Kelleen N. Flaherty

Headache is one of the most common complaints presenting in primary care. The pain of a headache can range from mild to severe, can be acute or chronic, and may last hours to days in duration. Severe headache and migraine are estimated to afflict one in seven individuals in the United States based on multiple population-wide studies and have a significant impact on quality of life and health care resource utilization (Burch et al., 2015). While there are three main categories of headaches according to the most recent International Classification of Headache Disorders (ICHD-3; Headache Classification Subcommittee of the International Headache Society [IHS], 2013), the most commonly encountered headaches seen in primary care are the primary and secondary headaches (Box 38.1). A primary headache is one with no identifiable underlying organic disease process; a secondary headache is one for which a specific etiology has been identified. The practitioner must first rule out a secondary headache (or more serious cause of headache pain) and then accurately diagnose the type of primary headache. In some instances, a primary and secondary headache can occur simultaneously. Primary headaches include tension-type headache (TTH), migraine, and cluster headache (CH). This chapter will focus on diagnosing and treating TTH and migraine, the most common forms of primary headache presenting in clinical practice.

Tension headaches have a dull quality, with pain that radiates bilaterally from the forehead to the occiput in a band-like fashion. The pain often radiates down the neck and sometimes even into the trapezius muscle. The pain is mild to moderate and can last from 30 minutes to several days in severe cases. Tension headaches are not typically present upon awakening, but begin later in the day and progress with time. The pain of these headaches is rarely debilitating, but it can affect a person’s ability to function, especially if prolonged or chronic. There are no associated symptoms of nausea, vomiting, photophobia, or phonophobia.

Migraine is a neurologic syndrome causing not only throbbing head pain but also often nausea, appetite change, photophobia, and phonophobia. The pain generally ranges from moderate to severe and can be disabling. The Global Burden of Disease Study in 2010 ranked migraine as the third most prevalent and seventh highest specific cause of disability in the world (ICHD-3, 2013). According to epidemiologic studies, migraine occurs in one in seven individuals in the United States and is two to three times more common in females than males. The National Health Interview Survey (2005-2015) estimated a national prevalence of 13.8%, 18.9% in females and 9% in males, with migraine occurring disproportionately higher in at-risk groups such as the unemployed, the uninsured, or those in lower socioeconomic strata (Burch et al., 2015). The age of onset is from 15 to 35, but peak prevalence is from ages 35 to 45. A family history of migraine has shown to be diagnostic in 60% of cases and is considered to be a significant risk factor. Significant comorbidity has also been demonstrated in population studies, including musculoskeletal complaints, cardiovascular disorders, psychiatric disorders, and epilepsy (Merikangas, 2013). Combined direct and indirect costs for migraine are estimated to be $3.2 billion in the United States, plus $700 million for emergency department visits and $375 million for in-patient treatment (Merikangas, 2013). Decreased productivity is a significant contribution to the indirect cost burden of migraine. Approximately 53% of migraine visits are to primary care offices, with another 16.7% presenting in emergency departments—adding to the financial burden (Burch et al., 2015). It is estimated that half of the individuals suffering from migraine do not report it or seek help for it, and many who do will discontinue treatment (Merikangas, 2013).

CHs may be chronic or acute and episodic and are far less common than migraine or tension headaches, occurring in less than 1% of the population. They are approximately three times more common in males than in females, and the acute/episodic variety is approximately six times more common than chronic CH (Fischera et al., 2008). The pain is disabling, burning, or boring and centered around one eye and is described by patients as being more severe than childbirth or passing a kidney stone. Attacks are unilateral, generally lasting from 15 to 180 minutes, and may occur one to eight times per day. Associated ipsilateral symptoms may include lacrimation, nasal congestion, rhinorrhea, miosis, ptosis, eyelid edema, or conjunctival injection. Restlessness and agitation may also accompany an attack; individuals often cannot lie down and instead pace the floor (ICHD-3, 2013). Significant disability and comorbidity (including cognitive impairment, anxiety, depression, agoraphobia, and even suicidal tendencies) may be associated with CH (Torkamani et al., 2015). A patient with symptoms suggestive of CH should be referred to a neurologist or headache specialist. Episodic CH occurs in a series of repeated headaches, with periods lasting anywhere from 1 week to 1 year, interrupted by periods of pain-free remission. Chronic CH, on the other hand, lasts at least for 1 year without remission, or without at least one full month of remission (ICHD-3, 2013). While the pathophysiology of CH is incompletely understood, hypothalamic dysfunction is believed to be involved; consequently, circadian rhythms are disrupted. CHs often occur at specific times during sleep-wake cycles, another indication of hypothalamic involvement (Francis et al., 2010).


Tension headaches are highly prevalent in the population, with a lifetime prevalence of 30% to 78% demonstrated in a variety of population studies. Prevalence is approximately twice as high in females as it is in males (Haque et al., 2012; ICHD-3, 2013). The high prevalence of TTH results in a more significant and costly socioeconomic burden than that of migraine (Bezov et al., 2010; ICHD-3, 2013). Chronic TTH has a global prevalence of 0.5% to 4.8%. While stress has been shown to be the most common precipitant of TTH, other precipitants have been identified (ICHD-3, 2013; Yu & Han, 2015). Sleep dysregulation has been shown to have a bidirectional relationship with TTH, with lack of sleep being a precipitant of TTH and TTH being a precipitant of insomnia (Rains et al., 2015). Other precipitants reported include sunlight, fatigue, anxiety, temperature (cold and warm), activity, traveling, and reading. Unlike migraine, food does not appear to be a trigger (Haque et al., 2012). Cigarette smoking has also been correlated with an increased number of days of headache per week.

Although more common in migraine patients, one cause of recurrent tension headaches is the overuse of over-the-counter (OTC) and prescription analgesic medications, leading to medication overuse headache (MOH; ICHD-3, 2013). The headache recurs as each dose of medication wears off, causing the patient to take another analgesic and thus continue the cycle of pain. Treating more than two headaches with an OTC analgesic for either migraine or TTH per week can lead to development of chronic daily headache. Other modifiable risk factors include obesity, caffeine overuse, alcohol consumption,
and temporomandibular issues. Nonmodifiable risk factors include female gender, genetics, socioeconomic status, head or neck injury, age, and life events (Cho & Chu, 2015; Yu & Han, 2015).


While TTH was originally assumed to be psychogenic in nature, evidence now suggests that these headaches have neurobiologic etiologies (ICHD-3, 2013) and may be a consequence of both centrally (chronic) and peripherally (episodic) processed pain. Central pain processing may result in increased tenderness and lower pain thresholds in pericranial and myofascial muscles. There may also be genetic, comorbid (e.g., chronic pain, depression, etc.), vitamin D deficiency, and vascular components to TTH. Other research has implicated nitric oxide (a vasodilator) as a local mediator of TTH. In one study, blocking nitric oxide production led to decreased pericranial muscle hardness and headache pain in patients with chronic TTH (Ashina et al., 1999).


The first step in determining the type of headache a patient has is to take a detailed headache history. The history should include the patient’s age; the time of day when the attack(s) occur(s); the duration and frequency of attacks; precipitating or relieving factors; the quality, location, and intensity of the pain; use of OTC analgesics; and associated symptoms. The social history and family history are also important. The results of physical and neurologic examinations should be unremarkable in a patient with primary headache, other than revealing possible tenderness of pericranial muscles. Diagnosis is mostly of exclusion: all possible secondary headaches, migraine headache, and CHs are ruled out. Tension headaches may be diagnosed as primary, secondary, or both. The Headache Classification Committee of the International Headache Society characterizes TTH by “frequent episodes of headache, typically bilateral, pressing or tightening in quality and of mild to moderate intensity, lasting minutes to days. The pain does not worsen with routine physical activity and is not associated with nausea, but photophobia or phonophobia may be present (ICHD-3, 2013).”

Diagnostic alarms in the evaluation of a headache patient that require further testing include headache onset after age 50, sudden-onset headache, accelerating headache pattern, headache with fever and stiff neck, and abnormal results on the neurologic examination. With regard to other types of diagnostic testing, the American Headache Society’s (AHS) “Choosing Wisely” recommendations counsel against the use of neuroimaging studies in patients with stable headaches that meet criteria for migraine and against the use of CT imaging for headache when MRI is available, except in the emergency setting (Loder et al., 2013). The ICHD-3 diagnostic criteria for frequent episodic tension headache can be seen in Box 38.2.


Before initiating drug therapy, it is critical to determine the type and frequency of OTC medication use. Patients with tension headaches and headaches in general frequently self-medicate and may be presenting with MOH. Again, treating more than two headaches per week for more than a few consecutive weeks can lead to development of a chronic daily headache pattern. Caffeine and butalbital products are notorious contributors to MOH. The initial treatment of MOH consists of withholding all OTC analgesics for 1 to 2 weeks.

It is also important to help identify headache triggers and to encourage a healthy lifestyle. Often, simple changes, such as eating and sleeping in a consistent pattern, decreasing alcohol and tobacco use, and using good posture, can decrease headache severity and frequency.

Adjuncts to pharmacotherapy include relaxation therapy, biofeedback, self-hypnosis, cognitive therapy, and manual therapy (massage). Data from a large meta-analysis show positive results with the use of biofeedback, particularly when combined with relaxation (Nestoriuc et al., 2008). Patients may also benefit from acupuncture or cervical physical therapy in the case of chronic tension headaches.

Headache sufferers (TTH and migraine) use a substantial amount of complementary and alternative medicine (CAM) for the self-management of headache. The alternative approaches include acupuncture, chiropractic, massage, yoga, homeopathy, and use of dietary supplements such as herbal compounds and vitamins. In one large literature review, some 30% to 70% of CAM users report the therapy to be effective. Most practitioners use CAM as adjunctive therapy to pharmacotherapy, rather than prior to or after treatment with medications. While there have been some studies on the efficacy of CAM, they are methodologically weak. Further, many patients are using CAM therapies concomitantly with conventional treatment and may not report its use to the health care practitioner. Health care practitioners should be vigilant and inquire about CAM use, to anticipate and avoid any potential adverse reactions (Adams et al., 2012).

Goals of Drug Therapy for Tension Headaches

The primary goals of drug therapy should be to reduce the severity and frequency of headaches, thus improving the patient’s quality of life and ability to function. The goals for patients with episodic tension headaches are to select appropriate analgesic agents that will have the fewest side effects. Prophylactic therapy should be considered in addition to abortive analgesic agents for patients with more than two significant headaches per week. In a patient with MOH, it is appropriate to start a prophylactic agent and abruptly stop abortive analgesic medications simultaneously (other than barbiturate drugs, which must be tapered). It is important to educate patients about MOH and to limit the use of analgesics to 2 days per week. Again, regular and frequent treatment with analgesics may cause development of chronic headache. It is important that patients do not overuse analgesics, as this is likely to interfere with the efficacy of preventive treatment (ICHD-3, 2013).

Acetaminophen and Aspirin

Acetaminophen at a dose of 1,000 mg can be very effective in treating mild to moderate tension headaches, although given the hepatotoxic qualities of the drug, a U.S. Food and Drug Administration (FDA) advisory committee in 2009 voted to lower the recommended single dose to 650 mg (making 1,000-mg tablets available by prescription only) and to lower the maximum daily limit from its presently recommended 4,000 to 3,250 mg (Schilling et al., 2010). Consequently, in 2011, McNeill Consumer Healthcare lowered the maximum recommended dose of Tylenol and increased the dosing interval for some of their OTC medications (DIH, 2014). Injectable acetaminophen carries a black box warning as of 2013 for potential liver failure, transplant, and death (DIH, 2014). The advantages of acetaminophen are that it is well tolerated and has few drug-drug interactions and side effects. Acetaminophen should be avoided in patients with heavy alcohol consumption, alcoholic liver disease, or chronic liver disease, as the drug is metabolized through the liver. Consumption of three or more alcoholic drinks a day in conjunction with acetaminophen use can have hepatotoxic effects. Chronic use of acetaminophen or use of acetaminophen at high doses can cause liver damage, particularly in older persons; the leading cause of acute liver failure in the United States is acetaminophen overdose (and the leading drug overdose seen in emergency departments is with acetaminophen). Acetaminophen overdose is often accidental; patients need to be cautioned not to exceed 4,000 mg/d and to take care not to take other acetaminophen-containing medications in the same day (Schilling et al., 2010). Prolonged use of acetaminophen and aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided.

Aspirin can also alleviate mild to moderate tension headaches. It inhibits prostaglandin synthesis via nonspecific and irreversible deactivation of both cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2), reducing the inflammatory response and platelet aggregation. Contraindications to aspirin use include a history of bleeding disorders, asthma, and hypersensitivity to salicylates or NSAIDs. Patients should avoid combining aspirin with other NSAIDs because decreased serum concentrations of NSAIDs result when these drugs are used together. The most common adverse effects associated with aspirin are gastrointestinal in nature, such as nausea, vomiting, or heartburn. Aspirin has also been recommended as first-line treatment for TTH and migraine, regardless of headache severity (Lampl et al., 2012).

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs work well for moderate tension headaches. They work by selectively inhibiting COX-2, responsible for prostaglandin synthesis, thereby reducing inflammation. These drugs take effect in 30 to 60 minutes, similar to aspirin and acetaminophen. Commonly used NSAIDs for the management of TTH include ibuprofen, naproxen, ketoprofen, diclofenac, and indomethacin.

Common side effects of NSAIDs are abdominal cramps, nausea, indigestion, and even headache. Occasionally, these drugs cause peptic ulcers and GI hemorrhage. Many NSAIDs contain boxed warnings about cardiovascular effects, GI effects, and/or use in patients with renal impairment. COX-2-specific inhibitors are not indicated specifically for headache, but are indicated for acute pain and have shown efficacy in stabbing headache (Ferrante et al., 2010) and migraine (Wentz et al., 2008). Its specificity for COX-2 tends to decrease GI effects, but COX-2 inhibitors also carry black box warnings, particularly for cardiovascular events.

Any given NSAID should be tried in a patient twice before deciding whether it is successful or not. It is not uncommon for a patient to respond poorly to one NSAID and extremely well to another. Route of administration may also be a consideration to improve NSAID response (Barbanti et al., 2014).

Antiemetic Agents

Although patients with tension headaches rarely suffer from nausea, antiemetic agents can augment the pain-relieving properties of analgesics by decreasing gastric emptying, therefore improving analgesic absorption (Barbanti et al., 2014). Commonly used antiemetics are promethazine and prochlorperazine. These medications can be sedating and have numerous other potential side effects, including rare but serious neurologic and bone marrow effects. Promethazine carries a boxed warning for use in children 2 years old and younger and for its injectable formulation. Prochlorperazine carries a boxed warning for use in older patients with dementia-related psychosis who are being treated with antipsychotics (DIH, 2014). Patients should be educated about these possible effects before starting on these medications and should be encouraged to use them sparingly.

Other Abortive Agents

For patients whose headaches do not respond to the above agents, certain combination agents can be considered. Some patients have a good response to OTC agents containing acetaminophen, aspirin, and caffeine (such as Excedrin Extra Strength). However, these agents have a high rate of analgesic MOH when used regularly and should not be used more than 1 to 2 days per week.

Prescription combinations that can be used include butalbital/acetaminophen/caffeine (Fioricet and others) and butalbital/aspirin/caffeine (Fiorinal and others). Butalbital is a barbiturate, which is sedating and potentially habit forming; these medications should not be used in patients with a history of substance abuse. Fiorinal and Fioricet very commonly cause MOH and should not be used for more than 3 days per month. If a patient is taking many butalbital-containing pills per day, they must be slowly tapered to avoid withdrawal symptoms. Patients taking these medications should be closely monitored.

Combination acetaminophen/narcotic products such as Vicodin and Percocet are not recommended; FDA has recommended their removal from the market or an inclusion of a black box warning if the drugs remain on the market (FDA, 2009). Opioid- or butalbital-containing medications should not be prescribed as first-line treatment for recurrent headache disorders (Loder et al., 2013). Table 38.1 gives an overview of selected drugs used to abort TTH.

TABLE 38.1 Overview of Selected Drugs to Abort Tension-Type Headaches

Generic (Brand) Name and Dosage

Selected Adverse Events


Special Considerations

acetaminophen (Tylenol) 325-650 mg q4h-6h limit dose to 3,250 mg/d

Severe hepatotoxicity on acute overdose, potential liver damage w/ chronic daily dosing, nephrotoxicity, agranulocytosis, rash (including potentially fatal Stevens-Johnson syndrome)

Chronic alcohol use, alcoholic liver disease, impaired liver or renal function, G6PD deficiency

Avoid using w/ alcohol

aspirin 325-650 mg q4h-6h, not to exceed 4,000 mg/d

GI upset (stomach pain, nausea, heartburn, vomiting); GI bleeding and angioedema (uncommon)

Platelet or bleeding disorders, renal dysfunction, erosive gastritis, peptic ulcer disease, asthma, rhinitis, nasal polyps, severe hepatic or renal failure, or sensitivity to salicylates

Avoid using w/ NSAIDs, alcohol, during pregnancy, and in children <16 y with viral infections; discontinue 1-2 wk prior to surgery


ibuprofen (Advil)

200-400 mg q4h-6h, not to exceed 1,200 mg/d; under clinical supervision not to exceed ≤2,400 mg/d

Note: Use lower doses in patients w/ renal or hepatic disease

3%-9%: Dizziness, rash, epigastric pain, heartburn, nausea, tinnitus

WARNING: NSAIDs are associated with an increased risk of adverse cardiovascular thrombotic events, including MI, stroke, and new onset or worsening of pre-existing hypertension. Use is contraindicated for treatment of perioperative pain in the setting of CABG surgery.

Recent GI bleed, third trimester of pregnancy, renal disease

Use w/ caution if history of CHF, HTN, GI bleeding; monitor for anemia w/ long-term use; older persons are at increased risk for AEs even at low doses; withhold for at least 4-6 half-lives prior to dental or surgical procedures; may increase risk of GI irritation, inflammation, ulceration, bleeding, and perforation

naproxen (Aleve)

Initial: 500 mg, then 250 mg q6h-8h not to exceed 1,250 mg/d

Note: Enteric-coated formulations not recommended for tx of acute migraine

3%-9%: Edema, dizziness, drowsiness, headache, pruritus, skin eruption, ecchymosis, fluid retention, abdominal pain, constipation, nausea, heartburn, hemolysis, tinnitus, dyspnea

Same as above, including BOXED WARNING

Same as above


25-50 mg q6h-8h

>10%: Dyspepsia, abnormal LFTs; 3%-9%: Headache, abdominal pain, constipation, diarrhea, flatulence, nausea, renal dysfunction

Same as above, including BOXED WARNING

Same as above


butalbital 50 mg, caffeine 40 mg, acetaminophen 325 mg (Fioricet)

1-2 tabs q4h, not to exceed 6 tabs/d

Note: Do not use butalbital for the management of acute migraine

Drowsiness, light-headedness, dizziness, sedation, shortness of breath, nausea, vomiting, abdominal pain, intoxicated feeling

Hepatic or renal dysfunction, peptic ulcer disease, history of substance abuse, porphyria, pregnancy, concomitant use w/ alcohol or other CNS depressants

Contains acetaminophen; use w/caution when taking other acetaminophen-containing drugs; do not exceed a total daily dose of 3,250 mg acetaminophen; may be habit forming or subject to abuse; avoid prolonged use or using w/ other sedating medications; not recommended for use in older persons

butalbital 50 mg/caffeine 40 mg/aspirin 325 mg (Fiorinal)

1-2 tabs q4h, not to exceed 6 tabs/d

Note: Do not use butalbital for management of acute migraine

Same as above

Hemorrhagic diathesis (e.g., hemophilia, hypoprothrombinemia, von Willebrand disease, thrombocytopenias, thrombasthenia and other ill-defined hereditary platelet dysfunctions, severe vitamin K deficiency, and severe liver damage); nasal polyps, angioedema and bronchospastic reactivity to aspirin or other NSAIDs; peptic ulcer or other serious GI lesions; porphyria

Use w/ caution in the debilitated; severe impairment of renal or hepatic function, coagulation disorders, head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison’s disease, or prostatic hypertrophy; not recommended for use in older persons

Prophylaxis of Tension Headaches

If a patient has more than two tension headaches per week, prophylaxis should be considered. Antidepressant medications are commonly used for headache prophylaxis. In meta-analyses, individuals with chronic headache taking antidepressants are twice as likely to report improvement of symptoms (Dharmshaktu et al., 2012). Abundant evidence exists for the efficacy of amitriptyline, with individuals experiencing relief even at low doses. Its antinociceptive effects are independent from its antidepressant effects (Yu & Han, 2015). There are data supporting the use of venlafaxine and mirtazapine, but data supporting the use of other antidepressants for headache prophylaxis (including migraine) are lacking. Smaller noncontrolled trials or case studies have shown efficacy with other tricyclic antidepressants (TCAs), such as imipramine, doxepin, and protriptyline. While there have been trials conducted on the efficacy of fluoxetine as headache prophylaxis, neither it nor the other selective serotonin reuptake inhibitors (SSRIs) have been shown to be effective as headache prophylaxis despite having a more favorable side effect profile compared with TCAs. Other antidepressants, such as monoamine oxidase inhibitors (MAOIs) and serotonin antagonists, have been studied, but safety issues and side effect profiles make them an inappropriate choice for headache prophylaxis. Antidepressants for which little support exists for the management of headache should
only be considered if the headache being treated is comorbid with depression. Alleviation or palliation of one comorbidity, however, will not necessarily resolve the other (Smitherman et al., 2011). Prophylactic medications should be started at low dosages and increased slowly. It can take 4 to 8 weeks before the full effect of these medications is seen. Finding the appropriate prophylactic agent for a patient is a process of trial and error, as medications work differently in different patients.

Amitriptyline, a TCA, is the medication most commonly used to prevent tension headaches and considered to be a first-line, gold standard drug. It can be used in doses much lower than those used for treating depression, ranging from 10 to 75 mg. Common side effects include sedation, constipation, blurred vision, and dry mouth. Amitriptyline should be used with caution in patients with a history of coronary artery disease, urinary retention, glaucoma, and seizures. Usually, only low doses of amitriptyline are needed, making discontinuation because of side effects uncommon. Higher doses of amitriptyline are typically used in headache patients with concomitant depression (Smitherman et al., 2011). Given its anticholinergic properties, amitriptyline is an inappropriate choice for use in older patients.

Second-line drugs that have been determined to be effective include venlafaxine (Effexor, a serotonin/norepinephrine reuptake inhibitor or SNRI) and mirtazapine (Remeron, a tetracyclic antidepressant) at 150 and 30 mg, respectively (Barbanti et al., 2014; Bendston & Jensen, 2011).

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Nov 11, 2018 | Posted by in PHARMACY | Comments Off on Headaches
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