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Introduction

Headaches are common and, especially when chronic, can be debilitating and impact daily living and quality of life. Approximately half of American adults have a headache as least once a year, and 1 in 7 experience migraine headaches.¹ The lifetime prevalence of headache is 96%, while the worldwide point prevalence of tension-type headache and migraine headache are approximately 40% and 10%, respectively.² As a group, neurological disorders were the leading cause of disability-adjusted life-years worldwide in 2015. The most prevalent conditions were tension-type headache (1.51 billion), migraine headache (958 million), and medication-overuse headache (59 million).³ According to the World Health Organization (WHO), migraine headache is a particularly disabling disorder because of its substantial effect on activities of daily living and quality of life.¹ Migraine headache is estimated to have caused 45 million years-lived with disability worldwide in 2016, and tension-type headache 7 million years-lived with disability in 2016.⁴ Patients often seek the advice of pharmacists to self-manage common primary headache disorders, including migraine and tension-type headaches, with nonprescription analgesics.^5,6Patients with migraine make up one-third or more of a pharmacy’s customers, according to 45% of pharmacists in one survey.⁷ Pharmacists are uniquely positioned to advise patients with common primary headache disorders to self-manage their symptoms safely with nonprescription analgesics.

Unmet Needs of Patients with Primary Headache Disorders

Case Scenario

A 33-year-old patient named Sally comes to the pharmacy counter and would like to speak to the pharmacist. She wants to know what OTC pain reliever she could take for her headaches. She has been taking 500 mg of acetaminophen occasionally, but says it no longer controls her headaches. She would like to know what might be stronger. What questions should the pharmacist ask to assess Sally’s headache?

1. What is your headache history? How long have you had these headaches and how long does each headache last? Do these current headaches feel different from others you’ve had in the past?
2. Where exactly is the headache pain felt? Is it on one side, or both sides? In what other locations is the pain felt?
3. Do you have any other symptoms, such as nausea, vomiting, fever, diarrhea, night sweats, or chills?
4. Does light, sound, or noise aggravate your headaches? What makes your headache better or worse?
5. Have you recently or in the past seen a physician or other medical provider for headaches? If so, what diagnosis and treatment did you receive?
6. Do your headaches have a gradual onset or a rapid onset?
7. Is your headache pain dull, sharp, aching, stabbing, pressure-like, pulsatile, or throbbing?
8. Have you had any recent head trauma, such as a motor vehicle accident or serious fall?
9. What other active medical conditions do you have?
10. What other medications do you take and do you have any drug allergies?

Tension-type headache and migraine headache are common examples of primary headache disorders, headaches with no known underlying cause.⁸ Headaches lead to significant disability, disrupting activities of daily living and affecting home life, work, and social activities. More than 60% of patients with migraine headache report their episodes leave them severely impaired,⁹ while more than 90% say they experience some headache-related disability.¹⁰ Headache is the most common pain-related condition that results in lost productivity in the US workforce.¹¹ The estimated annual cost of migraine and its treatment may total as much as $17 billion dollars.¹¹ Headaches are associated with deterioration in quality of life despite treatment, indicating significant unmet needs of patients with available therapies.^{1, 12-14}

More than half of patients who experience headache do not self-report having a medical diagnosis.⁹ A 2015 survey conducted by WebMD showed that 46% of respondents choose to “tough out” their headaches.¹⁵ This is contrary to general medical advice and may cause the person to experience avoidable headache pain and its consequences. The pharmacist can address this situation by taking proactive steps to identify patients with headache disorder.

These patients often ask questions about pain relievers and spend time searching for pain relief products. Additionally, if patients have symptoms of pain at the pharmacy, this is an opportunity for intervention, showing empathy for their condition and assessing their use of nonprescription analgesics and antiemetics. Patients may be on prescription preventive therapies (eg, topiramate), or migraine treatment medications (eg, triptans). Frequent refills of triptan medications may indicate undertreated headache. These patients may also not be adherent to their other medications because of the disabling side effects of chronic headache. Helping these patients understand that effective treatments are available is important.

Given that an estimated 60% of patients take an over-the-counter (OTC) product before making an appointment with a physician,¹⁶ the pharmacist is in an important position to help them initiate treatment or refer them to their primary care provider if appropriate.¹⁷ This is especially important since the effectiveness of nonprescription analgesics in providing sustained relief from a chronic primary headache disorder may be limited. Patients, like Sally, may experience limitations in their OTC treatment of headache. This may cause patients to escalate the dose of nonprescription analgesics as they search for pain relief, potentially resulting in medication-overuse headache.

Case Scenario Continued

Upon pharmacist questioning, Sally describes her headaches as occurring 2 or 3 times a week. While she is able to go to work at an office, concentrating at the computer can be difficult with the pain. The headaches tend to come on after she has been at work for several hours or focused on projects at her computer. She says they consist of a dull ache around most of her head and can last several hours. She further describes her headaches as feeling like “hatband-like pressure” and equal in intensity, bilaterally. She takes 500 mg of acetaminophen every 4 hours to try to relieve the pain. The last couple weeks it has not been helping. Sally denies a history of head trauma, does not have any other medical conditions, and does not take other medications. She denies any systemic symptoms and has no drug allergies. Sally denies that light aggravates her headache (photophobia), and her headaches do not worsen with sound (phonophobia). How would Sally’s headaches be classified?

Identifying Common Primary Headache Disorders

Headaches are classified as primary or secondary according to the International Classification of Headache Disorders (ICHD) 2018. Primary headaches are not caused by underlying illness. ICHD further classifies primary headaches as tension-type headache, migraine, trigeminal autonomic cephalalgias, or other primary headache disorders. Secondary headaches are associated with an underlying condition (eg, head injury or trauma, infection, stroke, substance withdrawal, or facial or cranial disorders).⁸ Medication-overuse headaches are considered secondary by ICHD although they are not caused by an underlying disease (but are attributed to the withdrawal effect of analgesic medication).¹⁸

Tension-type headaches often are caused by stress, depression, anxiety, emotional conflicts, or other stimuli. They are sometimes called stress headaches and may result from pericranial muscle contraction.⁸ Patients experience bilateral symptoms that may be over the top of the head to the neck and vary from diffuse ache to tight, pressing, and constricting pain. They have gradual onset and may last minutes to days. They are not accompanied by nausea or vomiting but may have either mild photophobia or phonophobia.⁸ Routine physical activity such as walking or climbing stairs does not aggravate the headache.⁸ Tension-type headaches may be episodic or chronic. Episodic headaches occur less than 15 days per month. Chronic headaches occur 15 or more days per month for at least 3 months.⁸

Migraine headaches may also be episodic or chronic and may occur with or without aura. Aura is a series of sensory disturbances that happen shortly before a migraine attack.⁸ They are caused by a complex interaction of vascular and neuronal factors. Some describe patients who suffer from constant migraines to have an over-sensitive brain.¹⁹ As the frequency of migraine episodes increases, the time for neurologic recovery between attacks is less distinct, causing increased sensitivity to stimuli that may trigger further headaches.¹⁹ Common migraine headache triggers include:¹⁸

• Stress
• Fatigue
• Irregular sleeping patterns
• Skipping or missing meals
• Food substances
• Caffeine
• Alcohol
• Hormonal changes
• Weather changes, especially barometric pressure
• Altitude
• Light, odors, and other sensory stimuli
• Neck pain
• Exercise
• Medications (eg, oral contraceptives or postmenopausal hormones)

Auras may precede a migraine headache.⁸ Examples include:

• Visual phenomena, such as seeing various shapes, bright spots, or flashes of light
• Vision loss
• Pins and needles sensations in an arm or leg
• Weakness or numbness in the face or one side of the body
• Difficulty speaking
• Hearing noises or music
• Uncontrollable jerking or other movements

A migraine headache may last hours to several days if left untreated. They are usually unilateral, with throbbing or pulsing on one side of the head. They are often accompanied by sensitivity to light, sound, and sometimes smell and touch, as well as nausea and vomiting. Patients usually experience fatigue after an episode.¹⁸

A useful, validated tool that can be used by pharmacists and patients to help determine if they have migraine headaches is called the ID Migraine.^20,21 The questions include:

• Has a headache limited your activities for a day or more in the last 3 months?
• Are you nauseated or sick to your stomach when you have a headache?
• Does light bother you when you have a headache?

Medication-overuse headaches result from excessive use of analgesics, which is thought to cause a change from episodic headaches to chronic headaches. Medication-overuse headaches occur as a “rebound phenomenon” from repeated (more than twice a week for 3 months or longer) and excessive use of analgesics for episodic headache disorder. Within hours of stopping the medication, headache usually occurs and readministration of the analgesic provides relief.²² Medication-overuse headaches can be associated with use of nonprescription products: acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen, and caffeine. Prescription medicines that may be associated with medication-overuse headache include triptans, opioids, butalbital, and ergotamine products.¹⁸

Identifying Patients for Self-Treatment of Headache

Many patients who suffer from headache can attain meaningful relief and reduction in headache frequency, intensity, and duration with proper medical management. This includes educating patients about headache types, causes, and treatments.

There are 2 useful tools that can assist the pharmacist in assessing whether a patient experiencing headache is a candidate for self-treatment:

• Four-Question Assessment Tool for Patients with Headache²³
• SNOOP: Systemic symptoms, neurologic symptoms, onset, older, previous headache²⁴

The first tool uses a series of questions to determine the extent headache impacts daily living, to distinguish headache type and frequency, and to learn what OTC products the patient has already tried. The 4-question assessment is in Table 1. The presence of nausea, photophobia, pulsating pain, or headache that worsens upon exertion points to migraine vs tension-type headache.⁸ Learning what medications the patient has tried and the frequency of their headache will also help the pharmacist make a decision whether to refer the patient to their primary health care provider for further assessment and possible preventive and prescription therapies. If patients indicate more than half of their headaches are disabling or that more than 20% of their migraines are accompanied by vomiting, they should be referred to their primary care provider.²³

When assessing patients who present with headache, it is also important to identify any warning features suggestive of secondary headache disorder or another cause. The mnemonic SNOOP (systemic symptoms/signs and disease, neurologic symptoms or signs, onset sudden or onset after the age of 40 years, and change of headache pattern) is a red flag detection tool for secondary headaches.²⁵ Refer to Table 2.

High blood pressure may be associated with headache, although studies are not conclusive.²⁶ The American Heart Association maintains that people do not usually experience headaches when their blood pressure is high unless it exceeds 180/120 mm Hg.²⁷ Pharmacists may recommend patients maintain a blood pressure measurement log and should check blood pressure when appropriate during patient assessment. Severe head pain, headaches that persist more than 10 days with or without treatment, high fever or signs of serious infections, history of liver disease or consumption of ≥ 3 alcoholic drinks per day, or headache occurring in the last pregnancy trimester or in patients < 8 year of age should not be self-treated.¹⁸

Applying these tools enables the pharmacist to determine the true nature of a patient’s headache, establish pertinent clinical information, and recommend the best course of action, including whether the patient should be under a physician’s care.

Case Scenario Continued

Based upon pharmacist questioning, Sally’s signs and symptoms are consistent with tension-type headache, which occurs 10 to 12 days a month. There are no red flags indicating she requires urgent medical attention. Her blood pressure is normal, and she does not have any significant past medical history. Sally also tells the pharmacist that she has not talked with her primary care provider about her headaches. While she may require medical attention at some point, Sally seems like a reasonably good candidate for OTC treatment with follow-up from her primary care provider if her headaches persist. What nonpharmacologic interventions could the pharmacist recommend?

Headache Treatment Goals

The goals of treating headache are to:¹⁸

• Reduce the severity and alleviate acute pain;
• Restore normal functioning;
• Prevent relapse; and
• Minimize medication-related side effects.

For patients with chronic headache, reducing the frequency of headache is an additional goal. Focusing on functional goals in addition to pain relief is important. For patients that suffer from chronic headache, it is important for the pharmacist to collaborate with the patient’s primary care provider and/or headache specialist. Utilizing the Pharmacists Patient Care Process is a useful framework for collaboration. In this process, “the pharmacist develops an individualized patient-centered care plan in collaboration with other health care professionals and the patient or caregiver that is evidence-based and cost effective. This process includes establishing a care plan that addresses medication-related problems and optimizes medication therapy.” See https://jcpp.net/patient-care-process/ for more detail.²⁸ In chronic headache, it is important to establish a strong patient relationship so that both the patient and pharmacist have responsibilities and shared goal development and decision-making. The patient may need to keep headache logs/diaries and monitor how treatments are working. The pharmacist should listen, validate the patient’s communication about their disease, and provide continued treatment recommendations as appropriate.¹⁹ The treatment spectrum includes providing patient education and support, discussing nonpharmacologic and pharmacologic options, ongoing assessment, and referral as appropriate.

Nonpharmacologic Treatment

Providing patient education and support allows patients to begin self-management. For chronic tension-type headache or migraine, understanding triggers can help patients make lifestyle modifications to address them. Lifestyle factors that are worth exploring include:^19,20

• Regular meal times and eating healthy food
• Good sleep hygiene and consistent sleep and wake times
• Daily exercise
• Stretching and strengthening head and neck muscles
• Maintaining or regaining normal weight
• Daily activities that provide fun and distraction from problems

Behavioral therapies may be helpful for patients with chronic headache. Biofeedback is a process that may bring involuntary physiological functions under voluntary control.¹⁹ Components include:

• Relaxation training to assist with a physiological break from the nervous system’s fight or flight response;
• Behavioral retraining to stop unhealthy thought patterns and behaviors that may provoke a headache and focus on protective thoughts that may elevate headache threshold; and
• Physiological recalibration where use of deep relaxation techniques are used to help patients revisit and/or reinterpret traumatic events associated with chronic headache

Additionally, ice or cold packs may help some patients obtain relief from acute headache pain.¹⁸

Medications for Tension-Type and Migraine Headache

Treatment may be acute or preventive. Acute treatments stop a tension-type headache or migraine attack that is in progress. These agents work best when taken early in the headache’s onset. Patients should be advised to have 2 acute agents on hand, one as their first-line treatment and another to use if their first choice fails. Patients who have received an acute agent need to treat 2 to 3 attacks with it to determine efficacy. If the drug fails to provide relief in at least 2 attacks, the patient should be switched to another acute agent. Patients who fail multiple acute agents or who use their acute medication more than 3 days a week should be referred to the patient’s primary care provider, or headache specialist.²³

Nonprescription analgesics, including acetaminophen, NSAIDs, and salicylates often relieve pain associated with tension-type headache and mild-to-moderate migraine headache when taken at onset of symptoms. Combination products containing acetaminophen, aspirin, and caffeine are effective first-line abortive treatments as well. Some patients who suffer from migraine may be able to predict them based on identified triggers, such as hormonal changes during menstruation or barometric pressure changes. If so, patients should take an analgesic preemptively.

If nonprescription products fail to meet treatment goals, especially for chronic headache, prescription acute therapies are available. Research demonstrates that migraine-specific medications, including triptans and dihydroergotamine, are the most effective agents for moderate-to-severe migraine attacks.²³ Even when acute therapy is effective, approximately 38% of patients with migraine headache need preventive therapy based on the number of headache days they experience each month and the level of impairment associated with the headache, yet only 13% receive it.²⁹ Adherence can be problematic, however, for patients who have been prescribed preventive therapies.^29,30 Newer therapies, such as oral calcitonin gene-related peptide (CGRP) receptor antagonists are also approved for acute migraine treatment, such as Ubrelvy (ubrogepant) and Nurtec ODT (rimegepant).

Prescription therapies used for preventing frequent episodic migraine headache include:¹⁹

• Neuromodulators: topiramate, sodium valproate, and gabapentin;
• Beta-blockers: propranolol, timolol, metoprolol, atenolol, and nadolol;
• Antidepressants: amitriptyline, nortriptyline, and protriptyline;
• Triptans: frovatriptan, zolmitriptan, and naratriptan for menstrual-related migraines; and
• CGRP inhibitors: Aimovig (erenumab-aooe), Ajovy (fremanezumab-vfrm), Emgality (galcanezumab-gnlm), Vyepti (eptinezumab-jjmr)

FDA-approved treatments are bolded. Those with established evidence of effectiveness (Level A) include: topiramate, sodium valproate, propranolol, timolol, metoprolol, and frovatriptan for menstrual-related migraine.³⁰ The neuromodulators mechanism of action is thought to be reduction of neuronal hyperexcitability through a number of ways, including augmentation of GABA.¹⁹ Beta-blockers are thought to work by reducing signaling to the somatosensory cortex through beta-1 adrenergic activity.¹⁹ Triptans are 5-HT1 receptor agonists that cause vasoconstriction and reduce inflammation associated with antidromic neuronal transmission.³¹

FDA-approved prescription preventive therapies for chronic migraine include onabotulinumtoxinA injection and the CGRP inhibitors. OnabotulinumtoxinA paralyzes muscle and injections are carefully placed based on clinical studies. It has established efficacy evidence for chronic migraine (AAN Botulinum Neurotoxin GLs 2016). CGRP inhibitors target a protein in the brain and nervous system that plays a role in the progression and pain of migraines.³¹ The American Academy of Neurology/American Headache Society migraine prevention guidelines were released before the FDA-approval of the CGRP inhibitors so their effectiveness is not rated.

Case Scenario Continued

After pharmacist questioning, Sally responds that she has headaches 10 to 12 days a month with symptoms consistent with tension-type headaches, and occasionally experiences nausea. With this information and knowing the decreased effectiveness of nonprescription acetaminophen for Sally’s headache, what should the pharmacist recommend?

Nonprescription Treatment Options

Nonprescription analgesics for headache pain include acetaminophen, NSAIDs (ibuprofen and naproxen), salicylates (aspirin and magnesium salicylate), and often, caffeine. Table 3 lists the recommended adult dosages of these nonprescription analgesics.

Acetaminophen

Acetaminophen is thought to produce pain relief through central inhibition of prostaglandin synthesis. It is rapidly absorbed with an onset of analgesic activity approximately 30 minutes after oral administration.¹⁸ Analgesic effect lasts approximately 4 hours with the immediate-release formulation and 6 to 8 hours with the extended release. Acetaminophen is approved for use in reducing fever and relieving mild-to-moderate pain.³¹ Studies have shown effectiveness of acetaminophen 1000 mg in relieving pain, functional disability, photophobia, and phonophobia in patients with migraine and tension-type headache.³²

Acetaminophen is generally very well tolerated when used as directed. However, liver toxicity with acetaminophen may occur and is a serious, dose-dependent effect. The maximum recommended dosage is 75 mg/kg/d (adults not to exceed 4000 mg/d), although some experts recommend a 3000 mg/d maximum dosage limit, even in low-risk patients if used for more than 7 days.³² Signs associated with acetaminophen toxicity include nausea, vomiting, diarrhea, and excessive sweating. Care should be taken not to exceed this threshold by administering higher doses more frequently than recommended. In 2011 and 2012, the manufacturer of Tylenol products voluntarily reduced the maximum daily dosage for self-treatment to 3000 mg, changing the dosing interval from 2 tablets every 4 to 6 hours to 2 tablets every 6 hours. The maximum daily dosage for Regular Strength Tylenol has been reduced to 3250 mg. 

In general, patients should be advised not to exceed more than 4000 mg in 24 hours due to risk of hepatotoxicity. However, this dose may be too high for certain patients.³² Heavy alcohol use, advanced age, liver disease, and concurrent use of drugs that slow acetaminophen metabolism may increase risk of hepatotoxicity; thus, a lower total daily dose (eg, 2000 mg/d) is recommended.³² Patients should also be alerted to the fact that various products contain acetaminophen and should not be used in combination. Allergic reactions can occur and the pharmacist should counsel the patient to discontinue the medication if they experience skin reddening, blisters, or rash.¹⁸

NSAIDs

NSAIDs relieve pain through central and peripheral inhibition of cyclooxygenase (COX) with consequent inhibition of prostaglandin synthesis.³¹ NSAIDs are rapidly absorbed with an onset of analgesic activity approximately 30 minutes after oral administration. Analgesic duration is 6 to 8 hours for ibuprofen and up to 12 hours for naproxen. FDA-approved uses for nonprescription NSAIDs include reducing fever and relieving minor pain associated with headache, the common cold, toothache, muscle ache, backache, arthritis, and menstrual cramps.¹⁸

The most common side effects with NSAIDs are gastrointestinal (GI) in nature, and include heartburn, nausea, anorexia, and dyspepsia. Pharmacists should counsel patients to take NSAIDs with food, milk, or antacids to minimize potential GI side effects and to take with a full glass of liquid. Suspension formulations should be shaken thoroughly, and enteric-coated or sustained-release preparations should not be crushed or chewed. The FDA required labeling for these products to address stomach bleeding in 2010:³³

• Stomach bleeding warning:This product contains an NSAID, which may cause severe stomach bleeding.

• The chance is higher if you:
  • are age 60 or older
  • have had stomach ulcers or bleeding problems
  • take a blood-thinning (anticoagulant) or steroid drug
  • take other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others)
  • have 3 or more alcoholic drinks every day while using this product
  • take more or for a longer time than directed
• Ask a doctor before use if:

• stomach bleeding warning applies to you:

• You have a history of stomach problems, such as heartburn.
• You have high blood pressure, heart disease, liver cirrhosis, or kidney disease.
• You are taking a diuretic

• Stop use and ask a doctor if:
  • You experience any of the following signs of stomach bleeding:
    • feel faint
    • vomit blood
    • have bloody or black stools
    • have stomach pain that does not get better

Patients who ingest 3 or more alcoholic drinks per day should be cautioned about the increased risk of adverse GI events, including stomach bleeding. There is increased bleeding risk in general with NSAIDs and that is a consideration in recommending their use. NSAIDs may also decrease renal blood flow and glomerular filtration rate. Advanced age, hypertension, diabetes, atherosclerotic cardiovascular disease, and use of diuretics appear to increase the risk of renal toxicity with ibuprofen use. Patients with a history of impaired renal function, congestive heart failure, or diseases that compromise renal hemodynamics should not self-treat with NSAIDs.¹⁸

In 2015, the FDA strengthened warnings regarding the risk of heart attack and stroke for prescription and OTC NSAIDs, including ibuprofen and naproxen.³⁴ The pharmacist should counsel patients to watch for symptoms that may suggest heart attack and stroke, including chest pain, trouble breathing, weakness in one part or side of the body, or slurred speech. The risk of heart attack or stroke can occur as early as within the first weeks of using an NSAID and may extend indefinitely. The risk may increase with prolonged use of the NSAID and appears to be dose-dependent. The American Heart Association recommends that patients with cardiovascular disease or those at high risk for cardiac events avoid NSAIDs, and patients with moderate risk use them with caution.

Salicylates

Salicylates, like NSAIDs, work by inhibiting prostaglandin synthesis by inhibiting both COX-1 and COX-2 enzymes; however, salicylates do so in an irreversible manner, while NSAIDs do so reversibly.³¹ Absorption in the gut is affected by the dosage form, gastric pH, gastric emptying time, dissolution rate, and food/antacids.¹⁸ Aspirin is widely bioavailable with an onset of analgesia within 30 minutes and lasting 4 to 6 hours. FDA-approved uses for salicylates include treatment of symptoms for osteoarthritis, rheumatoid arthritis, and other rheumatologic diseases, as well as temporary relief of minor aches and pains associated with backache or muscle aches.³¹ High-dose aspirin (900-1000 mg) has been established as an effective treatment option for acute migraine.³⁵ Aspirin causes dyspepsia and GI irritation even more frequently than OTC NSAIDs. Taking aspirin with food may help to improve tolerability. There are numerous formulations available to reduce GI impact: buffered products in tablet or effervescent forms, enteric-coated products, and sustained-release products. Patients who need rapid pain relief should avoid enteric-coated aspirin because of the delay in absorption and the time to onset of analgesic effect.

Aspirin should be used with caution in patients with a history of peptic ulcer disease or those taking anticoagulant or other antiplatelet medications, and should be avoided in patients with coagulation disorders. All salicylates should be avoided in patients with a history of gout or hyperuricemia because of dose-related effects on renal uric acid handling, and in patients under 18 with viral illness due to the risk of Reye’s syndrome.³⁷ When used in high doses, the development of tinnitus may be indicative of aspirin overdose.³¹

All nonprescription analgesic and antipyretic products for adult use bear a warning about alcohol use. Use of aspirin with alcohol intake increases the risk of adverse GI events, including stomach bleeding. Patients who consume 3 or more alcoholic drinks daily should be counseled about the associated risks.¹⁸

Combination Products

Caffeine is used with analgesics for tension-type and migraine headaches. It may also have its own analgesic properties and is known to cause withdrawal headache when taken regularly. Combining caffeine with analgesics may result in better efficacy.³⁶ Pharmacists and patients should be aware that, conversely, caffeine may also be a trigger for migraines in some patients. In patients who respond favorably to caffeine, combinations with NSAIDs, aspirin, and/or acetaminophen may achieve goals of pain relief with lower doses of the individual agents. It is important to closely monitor dosing limits for combination products.

The combination of acetaminophen, aspirin, and caffeine (AAC), available as Excedrin Migraine (acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg) , was approved by the FDA in January 1998 for the temporary relief of mild-to-moderate pain associated with migraine headache.³⁷ Studies have shown that the combination of these agents is more effective in achieving pain relief than the individual components when comparable doses are used.³⁸ An investigation of the combination AAC in 1743 patients found it to be more effective than the combination of acetaminophen and aspiring and each individual agent in reaching pain relief in 2 hours.³⁹ A post hoc analysis of 172 of the study patients with severe, debilitating migraine found “that 40% of the AAC users had mild or no pain at 2 hours vs 20% for placebo.”⁴⁰

Another study compared the combination AAC product with ibuprofen and placebo among 1555 patients with a primary endpoint of pain relief 2 hours post dose.⁴¹ Both the combination ACC and ibuprofen were better than placebo in relieving pain and migraine symptoms. The AAC combination was superior to ibuprofen with earlier time to pain relief.⁴¹ A new combination OTC analgesic with 500 mg acetaminophen and 250 mg ibuprofen was approved by the FDA in February 2020 for the temporary relief of minor aches and pains due to headache, toothache, backache, menstrual cramps, muscular aches, and minor arthritis pain for adults and children ages 12 and over.⁴² The product is expected to become available in 2020.

Patient Sally has already been taking 500 mg of acetaminophen, but states it no longer controls her headaches. At this point, the pharmacist should stress the importance of the nonpharmacologic interventions and consider recommending a different OTC preparation. A combination product, such as acetaminophen, aspirin, plus caffeine, or a product containing acetaminophen plus ibuprofen could be recommended. All doses should be taken at headache onset. It is critical to educate Sally on the importance of limiting the use of OTC analgesics to no more than 2 days per week to avoid medication overuse headache. If the medication does not provide relief in at least 2 of 3 headaches, it is considered a treatment failure. Sally may need to seek further medical attention if her headaches do not resolve with OTC medication.

Summary

Pharmacists are uniquely positioned to advise patients with common primary headache disorders to self-manage their symptoms safely with nonprescription analgesics. Pharmacists are often the first, and sometimes the only, health care professional that headache patients see. It is important for the pharmacist to ask key questions using validated tools to help evaluate a patient’s condition and recommend appropriate treatment. Suggesting that patients maintain a headache diary may help with the self-management of their headaches. Identifying patients appropriate for self-treatment and screening patients for referral to their primary care provider are important roles for the pharmacist.

Key Practice Points

• Use strategies to identify patients who may be untreated or undertreated for headache
• Use validated assessment tools to learn about their headache history, determine headache type, rule out secondary headache, and find what treatments have already been tried
• Based on clinical evidence and patient experience, recommend appropriate nonprescription analgesics and combination products for patients experiencing headache
• Counsel patients on the appropriate dose, frequency and timing for nonprescription therapies and on potential side effects and actions to take if they experience them
• Refer patients appropriate for preventive therapy or with chronic migraine to their primary care provider for treatment
• Stay current on headache guidelines through the American Headache Society: americanheadachesociety.org.

REFERENCES

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