Headache

Etiology and Pathogenesis

Headache is a symptom that may be caused by various underlying conditions and pathologic mechanisms. The International Classification of Headache Disorders, 3rd edition (ICHD-3), provides diagnostic criteria for common headache disorders 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 ICHD-3 divides headache into 2 groups: primary headaches, not caused by an underlying disease process, and secondary headaches, caused by an underlying disease process. In recent years the pathogenesis of various primary headache disorders has become better understood. While it was previously thought that migraine, for example, was solely due to an underlying vascular pathology leading to cerebral vasoconstriction/dilatation, it is now widely accepted that it is due to activation of the trigeminovascular system, which leads to the release of various vasoactive peptides including calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), neurokinin A, and substance P.

The pathogenesis of secondary headache varies based on the underlying causative disease process and usually involves irritation, ischemia, or stretching of pain-sensitive structures around the brain (meninges, vessels) or around the head (muscle, bone, peripheral nerve, joint, and sinus).

Classification of Headaches Based on ICHD-3

1. Primary headache: The 3 common primary headache types are tension-type headache, migraine (with or without aura), and cluster headache (trigeminal autonomic cephalalgias). Of note, the diagnostic criteria for all primary headache disorders require that the headache cannot be accounted for or explained by another diagnosis:

1) Tension-type headache: Features: Table 1. The most commonly encountered primary headache disorder.

2) Migraine: Features: Table 2. The second most common primary headache disorder after tension-type headache. Migraine can be divided into episodic migraine, present for <15 days per month, or chronic migraine. Chronic migraine 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).

3) Trigeminal autonomic cephalalgias: These headaches include cluster headache, paroxysmal hemicrania, hemicrania continua, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)/short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA).

These headache types are associated with unilateral cranial autonomic features such as conjunctival injection and/or lacrimation, nasal congestion and/or rhinorrhea, eyelid edema, forehead and facial sweating, miosis and/or ptosis.

The classification of trigeminal autonomic cephalalgias is mainly based on the frequency and duration of individual attacks.

a) Characteristics of cluster headache: Table 3.

b) Paroxysmal hemicrania refers to attacks of severe, strictly unilateral pain, which may be orbital, supraorbital, temporal, or represent any combination of these sites, lasts 2 to 30 minutes, and occurs at least several times a day. According to the diagnostic criteria, this headache responds absolutely to therapeutic doses of indomethacin (doses of up to 75-100 mg tid should be trialed for 2 weeks to determine responsiveness).

c) Hemicrania continua refers to continuous unilateral headache present for >3 months with exacerbations of moderate or greater intensity. Similar to paroxysmal hemicrania, according to the diagnostic criteria, this headache responds absolutely to therapeutic doses of indomethacin (doses up to 75-100 mg tid should be trialed for 2 weeks to determine responsiveness).

d) SUNCT/SUNA: The attacks are even more frequent (up to 100 times/d) and most often last <1 minute.

4) Other (rare) types of primary headache include 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.

2. Secondary headache: Causes of secondary headache are multiple and include, as listed by the ICHD-3, 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 one of the most common secondary headache disorders. It is defined as a 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/thunderclap headache: This is a common presentation in the emergency room or primary care setting. Often this headache is due to vascular causes (subarachnoid hemorrhage, intracranial hemorrhage, CVST, arteriovenous malformation, giant cell arteritis, arterial dissection); the other causes include tumors and meningitis. The label of thunderclap headaches is used to describe a severe headache with rapid onset, which peaks within one minute. Traditionally associated with subarachnoid aneurysm, this clinical syndrome may occur in other conditions, including reversible cerebral vasoconstriction syndrome (RCVS), posterior reversible encephalopathy syndrome (PRES), and intracerebral hemorrhage.

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

Diagnosis

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 4). “SNOOP10” 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, positional headache, precipitated by sneeze/cough/Valsalva maneuver, papilledema, posttraumatic onset, pathology of the immune system, progressive headache, pregnancy/puerperium, painful eye with autonomic features, painkiller overuse.

This may include clinical situations with presumed migraine but with unusual, prolonged, or persistent aura; clearly increasing frequency, severity, or change in clinical features; first or worst migraine; migraine with brainstem aura; migraine with confusion; migraine with motor manifestations such as hemiplegia. The other clinical scenarios may present as very severe headaches, especially of thunderclap variety, and physical activity–induced headache. 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 tests: Available tests include neuroimaging (computed tomography [CT], magnetic resonance imaging [MRI]). In cases of sudden-onset severe/thunderclap headache, urgent vascular imaging including angiography (computed tomography angiography [CTA], magnetic resonance angiography [MRA]) is often indicated. Other investigations may include CT cerebral venography, MRV, lumbar puncture, and blood tests, each depending on the suspected secondary headache (its presence and potential causes).

Based on consensus criteria from the American Headache Society, there is good evidence that it is not necessary to order neuroimaging in patients with headaches consistent with migraine who have a normal neurologic examination and in whom no atypical features or red flags are present.

There is lower-level evidence to consider neuroimaging for presumed migraine in the following cases:

1) Unusual, prolonged, or persistent aura.

2) Increasing frequency or severity, or change in clinical features.

3) First or worst migraine.

4) Migraine with brainstem aura.

5) Migraine with confusion.

6) Migraine with motor manifestations (hemiplegic migraine).

7) Late-life migraine accompaniments.

8) Aura without headache.

9) Side-locked headache.

10) Posttraumatic headache.

Neuroimaging/further workup is indicated in severe sudden-onset/thunderclap headache that is new or associated with red flag symptoms and in nonacute headache with abnormal neurologic signs/red flag features.

Treatment

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): naproxen 500 mg, 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 may be 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 the dose should be increased, the formulation changed, or another triptan tested. Triptans are contraindicated in patients with coronary artery, cerebrovascular, and peripheral vascular disease.

Newer agents such as gepants (small-molecule antagonists of CGRP receptor) and ditans (highly selective 5-HT1F receptor agonists without vasoconstrictive properties) may have fewer adverse effects and carry lower cardiovascular risk than triptans.

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 h; the headache may temporarily resolve but not for >4 h), 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 20 mg, subcutaneous sumatriptan 6 mg, IV lysine acetylsalicylate 1000 mg, and IV dexamethasone 4 to 8 mg.

2. Migraine prophylaxis:

1) Supplements and nutraceuticals should be considered as a first-line option given the evidence for their safety and efficacy. These include coenzyme Q10 100 to 300 mg, magnesium citrate 400 to 600 mg, and riboflavin 400 mg. The Canadian Headache Society makes a strong recommendation for these, based on low-quality evidence due to low risks/side effects and potential benefit.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to inconsistency and the risk of bias. Rajapakse T, Gantenbein AR. Nutraceuticals in migraine. Handb Clin Neurol. 2024;199:125-144. doi: 10.1016/B978-0-12-823357-3.00001-X. PMID: 38307641.

2) Migraine-preventive pharmacologic treatments:

a) Oral options for episodic and chronic migraine include metoprolol 50 to 200 mg/d, propranolol 20 to 240 mg/d, flunarizine 5 to 10 mg/d, valproic acid 500 to 1500 mg/d, topiramate 50 to 200 mg/d, amitriptyline 10 to 100 mg/d, candesartan 16 mg/d, venlafaxine 37.5 to 300 mg/d. There are no clear comparative data among those choices. Two oral gepants, rimegepant and atogepant, also have evidence for preventive treatment of migraine. However, rimegepant is currently approved for migraine prevention only in the United States, and not in Canada.

b) CGRP monoclonal antibodies are novel agents with evidence for use in both episodic and chronic migraine. These include erenumab, galcanezumab, fremanezumab (IM formulations), and eptinezumab (IV formulation).

c) Onabotulinum toxin type A is used for the treatment of chronic migraine at a dose of 155 to 195 IU (a total dose per 1 series) administered every 12 weeks to muscles around the head according to an appropriate protocol. It should be administered by an experienced clinician.

3) Nonpharmacologic therapies play a crucial role in the management of migraine and include counseling around trigger identification, regular sleep, morning protein, stress management, diet and exercise, caffeine reduction, and avoidance of medication overuse. Biofeedback, relaxation therapy, and cognitive behavioral therapy may also be effective.

Treatment of Cluster Headache

1. Acute attacks of cluster headache:

1) First-line agents: Sumatriptan 6 mg subcutaneously, zolmitriptan 5 to 10 mg as nasal spray. Oxygen 10 to 15 L for 15 to 20 minutes via a nonrebreather mask.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias. Petersen AS, Barloese MC, Jensen RH. Oxygen treatment of cluster headache: a review. Cephalalgia. 2014 Nov;34(13):1079-87. doi: 10.1177/0333102414529672. Epub 2014 Apr 10. PMID: 24723673.

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.

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.

There is also recent evidence of the utility of a CGRP monoclonal antibody galcanezumab in the treatment of episodic cluster headache.

Treatment of Paroxysmal Hemicrania and Hemicrania Continua

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

Treatment of Medication Overuse Headache

All patients should be educated regarding the risk of medication overuse headache. Most patients with medication overuse headache improve with discontinuation of the offending agent. When the overused agent is a simple analgesic (such as acetaminophen [INN paracetamol]/ibuprofen) or a triptan, management involves tapering or stopping the offending agent. Bridging therapies with long-acting NSAIDs or triptans can also be considered. Typically, a prophylactic medication should also be initiated at the time of tapering/stopping the overused agent. If the overused agent is an opioid or barbiturate, a more gradual tapering approach and often involvement of a multidisciplinary addiction team may be indicated.

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