How to Cite This Chapter: Oczkowski W, Rożniecki JJ, Bodzioch M. Headache. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.I.1.4 Accessed January 22, 2021.
Last Updated: September 5, 2019
Last Reviewed: September 5, 2019
Chapter Information

Causes and PathogenesisTop

Headache is a symptom that may be caused by various diseases. It may develop through a wide range of pathogenetic mechanisms that depend on the underlying condition. The International Headache Society (IHS) classifies headache using a hierarchical organization and specific diagnostic criteria based on symptoms, signs, and associated medical conditions. Classification is an important step in accurately identifying the probable headache etiology, natural history, and treatment.

The IHS divides headache into 2 groups: primary (not caused by an underlying disease process) or secondary (caused by an underlying disease process). The pathogenesis of primary headache, such as migraine, is not completely understood, although proposed mechanisms include various neuronal, vascular, receptor, and electrophysiologic changes. The pathogenesis of secondary headache usually involves irritation, ischemia, or stretching of pain-sensitive structures around the brain (meninges, vessels) or pain-sensitive structures around the head (muscle, bone, peripheral nerve, joint, and sinus).

1. Primary headache: The most common primary headache types are migraine (with or without aura), tension-type headache, and cluster headache (trigeminal autonomic cephalalgias).

1) Migraine: Features: Table 10.2-1. The headache cannot be better explained by another diagnosis. A particularly disabling form of migraine is chronic migraine, which is diagnosed in patients with a headache present ≥15 days in a month for ≥3 subsequent months, provided that on ≥8 days of each month the headache fulfills the criteria for migraine and the patient has a history of ≥5 migraine attacks (with or without aura).

2) Tension-type headache: Features: Table 10.2-2. The headache cannot be better explained by another diagnosis.

3) Trigeminal autonomic cephalalgias: These headaches include cluster headache (episodic or chronic), paroxysmal hemicrania (episodic or chronic), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). The classification of trigeminal autonomic cephalalgias is mainly based on the frequency and duration of individual attacks. In patients with paroxysmal hemicrania, headache episodes occur more frequently (≥20 times a day) but generally last a shorter time (2-30 minutes). The attacks in SUNCT are even more frequent (up to 100 times a day) and most often last <1 minute.

a) Characteristics of cluster headache: Table 10.2-3. The headache cannot be better explained by another diagnosis.

b) Paroxysmal hemicrania refers to attacks of severe strictly unilateral pain, which is orbital, supraorbital, temporal, or any combination of these sites, lasts 2 to 30 minutes, and occurs several or many times a day.

4) Other (rare) types of primary headache: Primary stabbing headache, primary cough headache, primary exertional headache, primary headache associated with sexual activity, hypnic headache, primary thunderclap headache, new-onset daily persistent headache, nummular headache, and hemicrania continua.

2. Secondary headache: Causes of secondary headache are multiple and include (as listed by the IHS) head or neck trauma (immediate or delayed); cranial or cervical vascular disorders (aneurysm, arterial dissection, cerebral vein and sinus thrombosis [CVST]); nonvascular intracranial disorders (tumor, after seizures); substance abuse or withdrawal (medication overuse headache); infections (meningitis, encephalitis); disorders of cerebrospinal fluid (CSF) flow (intracranial hypertension or hypotension); disorders of the neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures (cervical radiculopathy or myofascial pain, sinusitis); psychiatric disorders (depression, anxiety, posttraumatic stress disorder).

3. Additional considerations:

1) Medication overuse headache is a common cause of chronic headache that occurs on ≥15 days per month in a patient with a preexisting headache disorder and with regular overuse for >3 months of ≥1 drug that can be taken for acute or symptomatic treatment of headache. The headache cannot be explained by another diagnosis. Discontinuation of the involved drug (offending agent) can often improve the headache and also increases responsiveness to treatments for other headache etiologies.

2) Severe sudden-onset headache: Sudden-onset headache is a common presentation in the emergency room or primary care setting. Only a small percentage is a result of a life-threatening illness; more than half of the life-threatening diseases are due to vascular causes (subarachnoid hemorrhage, intracranial hemorrhage, CVST, arteriovenous malformation, giant cell arteritis, arterial dissection); the other causes include tumors and meningitis.

Patients with a severe sudden-onset headache require urgent evaluation, as the headache may be a symptom of subarachnoid hemorrhage or another life-threatening condition.


1. History and physical examination: Start from excluding secondary headache that may be life-threatening. Pay special attention to alarming symptoms (red flags), which may suggest a serious etiology of the headache and require urgent diagnostics (Table 10.2-4). “SNOOP4” is a useful bedside mnemonic for secondary causes: systemic symptoms/signs/disease, neurologic symptoms/signs, onset sudden, onset after the age of 50 years, pattern change. After excluding the most common and most serious causes of secondary headache, reevaluate the patient, paying particular attention to atypical features of the headache or comorbidities.

2. Diagnostic studies: Available tests include neuroimaging (computed tomography [CT], magnetic resonance imaging [MRI], in some cases angiography [CTA, MRA]), lumbar puncture, and blood tests, each depending on the suspected secondary headache (its presence and potential causes).

Neuroimaging is indicated in the following situations:

1) Severe sudden-onset headache that is new or associated with red flag symptoms.

2) Nonacute headache with abnormal neurologic signs.

Neuroimaging is suggested in:

1) Nonacute headache with red flag symptoms.

2) Patients with possible migraine that do not meet all the criteria for migraine or have some atypical symptoms.

Neuroimaging is generally not necessary if the patient’s history of headaches is consistent with typical and common headache disorders (migraine, tension-type headache) and no abnormal findings have been identified on physical (including neurologic) examination.


Treatment of Migraine

The approach to treating migraine is dependent on the severity and frequency of attacks and, most importantly, on the impact on the quality of life of the patient. Acute treatment is used at the start of migraine attacks; prophylactic treatment is used when the frequency, severity, or impact on the patient is such that prevention of attacks is warranted; and rescue therapy is used when acute treatment has not aborted the migraine attack and symptomatic treatment for pain and nausea or vomiting is required.

1. Acute attacks of migraine: Mild to moderate acute attacks of migraine may respond to oral analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs): acetylsalicylic acid (ASA) 1000 mg, acetaminophen (INN paracetamol) 1000 mg, ibuprofen 200 to 600 mg, diclofenac 50 to 100 mg, or a combination of these drugs taken as soon as possible with the onset of headache.

In patients with moderate to severe acute attacks of migraine or in those not responsive to analgesics or NSAIDs, triptan therapy is more effective. Various triptan drugs are available with different speed of onset, duration, and tolerability. Subcutaneous sumatriptan 6 mg has the most rapid mode of onset and highest probability of decreasing pain. Patient preference, individual response, and adverse effects guide the choice of a particular triptan drug and whether another should be tested. Triptans are contraindicated in patients with coronary artery, cerebrovascular, and peripheral vascular disease.

As migraine attacks are very often accompanied by nausea or vomiting, administer an antiemetic as soon as possible: metoclopramide 10 to 20 mg orally or 10 mg IM or IV or domperidone 10 mg orally.

Emergency room treatment of migraine, including status migrainosus (a migraine attack with a prolonged headache phase that lasts >72 hours; the headache may temporarily resolve but not for >4 hours), is often necessary when oral treatment has failed at home. Treatment in this situation can include IV rehydration in the context of nausea and vomiting, IV metoclopramide 10 to 40 mg, subcutaneous sumatriptan 6 mg, IV lysine acetylsalicylate 1000 mg, and IV dexamethasone 4 to 8 mg.

2. Prophylactic treatment of migraine: Migraine-preventive treatment should last ≥3 months, optimally ~6 months.

1) First-line agents: Metoprolol 50 to 200 mg/d, propranolol 40 to 240 mg/d, bisoprolol 5 to 10 mg/d, flunarizine 5 to 10 mg/d, valproic acid 500 to 1500 mg/d, topiramate 25 to 100 mg/d, amitriptyline 50 to 75 mg/d may all be effective.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Diener HC, Holle-Lee D, Nägel S, et al. Treatment of migraine attacks and prevention of migraine: Guidelines by the German Migraine and Headache Society and the German Society of Neurology. Clin Transl Neurosci. 2019 Jan 30;3(1). doi: 10.1177/2514183X18823377.

2) Second-line agents (drugs that are less effective or cause more adverse effects than first-line agents): Opipramol 50 to 150 mg/d, ASA 300 mg/d, magnesium 600 mg/d, magnesium + vitamin B2 400 mg/d + coenzyme Q10 150 mg/d, lisinopril 10 mg/d, candesartan 16 mg/d, or telmisartan 80 mg/d.Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias, imprecision, and inconsistency. Diener HC, Holle-Lee D, Nägel S, et al. Treatment of migraine attacks and prevention of migraine: Guidelines by the German Migraine and Headache Society and the German Society of Neurology. Clin Transl Neurosci. 2019 Jan 30;3(1). doi: 10.1177/2514183X18823377.

Nonpharmacologic treatments that may be considered, either used alone or in combination with other options, include biofeedback, relaxation therapy, and cognitive behavioral therapy.

3. Chronic migraine: Options include topiramate 100 to 200 mg/d, valproic acid 500 to 1500 mg/d, botulinum toxin type A 155 to 195 IU (a total dose per 1 series) administered to muscles around the head according to an appropriate regimen.

Treatment of Cluster Headache

Treatment of individual attacks is difficult because they are relatively short-lived and resolve spontaneously, which means that almost no traditional analgesics become effective before the spontaneous cessation of pain.

1. Acute attacks of cluster headache:

1) First-line agents: Sumatriptan 6 mg subcutaneously, zolmitriptan 5 to 10 mg as nasal spray, oxygen 6 to 12 L/min.

2) Second-line agents: Sumatriptan 20 mg as nasal spray, zolmitriptan 5 to 10 mg orally.

2. Prophylactic treatment of cluster headache:

1) First-line agents: Suboccipital steroid injection, civamide 0.025% nasally daily.

2) Second-line agents (limited data): Lithium 900 mg/d, verapamil 360 mg/d, warfarin with a target international normalized ratio (INR) of 1.5 to 1.9, melatonin 10 mg/d.

Treatment of Paroxysmal Hemicrania

The drug of choice is indomethacin 150 to 225 mg/d. A very good response to indomethacin additionally supports the diagnosis of paroxysmal hemicrania.

Treatment of Medication Overuse Headache

Agents used for abortive treatment of headache are strictly contraindicated because their overuse may be the underlying cause of the headache. Explain to the patient what has caused the pain and why they need to discontinue the overused drugs. An abrupt discontinuation is recommended in the case of overuse of simple analgesics, ergotamine, or triptans, while tapering the dose down to discontinuation is recommended in the case of overuse of opioids, benzodiazepines, and barbiturates. In some patients discontinuation of analgesic agents may be facilitated by using a preventive medication, such as topiramate 100 mg/d (maximum, 200 mg/d), a short course of glucocorticoids (prednisone or prednisolone ≥60 mg/d), or amitriptyline (maximum, 50 mg/d).



Table 10.2-1. Features of migraine headaches


≥5 attacks with headache attacks lasting 4-72 hours (when untreated or treated unsuccessfully)

Characteristics (≥2 of 4)

Unilateral location, pulsating quality, moderate or severe pain intensity, aggravated by or leading to avoidance of physical activity

Associated symptoms (≥1 of 2)

≥1 of nausea/vomiting, photophobia, and phonophobia

Table 10.2-2. Features of tension headaches


≥10 episodes of headache occurring on average on 1-14 days per month (12-180 days per year)


Lasting from 30 minutes to 7 days

Characteristics (≥2 out of 4)

– Bilateral location

– Pressing or tightening (nonpulsating) quality

– Mild or moderate intensity

– Not aggravated by routine physical activity (eg, walking or climbing stairs)

Further features

– No nausea or vomiting

– Photophobia or phonophobia may be present (but not both)

Table 10.2-3. Features of cluster headache


≥5 attacks, may occur from every other day to up to 8 per day


Lasting from 15 to 180 minutes (if untreated)


– Severe or very severe unilateral pain in the orbital, supraorbital, and/or temporal area

And ≥1 of:

– Conjunctival injection and/or lacrimation

– Nasal congestion and/or rhinorrhea

– Eyelid edema

– Forehead and facial sweating and/or flushing

– Miosis and/or ptosis

– Restlessness or agitation

Table 10.2-4. Alarming features (red flags) in a patient with headache


Most frequent causes

Recommended diagnostic studies

Sudden-onset headache (± signs of meningeal irritation)

Subarachnoid hemorrhage, bleeding from tumor or arteriovenous malformation, brain tumor (particularly in posterior fossa)

Neuroimaging,a CSF analysisb

Headache of constantly increasing severity

Brain tumor, subdural hematoma, medication overuse


Headache with accompanying systemic symptoms (fever, nuchal rigidity, rash)

Meningitis, encephalitis, Lyme neuroborreliosis, systemic infection, connective tissue disease (including systemic vasculitis)

Neuroimaging,a CSF analysis,b blood tests as needed

Focal neurologic signs or symptoms, or symptoms other than typical visual or sensory aura

Brain tumor, arteriovenous malformation, connective tissue disease (including systemic vasculitis)

Neuroimaging,a diagnostic workup for connective tissue diseases with vascular involvement


Brain tumor, idiopathic intracranial hypertension, encephalitis, meningitis

Neuroimaging,a CSF analysisb

Headache on coughing, exercise, or Valsalva maneuver

Subarachnoid hemorrhage, brain tumor (particularly in posterior fossa)

Neuroimaginga; consider CSF analysisb

Headache during pregnancy or in postpartum period

Cerebral vein or sinus thrombosis, carotid artery dissection, pituitary apoplexy


New-onset headache in patient with cancer

Cancer metastasis

Neuroimaging,a CSF analysisb

a Computed tomography or magnetic resonance imaging.

b After a mass lesion causing raised intracranial pressure has been excluded by neuroimaging.

CSF, cerebrospinal fluid.

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