Chronic Headaches

Etiology

The International Classification of Headache Disorders (ICHD) recognizes over 200 headache disorders and divides them into three groups, which are primary, secondary, and painful cranial neuropathies.[4] The ICHD system is hierarchical, with multiple subtypes within each main headache type.

All chronic headaches meet the criteria of occurring at least 15 times a month for at least three months, but both primary and secondary chronic headaches have unique characteristics.

Primary headaches lasting more than four hours include chronic migraines, tension headaches, persistent daily headaches, and hemicrania continua. 

• Chronic migraine has typical features of being unilateral, pulsatile, moderate to severe, and may or may not have an aura.[4] Episodic migraines may evolve into chronic migraines.
• Chronic migraine in children and adolescents is often bilateral, and associated symptoms such as photophobia and phonophobia are often inferred from behavior.[5]
• Chronic headaches, which are bilateral, non-pulsatile, and lack associated symptoms, are classified as chronic tension headaches.[4] Pericranial tenderness is often found on palpation.
• A new persistent daily headache (NDPH) occurs suddenly and becomes unremitting within 24 hours of onset. Patients typically have no prior history of headaches. NDPH is rare and refractory to treatment.[6]
• Hemicrania continua is unilateral, has autonomic symptoms, and is continuous with exacerbations. Responsiveness to indomethacin helps distinguish this form of headache.

Primary headaches lasting less than four hours include chronic cluster headaches, neuralgiform headache attacks, and primary stabbing headaches.

• Chronic cluster headache varies from the acute form in that there are no remissions, and headaches must occur over at least one year. Headaches are unilateral in the trigeminal distribution and associated with unilateral autonomic symptoms. Patients often experience agitation during the headache.
• The short-lasting neuralgiform headaches include short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). Both types have severe, unilateral pain associated with autonomic symptoms. In addition, SUNCT has both lacrimation and conjunctival injection. SUNA may have either but not both of those features and may be accompanied by rhinorrhea or nasal congestion.
• Primary stabbing headaches may frequently occur throughout the day. Sharp, sudden, jabbing pain occurs in the temporal or peri-orbital regions.

Secondary chronic daily headaches include medication overuse, CNS infection, CNS hematomas, intracranial tumor, raised intracranial pressure, low-pressure headache, vasculitis, aneurysms, and cerebrospinal fluid (CSF) leak.[2]

• Chronic medication overuse headaches often overlap with other acute and chronic headache types. Analgesics are widely used for symptom control in migraine and tension headaches. Patients inadvertently increase headache frequency by overuse of analgesics. The ICHD further classifies this disorder based on the medications used, including NSAIDs, triptans, ergotamines, non-opioid, and opioid analgesics.[7] Withdrawal of analgesics typically worsens these headaches.
• The remainder of the secondary chronic headache etiologies is beyond the scope of this article.

Epidemiology

Headache disorders have a large global burden. Both acute and chronic headaches are most prevalent between the teenage years and the fifth decade.[8]

Chronic headaches occur in 1 to 4% of the entire population.[9] Approximately 39 million people in the United States and 1 billion people worldwide are affected. Of patients seen in a headache clinic, 40% are diagnosed with chronic headaches. Prevalence rates in women are 3 to 5 times higher than in men.[4]

Chronic migraines are associated with significant comorbidities, including obesity, obstructive sleep apnea, depression, chronic pain disorders, and cardiovascular disease.[10]

Chronic migraine headaches also have a prevalence of 7 to 17% in children and adolescents.[5] The prevalence is equal between boys and girls until age 12, when females predominate.

Hemicrania continua is less common than chronic migraine or tension headache. It has a 2 to 1 female to male incidence, with the peak diagnosis occurring in the third decade.

Chronic cluster headache occurs more often in men but is also experienced by women. Women often have nausea and vomiting associated with chronic cluster headaches and may be initially diagnosed with migraine headaches.[11]

Pathophysiology

Although the pathophysiology of each type of chronic headache varies, shared features include sensitization of the trigeminal system, alterations in brain structure and function, and environmental factors.[12] Most chronic headaches result from the transformation of an episodic headache disorder. 

Modifiable risk factors, including sleep disorders, obesity, and high caffeine consumption, increase the chance of headache transformation from episodic to chronic headaches.

Serotonin, which has vasoconstrictive and anti-inflammatory effects, is a therapeutic target of triptans in migraines.

Serotonin, released from the brainstem serotonergic nuclei, may play a role in migraine; however, the exact role of its mechanisms remains a matter of controversy. Most likely, serotonin levels are low between attacks because it may cause a deficiency in the serotonin pain inhibition system, therefore helping the activation of the trigeminal system. It could mediate by acting directly over the cranial vessels, in central pain control pathways, or by cortical projections of brainstem serotonergic nuclei.[13][14]

Calcitonin gene-related peptide is abundant in trigeminal ganglion neurons. It is released from the peripheral and central nerve terminals and secreted within the trigeminal ganglion. When released from the peripheral terminals, it initiates an increased synthesis of nitric oxide and later sensitization of trigeminal nerves.[15][16] It is a strong vasodilator of cerebral and dura mater vessels, therefore a component of neurogenic inflammation. It also mediates trigeminal pain transmission from vessels to the central nervous system.

Medication overuse headaches share much of the pathophysiology of migraine and tension headaches as functional and structural changes in the central nervous system. Changes in the serotonergic neuromodulatory system and upregulation of vasoactive and pro-inflammatory mediators also contribute.[7] The condition exhibits both functional and structural changes in the central nervous system (CNS), particularly the hippocampal periaqueductal gray area, posterior cingulate cortex thalamus, cerebellum, and orbitofrontal cortex (OFC), and the mesocorticolimbic reward system.[17][18] Also found were changes in the serotonergic neuromodulatory system, upregulation of vasoactive and pro-inflammatory mediators, increased susceptibility to cortical spreading depression, central sensitization, and an increase in nociceptive sensory fields.[19] Some studies have theorized a potential genetic risk as to the etiology of the development of MOH. One such model is the renin-angiotensin system, known to have an active role in regulating neural plasticity.[20]

Trigeminal autonomic cephalalgias, cluster headache, SUNCT, SUNA, and hemicrania continua, have complex pathogenesis. Severe pain and autonomic symptoms are attributed to the trigeminal autonomic reflex via pain-producing innervation and cranial parasympathetic activation.[21]

History and Physical

A thorough history and physical exam are indispensable in the diagnosis of chronic daily headaches. As noted above, a chronic headache should have 15 or more monthly episodes for at least three months. One should determine the frequency, intensity, and characteristics of the pain, as well as the aggravating and alleviating factors. Many headache types involve ipsilateral autonomic symptoms such as lacrimation, conjunctival injection, conjunctival edema, ptosis, miosis, nasal congestion, rhinorrhea, etc.

A thorough medication reconciliation, including over-the-counter analgesics, is essential. Patients with medication-overuse headaches often have a primary headache disorder, and they frequently use pain medications.[22] Medication classes may include non-steroidal anti-inflammatory drugs (NSAIDs), triptans, ergotamines, opioids, or a combination of multiple analgesics. Key historical features include morning headaches, the onset of headaches when medication is delayed, and relief when medication is taken.[23]

Comorbidities, sleep history, and a family history of headaches should also be noted. A secondary headache disorder should be excluded from the history and examination. 

Recognition of headache "red flags" is critical in identifying secondary headaches and ordering additional diagnostic testing. Those "red flags" include:

• Age above 50
• A significant change in prior headache pattern
• Severe, "thunderclap" headache
• Systemic illness signs such as fever
• Known illness which increases the risk for secondary headaches such as cancer or HIV
• Neurologic symptoms 
• Headaches associated with Valsalva maneuvers[24]

Physical exam findings concerning secondary headache causes include focal neurological deficits, papilledema, bitemporal hemianopia, homonymous hemianopia, decreased visual acuity, or increased pain with the Valsalva method.

Primary chronic headaches often lack physical findings but may have autonomic activation or muscle tenderness in the occipital or cervical regions.

Evaluation

Further evaluation may not be warranted in a straightforward chronic primary headache disorder. Still, many clinicians will advise baseline laboratory testing and brain imaging to exclude the secondary treatable causes.

The necessary information that has to be gathered consists of these simple questions:

• Demographic features of the patient: age, gender, race, profession
• When did the headache start?
• Where does it hurt? Location, irradiation.
• What is the intensity of the pain?
• How is the pain? Which are the qualitative characteristics of the pain?
• How long does the pain last?
• At which moment of the day does the pain appear?
• How has it evolved since it started?
• What is the frequency of appearance?
• What are the triggering situations?
• Simultaneous symptoms?
• Is it related to sleep?
• How does it get better or worse?
• Which medications do you take to make it better? What is the frequency of this medication?

Laboratory workup includes a complete blood count to look for infection. Erythrocyte sedimentation rate (ESR) is increased in giant cell arteritis and other vasculitides. A metabolic panel looks for metabolic causes of headaches and endocrine testings to look for pituitary gland abnormalities.

Magnetic resonance imaging (MRI) of the brain is the imaging modality of choice.[25] A contrast study is often recommended to increase the sensitivity and specificity to detect structural abnormalities. A need for vascular imaging is based on the differential diagnosis. Further studies may be warranted depending upon the underlying cause. These may include positron emission tomography (PET) scan, magnetic resonance spectroscopy (MRS), and/or biopsy. A lumbar puncture may be required if there is suspicion of a CNS infection or idiopathic intracranial hypertension.

Medication Overuse Headache by Drug Class and Duration of Headache

• Ergotamine--> ten days/month for over three months
• Triptan--> ten days/month for over three months
• ASA-->15 days/month for over three months
• NSAIDs-->15 days/month for >3 months
• Acetaminophen/paracetamol-->15 days/month for over three months
• Opioids--> ten days/month for over three months
• Combination analgesics--> ten days/month for over three months
• Multiple drug classes--> ten days/month for over three months[22]

Treatment / Management

Treatment and management of chronic headache disorders depend upon the underlying etiology and may require an interprofessional approach.

The patient should maintain a headache journal documenting their headache episodes and any accompanying triggers. If found, stressors should be avoided or minimized. 

Chronic Migraine

• Chronic migraine treatment should begin with setting the expectation that headache frequency and severity will decrease, but headaches will not be eliminated.
• The patient should be counseled that high caffeine intake, sleep deprivation, overuse of analgesics, and comorbid conditions can worsen chronic migraines.
• Prophylactic pharmacologic treatment should be used. First-line therapy includes beta-blockers, anticonvulsants, and antidepressants. The most commonly used medications are propranolol, topiramate, and amitriptyline.[26]
• Botulinum toxin A is a Food and Drug Administration (FDA) approved treatment for chronic migraines and is considered second-line therapy.
• Monoclonal antibodies that target calcitonin gene-related peptide (CGRP) are the newest development in chronic migraine treatment. Erenumab, fremanezumab, and galcanezumab are approved for chronic migraines, which have failed to respond to other treatments.[26]
• Triptans, steroids, NSAIDs, and opioids are often used to abort acute episodes, but routine use of these medications increases the risk of developing a medication-overuse headache.
• Patients may also benefit from psychological counseling if anxiety or depression is present.
• Manual medicine, such as spinal manipulation and trigger point treatment, may be used as complementary or alternative therapy.[27]
• In drug-resistant cases, invasive procedures such as sphenopalatine ganglion and occipital nerve blockades may be tried with variable results. Deep brain stimulation (DBS) is also used in some treatment-resistant cases.[28][29] 
(B3)

Chronic Tension Headache

• Amitriptyline, a tricyclic antidepressant, is recommended as the first-line treatment for chronic tension headaches.
• Amitriptyline, in addition to inhibiting serotonin and noradrenaline reuptake, also reduces tenderness in pericranial muscles.
• Tricyclic antidepressants increase the risk for cardiac arrhythmia, and patients should be screened for cardiovascular disorders before initiating therapy. In addition, patients over 40 should undergo an ECG.
• Anticonvulsants, such as topiramate and gabapentin, can be considered second-line treatment.
• Addressing the potential musculoskeletal causes of tension headaches, treatment with physical therapy, acupuncture, trigger point injections, spinal manipulation, or muscle relaxants may be beneficial.[30]
• Behavioral therapy, including cognitive-behavioral therapy, biofeedback, and relaxation techniques, is particularly helpful for patients with coexisting anxiety or depression.
(A1)

Medication Overuse Headache

• Patient education about the potential for overuse of analgesic medication to lead to headache progression is key. Include the use of over-the-counter analgesics in the discussion.
• The physician initiates a preventative medication while simultaneously assisting the patient in discontinuing the causative drug.
• Patients may experience withdrawal symptoms of nausea and anxiety for 2 to 10 days when the analgesic medication is discontinued.
• There is no consensus on the most appropriate medication for bridge therapy following discontinuation of the offending drug. Long-acting NSAIDs, prednisone, dihydroergotamine, and antiemetics are options.[31] The medication should not be from the same class as the offending medication.
• Medications that may be effective for prophylaxis include topiramate, amitryptiline, valproic acid, and beta-blockers. The choice of medication should be based upon comorbidities and the primary headache disorder.[32]
(B3)

Chronic Autonomic Cephalgia

• Indomethacin is the drug of choice for paroxysmal hemicrania, hemicrania continua, primary stabbing headache, hypnic headache, and Valsalva-induced headaches (e.g., cough headache, exercise headache).
• Verapamil is the drug of choice for the prevention of chronic cluster headaches. However, Verapamil requires titration to become effective, and glucocorticoids or dihydroergotamine can be used for exacerbations.
• Chronic cluster headaches not responsive to pharmacologic therapy can be treated with a non-invasive vagus nerve stimulator or sphenopalatine ganglion microstimulator.[11]
• First-line prophylactic therapy for chronic SUNCT and SUNA is lamotrigine. Topiramate and gabapentin are alternatives.[33]

Differential Diagnosis

• Medication-overuse headache 
• Brain neoplasm 
• Chronic infections (e.g., CNS tuberculosis)
• Chronic sinusitis
• Cervical spine-related pain
• CNS vasculitis
• Temporomandibular joint pathologies
• Idiopathic intracranial hypertension
• Chronic hydrocephalus
• Cerebral aneurysms
• Chronic paroxysmal hemicrania
• Dissection syndromes
• Encephalitis
• Subarachnoid/intracranial hemorrhage
• Meningitis
• Temporal/giant cell arteritis

Treatment Planning

Table 1. Acute therapy for migraine *Adverse effects in this section pertain to all triptans unless specified

Table 2. Preventive therapy for migraine[48]

Prognosis

The prognosis of chronic headaches is variable. Anxiety and mood disorders, elevated stress levels, insufficient sleep, poor headache management, and low socioeconomic status are the primary prognostic characteristics—patients with higher expectations for treatment display a better prognosis for decreased headache intensity and frequency. No specific age group has an improved response to treatment. Incidence at an older age generally correlates to less severe symptoms. Employed patients responded better to treatment than those patients on medical leave.[9] Exercise, prophylactic medication regimen compliance, and cessation of overused medications tend to lead to a favorable prognosis.[1]

Complications

• Mood disorders
• Decreased quality of life
• Suicide
• Unemployment
• Progressive neurological deficits
• Vision loss
• Seizures
• Drowsiness
• Medication adverse effects