International Headache Society (IHS) has developed a system classifying all headaches into two broad types: primary and secondary.^9,10 Secondary headaches, or worrisome headaches, are those caused by a systemic process or some underlying pathology. The red flags for secondary headaches are listed in Table 2.^4,9,10

Primary headaches are generally divided into three categories: migraine, tension-type, and cluster. Each has distinct characteristics (see Table 3).^9,10

Migraine headaches are moderate to severe in intensity, lasting 4 to 72 hours.⁴ They are made worse by activity and almost always disrupt the patient’s normal activities of daily living (ADL). Slightly more migraines are unilateral than bilateral; patients describe the pain as throbbing rather than pressing. Many additional symptoms may be associated with migraine headaches, such as nausea and vomiting, photophobia, phonophobia, and sinus symptoms.

Tension-type headaches are mild to moderate in intensity, with bilateral pain described as a feeling of tightness. Because these headaches usually do not limit activity, patients often do not present in the office. Tension-type headaches can last only 30 minutes, or they can occur continuously for days, in which case the condition is referred to as chronic daily headache. Tension-type headaches are usually not associated with additional symptoms such as nausea and vomiting.^4,7,9,10

Cluster headaches are unique in their manifestations. Short and severe in intensity, they occur in clusters from once to many times a day for 2 weeks to 3 months. The unilateral pain is often described as stabbing and persists for 15 to 180 minutes. The headache is usually accompanied by ipsilateral facial symptoms such as lacrimation, rhinorrhea, miosis or ptosis, or eyelid edema. During an attack, the patient is often restless or markedly aggressive. The headache is usually followed by fatigue. If a second cluster of headaches follows the first, the patient is said to have chronic cluster headaches; however, if the headaches go into remission within the year following the first cluster of attacks, the diagnosis is episodic cluster headaches.^9,10,11  

Diagnosis

Correctly diagnosing a primary headache is essential because treatment depends on the type of headache the patient has. Before evaluating a primary headache disorder, rule out secondary causes of headache by looking for the red flags listed in Table 2. 

History and physical examination

A thorough history, essential to accurate diagnosis, should include open-ended questions allowing patients to describe their headaches and questions to determine the duration, location, quality, and severity of the pain. Also review additional symptoms occurring concurrently with the headache, such as nausea, vomiting, photophobia, and phonophobia. The history should cover the headache’s impact on the patient’s quality of life and ADL, aggravating or precipitating factors (headache triggers), and any family history of headaches.

Headache diary If a patient has difficulty giving an adequate history, a headache diary can be a useful tool. Ask the patient to record when headaches occur, their location, the duration and quality of the pain, any associated symptoms, possible triggers, and any medications taken to abort the headache.

Once you have an adequate picture of the disorder, use the physical examination to assess neurologic functioning, to determine the existence or absence of systemic problems, and to confirm that the headache is not secondary in nature.^6,9  

A difficult diagnosis

Applying findings from the history and physical examination to obtain a diagnosis for primary headache is not as straightforward as it may appear.¹² Cluster headaches—because of their unique nature—are fairly uncomplicated to diagnose, but differentiating between migraine and tension-type headache is not as easy. For example, a bilateral headache could be a tension-type headache, although migraine cannot be ruled out because 49% of migraines manifest this way. Furthermore, 71% of migraines cause nausea, leaving 29% that do not. Thus, although the classic descriptors of primary headache are valuable aids to diagnosis, the IHS classification criteria are not clinically sensitive when used alone. Primary headaches within each subtype can exhibit such diversity that the classic descriptions should only help to validate a diagnosis of headache type. Instead, focus more on the headache’s severity and impact on the patient’s life; then confirm the diagnosis with the classic descriptor.

An approach to primary headache that emphasizes its effect on the patient’s life helps the clinician to focus the treatment plan. This approach starts with ruling out secondary headache, then moves to evaluating the degree to which the headache is interrupting the patient’s ADL. When a headache is so disabling that the patient’s daily routine and lifestyle are compromised, migraine is the most likely diagnosis. When headaches are less intense in their severity and do not limit function, then they are likely to be tension-type. If the degree of disability leads you to suspect migraine or tension-type head-ache, confirm the diagnosis with the IHS classification system.^9,10  

Headache frequency

Migraine headache, once diagnosed, should be assessed by its frequency. If migraines occur more than 15 times a month, the condition is considered chronic; if they occur fewer than 15 times a month, the condition is episodic. Chronic migraine should be treated prophylactically, but episodic migraine can be treated either prophylactically or with abortive medications alone. The general guideline for treating episodic migraines states that those occurring more than four times a month or lasting longer than 12 hours should be treated prophylactically.^4,9,10

Tension-type headache that is episodic (occurring fewer than 15 times per month) is treated with abortive pain medications; however, chronic tension-type headaches (occurring more than 15 times per month) necessitate evaluating how much medication the patient takes to abort the headaches. If the patient takes medication more than twice a week, consider the possibility that rebound headaches are occurring due to medication overuse. The chronic tension-type headache treated with abortive medication less than twice a week can be treated prophylactically, but patients with rebound headache must go through a withdrawal regimen before initiating prophylactic medications.^6,9,10,13  

Two categories of treatment

All patients with primary headache are offered abortive treatment. Some, depending on the type, severity, and frequency of their headaches, may be given prophylactic treatment as well.

Abortive medications are taken at the onset of a headache with the intent of relieving the symptoms within 2 hours.^4,6,14 Tell the patient that taking the abortive medications early in the development of a headache increases the medication’s effectiveness.

Prophylactic medication is taken daily with the intent of preventing headaches from occurring. The immediate goal is to decrease the frequency, duration, and severity of headaches and to increase the effectiveness of abortive medications when breakthrough headaches do occur. The ultimate goal of this treatment is to increase the patient’s functioning and decrease disability caused by headache.^4,15 Treatment depends on diagnosis of primary headache type; Table 4 summarizes medication options.  

Abortive medications for migraine

Several different agents are available to abort migraine headaches. Selection of the agent should depend on the severity of the headache.

OTC NSAIDs are often used for mild or moderate migraine headaches. Combination NSAID medications (acetaminophen/aspirin/caffeine) are more effective than either acetaminophen alone or NSAIDs like ibuprofen.^2,4,8,14 Studies have shown that caffeine, which acts as a vasoconstrictor, can increase an analgesic’s potency by 40%.⁸

Triptans are first-line medications if a patient has severe migraines or when treatment with NSAIDs alone has failed. Triptans work by both blocking the release of vasoactive peptide and interacting with the serotonin receptors to help decrease central sensitization. They are also vasoconstrictors, and while this helps with the vasodilation of meningeal vessels that occurs during headache, it can limit the use of these agents in persons with hypertension and peripheral vascular disease.^2,4,8,14 Triptans have various routes of administration—oral, intranasal, or injectable—a flexibility that especially benefits patients whose nausea and vomiting limit the absorption of oral medications.⁸ Studies comparing the different triptans have found no one of them to be more effective than the others.^14,16 The clinician can allow cost and availability to guide the selection of triptan. If one does not work, another one may be effective.

Ergot derivatives include dihydroergotamine (DHE) and ergotamine/caffeine. These medications also have multiple routes of administration, but because they cause more side effects and are not as safe as triptans, they are usually considered second-line choices.^2,4,8,14    

Prophylactic medications for migraine

If migraine headaches last longer than 12 hours or if the patient is having more than four moderate to severe headaches a month, prophylactic medication is indicated.^2,4,14 Several agents may be tried, including beta-blockers, anticonvulsants, and low-dose antidepressants.

Beta-blockers are most useful for a patient who has infrequent but severe migraines. The beta-blockers propranolol and timolol are used most commonly; these prevent migraine headaches through their effects on 5-HT2 receptors.^4,8,15 Propranolol is often used because it is a membrane-stabilizing agent with a high lipid solubility, which allows it to cross the blood-brain barrier. However, the agent is not beta-receptor selective, so it may have more side effects than other beta-blockers. Since 3 months are usually required to achieve the full benefits of beta-blocker migraine prophylaxis, wait that long before adjusting dosages or switching medications. If one beta-blocker fails, another one may work.

Anticonvulsants used for migraine prophylaxis include divalproex and topiramate. Divalproex synthesizes and inhibits breakdown of gamma aminobutyric acid, which inhibits central pain transmission.⁸ This agent is effective in about 50% of patients who have migraines and has the benefit of being a mood stabilizer in those with comorbid conditions such as depression or anxiety. However, side effects—which include nausea, alopecia, tremor, and weight gain—can make divalproex difficult for the patient to tolerate.¹⁵ To-piramate, a medication that randomized, controlled trials have shown to be safe and effective, has recently been approved by the FDA for migraine prevention.^4,5,15 Topiramate does not interact with other headache medications such as the triptans, amitriptyline, or propanolol and also has the side effect of weight loss, which makes it an especially good choice for the overweight migraine patient.⁵

Tricyclic antidepressants (TCAs) in low doses have also been useful in migraine prophylaxis. Amitriptyline, the agent used most commonly, enhances the effects of serotonin, which inhibits the transmission of pain signals and consequently increases pain tolerance. Ami-triptyline is a good choice for the patient with less intense but frequent migraine headache.⁸ Since it is sedating, it should be taken at night and is especially helpful for those with insomnia.  

Abortive treatment for tension-type headache

Since tension-type headaches usually cause mild pain, OTC analgesics are the most commonly used abortive medication. Both ibuprofen and acetaminophen are effective, with ibuprofen being the more helpful of the two.⁶ Since patients treat their own tension-type headaches with OTC medications, it is important to educate them about rebound headache if they use such agents more than three times a week. Put patients with rebound headache on a withdrawal regimen first, and then consider prophylactic medication.^6,9,10,13 

Prophylactic treatment for tension-type headache

Antidepressants have been the agent of choice for prophylactic treatment of tension-type headaches. Although it has anticholinergic side effects, amitriptyline is the most researched preventive agent. Selective serotonin reuptake inhibitors (SSRIs) are also used prophylactically for tension-type headache, though less research supports their use than exists for amitriptyline. SSRIs have fewer side effects than TCAs, however, so the patient may tolerate them better. Because the onset of maximum effectiveness of antidepressants is delayed, these drugs should be taken for at least 2 months before conclusions about their usefulness are drawn.^6,17

Abortive treatment for cluster headache

The gold standard abortive medication for cluster headache has been inhaled oxygen.^11,17 The mechanism by which oxygen inhalation aborts cluster headache is unknown, but it is both an effective and a well-tolerated treatment. The primary disadvantage is that oxygen therapy is not practical; unless an attack occurs either at home or in a clinic, oxygen may not be readily available. For this reason, other agents are also used for abortive treatment of cluster headache. The usual choice is a triptan or DHE, both of which act to decrease headache severity significantly for most patients.^11,17   

Prophylactic treatment for cluster headache

These headaches are severe and disabling, and for this reason, patients need a preventive medication that works immediately and can be used throughout the cluster of attacks.

Corticosteroids are the first-line medication in prophylaxis.^11,17 They have a rapid onset and are effective in preventing cluster headaches, although their exact mechanism of action is unknown. The mechanism is not likely to involve the anti-inflammatory properties of corticosteroids because these agents start to work against the headaches in about 24 hours whereas their anti-inflammatory effects take 48 to 72 hours to begin.

Corticosteroids are not a good long-term option for cluster headache prophylaxis because of their many systemic side effects, including weight gain, decreased bone mineral density, glucose intolerance, and altered lipid metabolism. These agents are usually combined with other prophylactic medications, such as anticonvulsants and calcium channel blockers. The two agents are started together, and the corticosteroid dosage is tapered and the drug is eventually stopped while the other prophylactic agent is continued. Most prophylactic headache medications take a while to achieve their full effectiveness; starting the corticosteroid and the other agent together allows for effective prophylaxis immediately yet avoids the adverse effects of long-term corticosteroid use.^11,17  

On the horizon

Currently, many new medications are undergoing testing in clinical trials. Some of those being studied are botulinum toxin (BTX), new anticonvulsants, new antidepressants, and ACE inhibitors.^5,18

BTX injections are used to treat many pain disorders and have been suggested as a possible preventive medication for both migraine and tension-type headaches.⁵ BTX reduces the amount of CGRP released by trigeminal stimulation, resulting in decreased vasodilation of meningeal vessels. A recent double-blind clinical trial showed a reduction in the number and severity of migraine headaches in study patients, as well as a decrease in the number of doses of abortive medications needed when breakthrough headaches did occur.⁵ Side effects of BTX injections include frontal weakness, ptosis, and pain at the site of injection. While BTX injections appear to be a promising treatment, more clinical trials are needed.

Levetiracetam is an anticonvulsant with an unclear mechanism of action. Several small trials have shown it to be effective in reducing the number and intensity of migraine headaches.⁵ Side effects of levetiracetam include fatigue, dizziness, and respiratory infection. Double-blind trials are being conducted to better determine the efficacy of levetiracetam against headache. Another anticonvulsant, zonisamide, is being studied as a potential treatment for migraine.

Mirtazapine is a specific serotonergic antidepressant being studied for tension-type headache prophylaxis. A recent clinical trial showed it to be as effective as amitriptyline against chronic tension-type headaches.¹⁸ Mirtazapine can cause sedation and weight gain, but it has fewer side effects and is safer than amitriptyline overall. Further studies are needed, but mirtazapine is a promising new therapy for treatment of chronic tension-type headache.

Lisinopril has also been studied as a prophylactic medication for migraine.⁵ Patients with migraine headaches usually have genes that code for high ACE activity, which has led many investigators to question if inhibiting ACE may decrease the frequency, severity, and duration of migraines. Small double-blind trials have shown ACE inhibitors to reduce both the frequency and severity of migraines, but more research is needed to assess their actual effectiveness against headache.   

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