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Chapter 5: Headache
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Authors: Julie J. Wilkinson, Katherine TrompJulie J. Wilkinson, Katherine Tromp

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Headache is an important cause of pain and disability worldwide. The prevalence of

migraine headache is 1.04 billion; for tension-type headache, the rate is 1.89 billion.1
Tension headache is much more common, but migraine is more severe. Migraine is
the second leading cause of disability globally.1 Worldwide, 50% of the population
has suffered from headache within the previous year, and among persons afflicted
with headache, 30% had migraine.2 Headaches caused by sinus congestion and
those resulting from the overuse of analgesics also are common.

Headaches generally are classified as primary or secondary. Primary headaches

(approximately 90% of headaches) are not associated with an underlying illness.
Examples are episodic and chronic tension-type headaches, migraine headache with
and without aura (sensory disturbances), and cluster headaches. Secondary
headaches are symptomatic of an underlying condition, such as head trauma,
stroke, substance abuse or withdrawal, bacterial and viral diseases, and disorders of
craniofacial structures. Medication overuse headaches are considered a complication
of the underlying headache disorder and are related to a withdrawal effect of
medications.3 Cluster headaches and secondary headaches are not discussed in this
chapter because they are not amenable to self-care management.

Tension-type headaches, also called stress headaches, can be episodic or chronic.

Chronic headaches occur 15 or more days per month for at least 3 months, whereas
episodic tension-type headaches occur less than 15 days per month.3Episodic
tension-type headaches are further classified as frequent episodic if at least 10
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episodes of headache occur on 1–14 days per month.3 The usual onset of tension-type
headache is during the teenage years; women are affected more commonly than
men, in a ratio of 3:2.2 Tension-type headache is generally less severe than migraine,
but it may occur more frequently, leading to substantial disability.4

Two primary types of migraine headache are recognized: with and without aura.
Migraine of either type is characterized by the presence of at least two of the
following criteria: moderate to severe head pain, unilateral pain, pulsating quality of
pain, and aggravation of pain by routine physical activity. In addition, the episode
must be accompanied by either nausea/vomiting or photophobia/phonophobia.5
Migraine with aura further includes neurologic signs and symptoms that precede or
coincide with onset of the head pain and subsequently resolve fully. The neurologic
manifestations may be visual, sensory, speech, language, or motor. Aura should be
considered in patients with or without a headache if they have at least one
neurologic sign or symptom that develops slowly during a period of at least 5
minutes, lasts for 5–60 minutes, and resolves fully. Both types of migraine may also
include a prodrome or postdrome of symptoms and signs such as hyperactivity,
hypoactivity, depression, food cravings, yawning, fatigue, and neck pain or stiffness.
A prodrome refers to one or more such signs and symptoms occurring before clinical
onset of the migraine; a postdrome is one or more manifestations emerging after
the migraine episode.3

The prevalence and impact of migraine and severe headache of other etiology in the
United States have been evaluated in several national surveys.6 Researchers found
that nearly 1 of every 6 Americans reported suffering from severe headache within a
3-month period (15.3% overall [95% CI 14.75–15.85]. The prevalence was twice as high
in females as in males (20.7% versus 9.7%). Among ethnic groups, the rate was
highest in American Indian or Alaska Natives at 18.4% and lowest in Asians at 11.3%.
The estimated rates for whites, blacks, and Hispanics were 16.6%, 15.4%, and 14.5%,
respectively. This condition is more common in younger adults without other health
conditions. Headache is the fifth most common reason for emergency department
visits, accounting for 3% of all such visits.6

Patients with a preexisting headache disorder who experience headache on 15 or

more days per month and who regularly use headache medications for longer than 3
months may be suffering from medication overuse headaches. This problem is
clinically important: Estimated frequency of medication overuse ranges from 11% to
63%.7 The available research methods are limited in their ability to clarify the effect of
the medication overuse as a factor distinct from underlying headache severity.7

Sinus headache is frequently reported in patients with acute sinusitis. These patients
also experience other sinus symptoms such as facial tenderness and pain, nasal
congestion, and nasal discharge. Although rhinosinusitis leads to pain, it does not
usually manifest as frontal head pain. If the patient is experiencing head pain while
congested, it also may be caused by migraine or tension-type headache.8

The economic impact of headache is substantial. Researchers have estimated the

burden of the disease using the measure of years of life lived with disability (YLDs).
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Migraine was found to have caused 45 million YLDs and tension-type caused 7
million YLDs worldwide in 2016.1 Most studies looking at the economic burden of
headache have focused on migraine headache. Annual direct medical costs of
migraine average $13,045 per patient.9 The combination of direct costs for medical
services and indirect costs from lost productivity and wages adds up to more than
$14 billion annually for U.S. employers.9

This chapter focuses on the most common types of headaches that are amenable to
self-treatment: tension-type, diagnosed migraine, and sinus headaches. Medication
overuse headache also is discussed, in keeping with the pharmacist’s role in
preventing this type of headache through counseling; however, this type of
headache requires a medical referral if it occurs. Nonprescription analgesics are
useful for treating headache, either in monotherapy regimens or as adjuncts to
nonpharmacologic or prescription therapy. An important category of these
medications is the class of nonsteroidal anti-inflammatory drugs (NSAIDs), which
include aspirin and other salicylates as well as ibuprofen and naproxen. Many
headache sufferers self-treat with nonprescription remedies, rather than seeking
medical attention. As much as two thirds of nonprescription analgesic use may be
for headache.10 Researchers found that 24% of patients chronically overused
medication and that only 14.5% had ever been advised by a health care provider to
limit their intake of acute headache remedies.10 Careful evaluation, counseling, and
referral for prescription-only treatments have great potential to improve quality of
life for many affected persons.

Pathophysiology of Headache
Tension-type headaches often arise in response to stress, anxiety, depression,
emotional conflicts, or other stimuli. Myofascial tissues in the pericranial area contain
nociceptors that play a role in the pathophysiology of tension-type headaches.11 The
episodic tension-type headache subtype is thought to result in pain sensed by the
peripheral nervous system, whereas the chronic subtype is thought to result from
stimuli to the central nervous system.3 A genetic component is likely in
predisposition (or resistance) to development of tension-type headaches.
Furthermore, tensiontype and migraine headaches appear to share
pathophysiologic features, making them more similar than distinct.12

Migraine headache is a neurobiologic disorder. According to current evidence-based

theory, migraine-associated pathophysiologic changes originate in the central
nervous system, rather than primarily in the vascular system. Pain pathways are
stimulated and messenger molecules are involved, including nitric oxide, serotonin,
and calcitonin gene–related peptide. The trigeminovascular system also plays a role.3
Stress, fatigue, irregular sleep patterns, fasting or missing a meal, vasoactive
substances in food, caffeine, alcohol, changes in female hormones, changes in
barometric pressure and altitude, bright lights, odor, neck pain, exercise, and
smoking all may trigger migraine.5 Medications (e.g., reserpine, nitrates, oral
contraceptives, postmenopausal hormones) also have been identified as triggers.
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The pathophysiology of migraine with aura involves neuronal depolarization that

spreads slowly across the cerebral cortex during the aura phase.13 Magnesium
deficiency may contribute to this state.14 During the headache phase, stimulation
(by an axon reflex) of trigeminal sensory fibers in the large cerebral and dural vessels
causes neuropeptide release with concomitant neurogenic inflammation,
vasodilation, and activation of platelets and mast cells.13

As mentioned previously, changes in female hormone levels may cause migraines.

Migraines related to the menstrual cycle occur in less than 10% of women and
generally are not associated with aura.3 Attacks during menstruation may have a
longer duration and feature more severe nausea. With menstrual migraine,
pathophysiologic changes are mediated by estrogen withdrawal.15Medication
overuse headache results from excessive use of analgesics, which may cause a
change from episodic headaches to chronic headaches. This type of headache is
distinct from that occurring as an adverse effect of certain medications such as
nitrates and phosphodiesterase type-5 inhibitors. Some patients who suffer from
migraine or tension-type headaches receive limited relief from analgesics and over
time may increase their use of one or more such drugs, which can lead to
development of medication overuse headaches. These headaches usually are
associated with frequent medication use (more than twice weekly) for 3 months or
longer. Onset of the headache occurs within hours of stopping the agent, and
readministration of the agent provides relief. Medication overuse headache should
be suspected if the frequency of headaches is 15 days per month or greater in
patients taking analgesics including acetaminophen, aspirin, ibuprofen, naproxen, or
prescription NSAIDs for a duration of 3 months. Headache frequency of 10 days per
month after taking triptans, opioids, ergots, or combination analgesics for 3 months
should be evaluated.16 Caffeine, butalbital, and ergotamine also may cause
medication overuse headache. Sinus headache occurs when infection or blockage of
the paranasal sinuses causes inflammation or distention of the sensitive sinus walls
(see Chapter 11). Sinus congestion may be caused by viral or bacterial infection, or by
allergic rhinitis. Pathophysiologic mechanisms at work during migraine headache
can result in prominent sinus congestion, leading to confusion about which problem
is the cause and which is the effect.

Clinical Presentation of Headache

Headaches can be differentiated by their signs and symptoms; the major defining
characteristics are listed in Table 5–1. It is important to distinguish primary from
secondary headaches because a headache can indicate a life-threatening condition.
Exclusions to self-care, shown in Figure 5–1, are important because of the seriousness
of certain disorders that manifest with headache. The severity of pain associated
with tension-type headaches is highly variable. Some headaches are so mild they do
not require treatment, whereas others are sufficiently severe to be disabling.
Episodic tension-type headaches may last a few hours, but duration up to several
days has been described. Chronic tension-type headaches often are more severe and

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frequently last for several days. The pain initially feels like pressure or tightening on
both sides of the head and subsequently may spread to feel like a band around the
head.2,3

Table 5–1 Characteristics of Tension-Type, Migraine, and Sinus Headaches

Feature Tension-Type Headache Migraine Sinus Headache

Headache

Location Bilateral Usually unilateral Face, forehead, or periorbital

area

Nature Diffuse ache, tightening, Throbbing, Pressure behind eyes or face, dull
pressing, constricting pulsating and bilateral pain

Intensity Mild–moderate Moderate–severe Mild–severe

Onset Gradual Sudden Simultaneous with sinus

symptoms

Duration 30 minutes to 7 days 4–72 hours Days (resolves with sinus

symptoms)

Aggravating Stress, anxiety Physical activity, Nasal congestion

factors light, sound

Non-headache Scalp tenderness, neck pain Nausea, Nasal congestion nasal

symptoms and muscle tension vomiting, aura discharge

Source: References 3 and 16.

Migraine headaches are classified as migraine with or without aura. Aura manifests
as a series of neurologic signs and symptoms: ocular perceptions of shimmering or
flashing areas or blind spots, visual and auditory hallucinations, muscle weakness
that usually is one-sided, and difficulty speaking (occurring rarely). These symptoms
may last up to 30 minutes, and the throbbing headache pain that follows may last
from several hours to 3 days. Of note, however, aura is not always followed by a
migraine headache. Migraines without aura begin immediately with throbbing
headache pain. Both forms of migraine often are associated with nausea, vomiting,
photophobia, phonophobia, sinus symptoms, tinnitus, light-headedness, vertigo, and
irritability and are aggravated by routine physical activity.5 Premonitory (prodrome)
signs and symptoms in migraine can be neuropsychiatric (e.g., anxiety, irritability,
yawning, emotional distress, insomnia), sensory (e.g., phonophobia, photophobia,
focusing difficulties, speech difficulties), digestive (e.g., food craving, nausea,
vomiting, diarrhea, constipation), or general (e.g., asthenia, fatigue, fluid retention,
urinary frequency). Premonitory signs and symptoms can be a feature of migraine
headaches with and those without aura.
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Medication overuse headache occurs as a rebound phenomenon after repeated and

excessive use of the implicated drug in a patient with an episodic headache disorder.
Continued overuse causes headache symptomatology to shift from the baseline
headache type to a nearly continuous headache, particularly noticeable on
awakening. Additional symptoms may include difficulty concentrating, lethargy,
irritability, and nausea.

Sinus headache usually is localized to facial areas over the sinuses and is difficult to
differentiate from migraine without aura. The pain of a sinus headache typically is
described as dull and pressure-like. Stooping or blowing the nose often intensifies
the pain, but the headache is not accompanied by nausea, vomiting, or visual
disturbances. Persistent sinus pain and/or discharge suggests possible infection and
warrants referral for medical evaluation.

Algorithm: Headache

Figure 5–1 Self-care for headache. Key: CABG = Coronary artery bypass graft; CHF =
congestive heart failure; GI = gastrointestinal; HBP = high blood pressure; HIV =
human immunodeficiency virus; NSAID = nonsteroidal anti-inflammatory drug.

Treatment of Headache
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Treatment Goals
The goals of treating headache are (1) to reduce the severity and alleviate acute pain,
(2) to restore normal functioning, (3) to prevent relapse, and (4) to minimize adverse
effects. For chronic headache, an additional goal is to reduce the frequency of
headaches.

General Treatment Approach

Most patients with episodic headaches obtain an adequate response to self-
treatment with nonpharmacologic interventions, nonprescription medications, or
both. However, some patients with episodic headaches and most with chronic
headaches are candidates for prescription treatments.

Episodic tension-type headaches often respond well to nonprescription analgesics,

including acetaminophen and NSAIDs such as salicylates, especially when taken at
the onset of the headache.16 If nonprescription analgesics are used to treat chronic
headache, frequency of use should be limited to less than 3 days per week or 14 days
per month, to prevent medication overuse headache.17 Patients with chronic
tension-type headaches may benefit from physical therapy and relaxation exercises
in addition to nonprescription or prescription medications. Figure 5–1 outlines
selfcare for headaches and lists exclusions for self-treatment.5,11,17–19

A medical diagnosis of migraine is required before self-treatment can be

recommended. First-line pharmaceutical agents for relief of migraine headache
include triptans, NSAIDs, and combinations of a triptan with acetaminophen or an
NSAID.16 Taking an NSAID, such as a salicylate, at the onset of symptoms can abort
mild or moderate migraine headache. Analgesics work best in the early stages of a
migraine. Patients with migraine who can predict the occurrence of the headache
(e.g., during menstruation) should take an analgesic before occurrence of the event
known to trigger the headache, as well as throughout the duration of the event. For
patients with coexisting tension and migraine headaches, treatment of the initiating
headache type can abort the mixed headache. Antiemetic treatment also is
indicated.16 Prophylactic therapy for migraine includes various regimens of beta
blockers, tricyclic antidepressants, calcium channel blockers, divalproex, topiramate,
or gabapentin.5

When medication overuse headache is suspected, use of the offending agent(s)

should be stopped immediately for a period of at least 1 month. Discontinuation of
the medication should be done with medical supervision because prescription
therapies may be needed to combat the increased headaches that temporarily
ensue during the days to weeks of the withdrawal period. Additionally, medication
may be needed to treat the baseline headache disorder that caused the initial
overuse of the headache medications.16

Sinus headaches respond well to oral and nasal decongestants (e.g.,

pseudoephedrine, oxymetazoline), which reduce congestion by causing

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vasoconstriction in the nasal passages (see Chapter 11). Concomitant use of

decongestants and nonprescription analgesics can relieve sinus headache pain.
Chronic congestion and sinus infections may be a sign of structural abnormalities
and indicate the need for an appropriate medical referral.

Nonpharmacologic Therapy
Patient education is an important component of self-care management of
headache. Information about the underlying diagnosis, safe medication use, and
lifestyle modification should be included to optimize the self-treatment regimen.
Keeping a headache diary for a minimum of 8 weeks to record frequency, duration,
related symptoms, precipitating factors, medications used for relief, and
menstruation schedule may improve diagnostic accuracy and medication
management.16 Acupuncture studies have yielded some evidence supporting a role
for this modality in reducing the frequency and intensity of headache. Manual
therapy offered by osteopathic physicians, chiropractors, and massage therapists has
been shown to result in short-term improvement in persons with headache.20
Adjunctive therapy for tension-type headache includes stress management and
physical therapy.5

General treatment measures for migraine include maintaining a regular schedule for
sleeping, eating, and exercise; stress management; biofeedback; and cognitive
therapy. Some patients obtain relief from the pain of acute migraine attacks by
resting in a quiet dark room and applying ice or cold packs combined with pressure
to the forehead or temple areas. Nutritional strategies are intended to prevent
migraine and are based on (1) dietary restriction of foods that contain trigger
substances, (2) avoidance of hunger and low blood glucose (a trigger of migraine),
and (3) magnesium supplementation.14,21 Advocates of nutritional therapy
recommend avoiding known food allergens and foods with vasoactive substances,
such as nitrites (found in cured meats), tyramine (found in red wine and aged
cheese), phenylalanine (found in the artificial sweetener aspartame), monosodium
glutamate (often found in Asian food), caffeine, and theobromines (found in
chocolate).21

Pharmacologic Therapy
Available nonprescription analgesics for the management of headache include
acetaminophen and NSAIDs such as ibuprofen and naproxen and especially
salicylates (aspirin and magnesium salicylate). Selection of an analgesic should be
based on a careful review of the patient’s medical and medication histories. Medical
management of nausea accompanying migraine headache also may be indicated to
improve symptomatic relief and to facilitate medication delivery by the oral route.

Acetaminophen
Acetaminophen is an effective analgesic and antipyretic. According to long-standing
hypothesis, acetaminophen produces analgesia through central inhibition of
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prostaglandin synthesis. A broader view, however, is that its mechanism of action

may be more complex, involving aspects that are not yet fully understood. Other
suggested mechanisms, for example, include descending serotonergic pathway
activation and endocannabinoid reuptake inhibition.22

Acetaminophen is absorbed rapidly from the gastrointestinal (GI) tract and

extensively metabolized in the liver to inactive glucuronic and sulfuric acid
conjugates. Acetaminophen also is metabolized by the cytochrome P450 enzyme
system to a hepatotoxic intermediate metabolite that is detoxified by glutathione.
When given by suppository, acetaminophen has a rectal bioavailability of
approximately 50%–60% of that achieved with oral administration. Onset of analgesic
activity of acetaminophen occurs approximately 30 minutes after oral
administration. Duration of activity is approximately 4 hours and is increased to 6–8
hours with an extended-release formulation.

U.S. Food and Drug Administration (FDA)-approved uses for nonprescription

acetaminophen include reducing fever and relieving mild to moderate pain. It is
effective in relieving mild to moderate pain of nonvisceral origin (i.e., pain that is not
organ-related). Randomized, double-blind studies have documented the
effectiveness of acetaminophen 1000 mg over placebo in patients with migraine and
tension-type headache.23

Recommended child and adult dosages of acetaminophen are provided in Tables 5–

2 and 5–3.24 Table 5–4 lists selected trade-name products. Acetaminophen is
available for administration in various oral and rectal dosage forms.

Table 5–2 FDA-Approved Dosages for Nonprescription Analgesics in Children Younger Than 12 Years

Dosage Ibuprofen (mg) Acetaminophen (mg)

Basics

Weight- 5–10 mg/kg 10–15 mg/kg

based
dosing

Dosing Every 6–8 hours as needed Every 4–6 hours as needed

schedule

Maximum 300 mg per dose up to 4 doses, or 480 mg per dose up to 5 doses, or

daily dose 40 mg/kg/day; not to exceed 1200 75 mg/kg/day; not to exceed 2400
mg total daily dose mg total daily dose

Specific Doses by Patient Age/Weight Ibuprofen Acetaminophen

Age Weight (lb)

Group

6–11 12–17 50 80 mga

months

12–23 18–23 75 120 mga

months

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Dosage Ibuprofen (mg) Acetaminophen (mg)

Basics

2–3 years 24–35 100 160

4–5 years 36–47 150 240

6–8 years 48–59 200 320

9–10 years 60–71 250 400

11 years 72–95 300 480

a
Labeling recommends referral to primary care provider before use.

Key: FDA = U.S. Food and Drug Administration.

Source: Reference 24.

Table 5–3 Recommended Dosages of Nonprescription Analgesics for Adults and Children 12 Years and
Older

Agent Dosage Forms Usual Adult Dosage (maximum daily dosage)

Acetaminophen Immediate-release, extended- 325–1000 mg every 4–6 hours as needed for

release, effervescent, dispersible, immediate-release products (3000 mg, or 4000
and chewable tablets; capsules; mga) 650–1300 mg every 8 hours as needed for
liquid; suppositories; powder extended-release products (3000 mg, or 4000 mga)
packet

Ibuprofen Immediate-release and chewable 200–400 mg every 4–6 hours as needed (1200 mg)
tablets; capsules; suspension

Naproxen Immediate-release and delayed- 220 mg every 8–12 hours as needed (660 mg) For
sodium release tablets, capsules initial dose: 2 tablets within the first hour

Aspirin Immediate-release, buffered, 325–1000 mg every 4–6 hours as needed (4000 mg)
enteric-coated, film-coated,
effervescent, and chewable
tablets; suppositories

Magnesium Tablets 1160 mg every 6 hours as needed (4640 mg)

salicylate

aMaximum daily dose of regular-strength (325 mg) products: 3250 mg, or 4000 mg with
supervision of HCP; extra-strength (500 mg) products: 3000 mg, or 4000 mg with supervision
of HCP; extended-release (650 mg) products: 3900 mg.

Key: FDA = U.S. Food and Drug Administration; HCP = health care provider.

Source: Reference 24.

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Table 5–4 Selected Single-Entity Nonprescription Acetaminophen Products

Trade Name Acetaminophen Content

Pediatric Formulations

FeverAll Infants’ Suppository 80 mg

FeverAll Children’s Suppository 120 mg

FeverAll Jr. Strength Suppository 325 mg

Children’s Tylenol Oral Suspension 160 mg/5 mL

Adult Formulations

Tylenol Regular Strength Tablets 325 mg

Tylenol Extra Strength caplet 500 mg

Tylenol 8 HR Arthritis Pain Extended-Release caplet 650 mg

Tylenol 8 HR Muscle Aches & Pain Extended-Release tablet 650 mg

Tylenol Cold + Sore Throat COOL BURST Liquid 500 mg/15 mL

Source: Reference 24.

Acetaminophen oral capsules contain tasteless granules that can be added to a

spoon containing a small amount of cold beverage (hot beverages result in a bitter
taste) or soft food. Capsule contents should not be combined with larger quantities
of liquid because a significant proportion of the granules may adhere to the
container surface.

Acetaminophen is potentially hepatotoxic in doses exceeding 4 g daily, especially

with chronic use. Patients should be cautioned against exceeding the dose limit.
More conservative dosing (i.e., ≤2 g daily) or complete avoidance may be warranted
in patients at increased risk for acetaminophen-induced hepatotoxicity, specifically
those with diagnosed liver disease, concurrent use of other potentially hepatotoxic
drugs, poor nutritional intake, or consumption of three or more alcoholic drinks per
day.25 One alcoholic drink is defined as 12 ounces of beer, 5 ounces of wine, or 1.5
ounces of 80 proof liquor.

FDA requires manufacturers to include a boxed warning on acetaminophen

products that addresses its potential to cause hepatotoxicity. The basic language of
the warning is as follows:

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Liver warning: This product contains acetaminophen. Severe liver damage may
occur if

an adult takes more than 4000 mg of acetaminophen in 24 hours

a child takes more than 5 doses in 24 hours, which is the maximum daily
amount
the product is taken with other drugs containing acetaminophen
an adult has three or more alcoholic drinks every day while using this product

The warning varies depending on whether the product is labeled for use in children
and/or adults. In order to decrease acetaminophen-induced hepatic injury, FDA
limited the acetaminophen content of prescription-only combination opioid
analgesics to 325 mg per dosage unit.26,27 FDA also has recommended that
manufacturers of nonprescription products lower the maximum daily dose from
4000 mg to 3250 mg per day and to limit pediatric oral dosage forms to a single
strength of 160 mg.28,29 McNeil followed this recommendation by listing a maximum
daily dose of 3250 mg for regular-release products and 3000 mg for extra-strength
products (dosing interval of every 6 hours as opposed to every 4–6 hours). However,
650-mg extended-release products have a maximum daily dose listed as 3900 mg.
Errors in dosing occur with the 650-mg extended-release formulation because
patients do not understand that they need to wait 8 hours between doses.26

Acetaminophen poisoning is a major reason for contacting poison control centers

and constitutes the leading cause of acute liver failure in the United States.30
Unintended chronic overdose accounts for approximately one half of the cases of
acetaminophen-induced acute liver failure. Researchers have documented that
significant knowledge gaps lead to incorrect dosing.31 Contributing factors include
repeated dosing in excess of package labeling, use of more than one product
containing acetaminophen, and concurrent alcohol ingestion. It is estimated that in
30% of emergency department visits for acetaminophen poisoning, the overdose
was unintentional.31

Acetaminophen toxicity evolves in four stages. Stage I includes signs and symptoms
of nausea, vomiting, drowsiness, confusion, and abdominal pain, but such early
manifestations may be absent or delayed, belying the potential severity of the
exposure. Stage II is characterized by emergence of the first symptoms of
hepatotoxicity and begins 24–48 hours after acute ingestion of acetaminophen.
Stage II signs and symptoms include increased aspartate aminotransferase (AST)
and alanine aminotransferase (ALT), increased bilirubin with jaundice, prolonged
prothrombin time, and obtundation. Stage III develops after 3 or 4 days and
progresses to liver failure in the absence of treatment. Signs and symptoms at this
stage may include metabolic acidosis, encephalopathy, cerebral edema, and renal
failure. GI symptoms may also be present during this stage. Stage IV begins 4 days
after ingestion and can last for several weeks. During this stage, in a majority of
cases, hepatic damage is reversible over a period of weeks or months, but more
severe cases may require liver transplantation or result in fatal hepatic necrosis.32

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Because of the potential seriousness of acetaminophen overdose, all cases should be

referred to a poison control center or hospital emergency department. Supportive
care is provided, along with activated charcoal to reduce acetaminophen absorption
in patients who present for treatment within 1 hour after ingestion. When
acetaminophen serum levels, with consideration of time since ingestion, exceed
those known to cause hepatic injury, prompt administration of acetylcysteine is
warranted to supplement glutathione, which is essential for deactivation of a toxic
intermediate metabolite of acetaminophen. Acetylcysteine’s effectiveness decreases
if it is administered more than 8 hours after acute ingestion. Asymptomatic
elevations in ALT have been reported in otherwise healthy persons taking
acetaminophen 4 g daily. In a prospective study, 39% of patients experienced ALT
elevations to greater than three times the upper limit of normal. These elevations
generally appeared in the first week of use, with some resolution occurring despite
continued dosing. The clinical significance of this observation is uncertain.33

Patients with glucose-6-phosphate dehydrogenase deficiency, a hereditary disease

that causes premature breakdown of red blood cells, are at increased risk for adverse
reactions to acetaminophen. It is unclear whether regular doses of acetaminophen
will cause toxicity in patients with such deficiency; however, case reports of
hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency who
took an excessive amount of acetaminophen have been recorded.34 In patients with
hypersensitivity to acetaminophen, the drug is contraindicated for future use.

Rare but serious cutaneous adverse reactions (SCARs) have been found to be
associated with use of acetaminophen as well as other analgesics including NSAIDs.
Skin reactions may occur in either new or current users of the drug and have the
potential to progress to a life-threatening rash, as in Stevens-Johnson syndrome and
toxic epidermal necrolysis. Although these events are very rare, it is important to be
aware of the possibility and to refer patients as appropriate for further evaluation.35
FDA recommends that the following language appear in the Warnings section of the
Drug Facts Label for all single-ingredient and combination-ingredient
acetaminophen products:

Allergy alert: Acetaminophen may cause severe skin reactions. Symptoms may
include

skin reddening
blisters
rash

If a skin rash occurs, stop use and seek medical help right away.35

Clinically important drug interactions for acetaminophen are listed in Table 5–5. In
patients taking warfarin, acetaminophen is considered the analgesic of choice;
however, it has been associated with increases in the international normalized ratio
(INR). Regular acetaminophen use should be discouraged in patients on warfarin.
Patients who require higher scheduled doses (e.g., those with osteoarthritis) should

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have their INR monitored and warfarin dose adjusted as acetaminophen doses are
titrated.

Table 5–5 Clinically Important Drug-Drug Interactions With Nonprescription Analgesic Agents

Analgesic/Antipyretic Interactive Potential Interaction Management/Preventive

Drug Measure(s)

Acetaminophen Alcohol Increased risk of Avoid concurrent use if possible;

hepatotoxicity minimize alcohol intake when
using acetaminophen.

Acetaminophen Warfarin Increased risk of Limit acetaminophen to

bleeding (elevations in occasional use; monitor INR for
INR) several weeks when
acetaminophen 2-4 g daily is
added or discontinued in
patients on warfarin.

Aspirin Valproic acid Displacement from Avoid concurrent use; use

protein-binding sites naproxen instead of aspirin (no
and inhibition of interaction).
valproic acid
metabolism

Aspirin NSAIDs, Increased risk of Avoid concurrent use if possible.

including COX-2 gastroduodenal ulcers
inhibitors and bleeding

Salicylates Live influenza Risk of Reye syndrome Avoid concurrent administration

virus vaccine in children and in children younger than 18 years.
adolescents

Ibuprofen Aspirin Decreased antiplatelet Aspirin should be taken at least

effect of aspirin 60 minutes before or 8 hours
after ibuprofen. Use
acetaminophen (or other
analgesic) instead of ibuprofen.

Ibuprofen Phenytoin Displacement from Monitor free phenytoin levels;

protein-binding sites adjust dose as indicated.

Salicylates and other Bisphosphonates Increased risk of GI or Use caution with concomitant
NSAIDs esophageal ulceration use.

NSAIDs Digoxin Renal clearance of Monitor digoxin levels; adjust

digoxin inhibited dose as indicated.

Salicylates and other Agents with Increased risk of Monitor therapy

NSAIDs antiplatelet bleeding
properties (SSRIs,
NSAIDs, P2Y12
inhibitors)

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Analgesic/Antipyretic Interactive Potential Interaction Management/Preventive

Drug Measure(s)

Salicylates and other Antihypertensive Antihypertensive Monitor blood pressure, cardiac

NSAIDs agents, beta effect inhibited; function, and potassium levels.
blockers, ACE possible hyperkalemia
inhibitors, with potassium-
vasodilators, sparing diuretics and
diuretics ACE inhibitors

Salicylates and other Anticoagulants Increased risk of Avoid concurrent use, if possible.
NSAIDs bleeding, especially GI

Salicylates and other Alcohol Increased risk of GI Avoid concurrent use, if possible;
NSAIDs bleeding minimize alcohol intake when
using salicylates and NSAIDs.

Salicylates and other Methotrexate Decreased Avoid salicylates and NSAIDs with
NSAIDs methotrexate high-dose methotrexate therapy;
clearance monitor levels with concurrent
treatment.

Salicylates (moderate– Sulfonylureas Increased risk of Avoid concurrent use, if possible;

high doses) hypoglycemia monitor blood glucose levels
when changing salicylate dose.

Key: ACE = Angiotensin-converting enzyme; COX = cyclooxygenase; GI = gastrointestinal; INR =

international normalized ratio;

NSAIDs = nonsteroidal anti-inflammatory drugs: SSRIs = selective serotonin reuptake

inhibitors.

Source: Reference 24.

Nonsalicylate Nonsteroidal Anti-inflammatory Drugs

NSAIDs relieve pain through central and peripheral inhibition of cyclooxygenase
(COX) with consequent inhibition of prostaglandin synthesis.

All nonprescription NSAIDs are rapidly absorbed from the GI tract, with consistently
high degree of bioavailability. They are extensively metabolized, mainly by
glucuronidation, to inactive compounds in the liver. Elimination occurs primarily
through the kidneys. Time to onset of activity for naproxen sodium and ibuprofen is
approximately 30 minutes. Duration of activity is up to 12 hours for naproxen sodium
and 6–8 hours for ibuprofen. 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. NSAIDs
have analgesic, antipyretic, and anti-inflammatory activity, and they are useful in
managing mild to moderate pain of nonvisceral origin. Ibuprofen and naproxen
sodium and became available for nonprescription use in 1984 and 1994, respectively,
and both are propionic acid derivatives. Although FDA has approved ketoprofen for

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nonprescription use, no commercially available nonprescription analgesics currently

contain this agent.

Recommended child and adult dosages of nonprescription NSAIDs are provided in

Tables 5–2 and 5–3. Table 5–6 lists selected trade-name products. Ibuprofen is
available as a liquid for pediatric use and comes in two different strengths (50
mg/1.25 mL and 100 mg/5 mL). This dual option may contribute to the potential for
dosing errors. A dose–effect relationship has been demonstrated for ibuprofen
analgesia in the range of 100–400 mg.

Table 5–6 Selected Single-Entity Nonprescription Nonsalicylate Nonsteroidal Anti-inflammatory Drugs

Trade Name Primary Ingredient

Ibuprofen Products: Pediatric Formulations

Children’s Advil Suspension Ibuprofen 100 mg/5 mL

Children’s Motrin Suspension Ibuprofen 100 mg/5 mL

Motrin Infants’ Drops Suspension Ibuprofen 50 mg/1.25 mL

Junior Strength Advil Chewable Tablet Ibuprofen 100 mg

Ibuprofen Products: Adult Formulations

Advil tablet/capsule Ibuprofen 200 mg

Motrin IB Ibuprofen tablet Ibuprofen 200 mg

Advil Migraine capsule Ibuprofen 200 mg

Naproxen Products

Aleve tablet/capsule Naproxen sodium 220 mg

Mediproxen tablet Naproxen sodium 220 mg

All Day Relief tablet Naproxen sodium 220 mg

The most frequent adverse effects of NSAIDs involve the GI tract and include
dyspepsia, heartburn, nausea, anorexia, and epigastric pain. NSAIDs may be taken
with food, milk, or antacids if upset stomach occurs. Tablets should be taken with a
full glass of water, suspensions should be shaken thoroughly, and enteric-coated or
sustained-release preparations should never be crushed or chewed. Other adverse
effects include dizziness, fatigue, headache, and nervousness. Rashes or pruritus
(itching), photosensitivity, and fluid retention or edema may occur in some patients;
at normal doses, however, these effects usually are rare.

GI ulceration, perforation, and bleeding are serious potential complications of NSAID

use. Risk factors include age older than 60 years, previous ulcer disease, concurrent

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use of anticoagulants (including aspirin), higher dose or longer duration of

treatment, and consumption of three or more alcoholic drinks per day. Product
labeling for NSAIDs includes warnings about stomach bleeding with adult doses (see
the box “A Word About NSAIDs and Stomach Bleeding”).36 Labeling for prescription
products that contain ibuprofen and naproxen includes the following warning:

NSAIDs cause an increased risk of serious gastrointestinal adverse events

including bleeding, ulceration, and perforation of the stomach or
intestines, which can be fatal. These events can occur at any time during
use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events.

NSAID use is associated with increased risk for myocardial infarction (MI), heart
failure, hypertension, and stroke. While not completely understood, the
pathophysiologic mechanism for increased cardiovascular risk includes increased
thromboxane A2 activity and suppressed vascular prostacyclin synthesis, resulting in
vasoconstriction and platelet aggregation. The cardiovascular risk associated with
nonselective NSAIDs appears to depend on dose and duration; people with
underlying risk factors such as hypertension, heart failure, and diabetes are at
greater risk. Limited data suggest that the risk may not be the same for all
nonselective NSAIDs.37

The American Heart Association recommends that patients with cardiovascular

disease or those at high risk for cardiac events (e.g., hyperlipidemia, hypertension,
diabetes, other macrovascular disease) avoid NSAIDs. Patients at low cardiac risk
should nevertheless exercise caution with use of NSAIDs by taking the minimum
dose for the shortest duration needed to control symptoms. Clinical evidence has
shown that the use of NSAIDs in patients with a history of MI is associated with an
increased risk of future cardiovascular events, extending indefinitely.38 Labeling for
prescription products that contain ibuprofen and naproxen includes the following
warning24:

NSAIDs may cause an increased risk of serious cardiovascular thrombotic

events, myocardial infarction, and stroke, which can be fatal. This risk may
increase with duration of use. Patients with cardiovascular disease or risk
factors for cardiovascular disease may be at greater risk.

Ibuprofen and naproxen tablets are contraindicated for treatment of perioperative

pain in the setting of coronary artery bypass graft (CABG) surgery. NSAIDs may
decrease renal blood flow and glomerular filtration rate through inhibition of renal
prostaglandin synthesis. Consequently, blood urea nitrogen and serum creatinine
levels can increase, often with concomitant sodium and water retention. Advanced
age, hypertension, diabetes, atherosclerotic cardiovascular disease, and use of
diuretics appear to increase the risk of renal toxicity with ibuprofen use. Congestive
heart failure may be exacerbated by the use of NSAIDs because of sodium and water
retention, increased systemic vascular resistance, and impaired response to
diuretics.39 Therefore, patients with a history of impaired renal function, congestive

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heart failure, or diseases that compromise renal hemodynamics should not self-treat
with NSAIDs.

Clinically important drug–drug interactions of NSAIDs are listed in Table 5–5.

Ibuprofen increases bleeding time by reversibly inhibiting platelet aggregation.
Patients on aspirin for cardiovascular prophylaxis should take it at least 1 hour before
or 8 hours after ibuprofen to avoid a pharmacodynamic interaction that inhibits the
antiplatelet effect of aspirin. Ibuprofen should not be recommended for self-
treatment in patients who concurrently are taking anticoagulants, because its
antiplatelet activity could increase GI bleeding. Owing to concerns regarding
decreased cardiovascular protection and increased bleeding risk, great caution is
warranted in combining aspirin and ibuprofen.

Patients who ingest three or more alcoholic drinks per day should be cautioned
about the increased risk of adverse GI events, including stomach bleeding. They also
should be referred to a primary care provider for monitoring of their NSAID use.

NSAID overdoses usually are associated with minimal signs and symptoms of toxicity
and are rarely fatal. GI manifestations are common and include nausea, vomiting,
abdominal pain, and diarrhea. The most serious effects of large NSAID overdoses
include renal failure, neurologic toxicity, and acid–base changes. Examples of specific
neurologic symptoms are drowsiness, changes in vision, headache, and confusion.
Convulsions have been reported in children who have taken an overdose of
ibuprofen. Case reports of GI bleeding also exist.40

A Word About NSAIDs and Stomach Bleeding

The following label wording is required for the FDA warning concerning
stomach bleeding for nonprescription products that contain NSAIDs in adult
doses:

Stomach bleeding warning: This product contains an NSAID, which may cause
severe stomach bleeding. The chance is higher if you

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)
take more or for a longer time than directed
are age 60 or older
have three or more alcoholic drinks every day while using this product

Ask a doctor before use if the 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.

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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

Key: FDA = U.S. Food and Drug Administration; NSAID = nonsteroidal anti-
inflammatory drug.

Source: Reference 36.

Salicylates
Salicylates inhibit prostaglandin synthesis from arachidonic acid by inhibiting both
isoforms of the COX enzyme (COX-1 and COX-2). The resulting decrease in
prostaglandins reduces the sensitivity of pain receptors to the initiation of pain
impulses at sites of inflammation and trauma. Although some evidence suggests
that aspirin also produces analgesia through a central mechanism, its site of action is
primarily peripheral.

Salicylates are absorbed by means of passive diffusion of the nonionized drug in the
stomach and small intestine. Factors affecting absorption include dosage form,
gastric pH, gastric emptying time, dissolution rate, and the presence of antacids or
food. Absorption from immediate-release aspirin products is complete. Rectal
absorption of a salicylate suppository is slow and unreliable, as well as proportional
to rectal retention time.

Once absorbed, aspirin is hydrolyzed in the plasma to salicylic acid in 1–2 hours.
Salicylic acid is widely distributed to all tissues and fluids in the body, including
central nervous system tissue, breast milk, and fetal tissue. Protein binding is
concentration-dependent. At concentrations lower than 100 mg/mL, approximately
90% of salicylic acid is bound to albumin, whereas at concentrations greater than
400 mg/mL, approximately 75% is bound. Salicylic acid is largely eliminated through
the kidney. Urine pH determines the amount of unchanged drug that is eliminated,
with urinary concentrations increasing substantially in more alkaline urine (pH ~8).

Dosage form alterations include enteric coating, buffering, and sustained release.
These formulations were developed to change the rate of absorption and/or to
reduce the potential for GI toxicity. Enteric-coated aspirin is absorbed only from the
small intestine; its absorption is markedly slowed by food, which is attributed to
prolonged gastric emptying time. Hypochlorhydria from acid-suppressing agents
(especially proton pump inhibitors) may result in dissolution of enteric-coated
products in the stomach, negating any potential benefit in preventing local gastric
irritation. For patients requiring rapid pain relief, enteric-coated aspirin is
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inappropriate because of the delay in absorption and time to onset of analgesic

effect.

Buffered aspirin products are available in both tablet and effervescent forms.
Although buffered products are absorbed more rapidly than nonbuffered products,
time to onset of effect is not improved appreciably. Common buffers include
aluminum hydroxide; magnesium carbonate, hydroxide, or oxide; calcium carbonate;
and sodium bicarbonate (in effervescent formulations). Some effervescent aspirin
solutions contain large amounts of sodium and must be avoided by patients who
require restricted sodium intake (such as those with hypertension, heart failure, or
renal failure). Sustained-release aspirin is formulated to prolong duration of action by
slowing dissolution and absorption. Other salicylates approved for nonprescription
use are magnesium salicylate and sodium salicylate. Currently, sodium salicylate is
not available in a commercial product; however, magnesium salicylate is available as
a tablet.

FDA-approved uses for salicylates include treatment of symptoms for osteoarthritis,

rheumatoid arthritis, and other rheumato-logic diseases, as well as temporary relief
of minor aches and pains associated with backache or muscle aches. Salicylates also
are effective in treating mild to moderate pain from musculoskeletal conditions and
fever.

Because of its inhibitory effects on platelet function, aspirin is also used for
prevention of thromboembolic events (e.g., MI, stroke) in high-risk patients. Unlike
with the NSAIDs previously discussed, this inhibitory effect is irreversible for aspirin.
Thus, the inhibition continues for the duration of the platelet’s life. With NSAIDs, the
duration of inhibition depends on factors such as dose, serum level, and half-life.
Aspirin’s use for prophylaxis against MI and other forms of ischemic cardiovascular
disease must be guided by a primary care provider. In March 2019, the American
College of Chest Physicians and the American Heart Association issued a Guideline
on the Primary Prevention of Cardiovascular Disease.41 The guideline provides
evidence-based recommendations for decreasing the risk of developing
atherosclerotic cardiovascular disease (ASCVD). Adults aged 40–75 years should be
screened to determine their estimated 10-year risk of developing ASCVD. Online risk
assessment tools are available to quantify this risk
([Link]

The use of aspirin for ASCVD prevention is discussed in the guideline. On the basis of
recent findings, the guidelines state that aspirin use for primary prevention is not
recommended for most patients. For some patients at high risk for development of
ASCVD coupled with a low risk for bleeding, the use of low-dose aspirin (75–100 mg
orally daily) may be recommended. Patients older than age 70 are at increased risk
for bleeding and should not routinely receive aspirin for primary prevention, nor
should patients of any age identified as being at increased risk for bleeding.

The decision to use low-dose aspirin for primary prevention must consider risk
factors for developing a cardiac event and risk factors for bleeding. The guideline
includes a list of factors that may favor the use of aspirin including family history of
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early MI; inability to achieve goals for lipids, blood pressure, or glucose; or significant
elevation of coronary artery calcium score. The guideline also includes a list of factors
that may signify a greater risk of bleeding from aspirin, including a history of GI
bleeding or peptic ulcer disease, bleeding at other sites, age older than 70 years,
thrombocytopenia, coagulopathy, chronic kidney disease, use of medications that
increase the risk of bleeding such as NSAIDs, steroids, direct oral anticoagulants, and
warfarin. As noted by the guideline authors, these lists are not exhaustive, however,
and a careful patient-specific analysis of the potential risks and benefits must
include consideration of the patient’s understanding of the decision.41
Recommended child and adult dosages of nonprescription salicylates are provided
in Tables 5–2 and 5–3. Table 5–7 provides selected salicylate products. Aspirin
dosages of 4–6 g daily usually are needed to produce anti-inflammatory effects. The
maximum analgesic dosage for self-medication with aspirin is 4 g daily; therefore,
anti-inflammatory activity often will not occur unless the drug is used at the high
end of the acceptable dosage range.

Table 5–7 Selected Adult Formulations of Nonprescription Single-Entity Salicylate Products

Trade Name Primary Ingredient

Bayer Low-Dose Aspirin tablet Aspirin 81 mg

St. Joseph Chewable Aspirin 81 mg tablet Aspirin 81 mg

Ecotrin Enteric-Coated tablet Aspirin 325 mg

Bayer Aspirin Delayed Release tablet Aspirin 325 mg

Bayer Plus Extra Strength tablet Aspirin 500 mg

DeWitts Pain Reliever tablet Magnesium salicylate 325 mg

Extra Strength Doan’s tablet Magnesium salicylate tetrahydrate 580

mg

Percogesic Maximum Strength Backache Relief Coated Magnesium salicylate tetrahydrate 580
caplet/tablet mg

Aspirin is known to commonly cause dyspepsia, which may be minimized by taking

it with food. In addition, aspirin is associated with development of gastritis and
ulceration of the upper GI tract. It produces GI mucosal damage by compromising
the protective mucous and bicarbonate layers of the gastric mucosa, thereby
permitting back-diffusion of acid, with consequent cellular damage and vascular
erosion. Two distinct mechanisms are involved: (1) a local irritant effect resulting
from contact of the medication with the gastric mucosa and (2) a systemic effect
from prostaglandin inhibition. Lack of upper abdominal pain or discomfort is not a
reliable indicator for the absence of GI damage associated with use of NSAIDs.43,44

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The use of aspirin has been shown to increase the risk for serious upper GI events
two- to fourfold.43 Patients with risk factors for upper GI bleeding should avoid self-
treatment with aspirin. Recognized risk factors are (1) history of stomach bleeding or
ulcers; (2) age older than 60 years; (3) concomitant use of NSAIDs, anticoagulants,
antiplatelet agents, or systemic corticosteroids; (4) infection with Helicobacter pylori;
(5) consumption of three or more alcoholic drinks per day; and (6) use for longer than
directed.36,45 Use of aspirin products with enteric coating may reduce the impact of
local gastric irritation. However, presence of enteric coating or buffering does not
decrease the risk of serious GI toxicity because it is caused by a systemic effect of
reduced production of prostaglandins that are important in maintaining the
protective lining of the GI tract.

Serious aspirin intolerance is uncommon and consists of two types: cutaneous

(manifesting as urticaria and angioedema) and respiratory (manifesting as
bronchospasm, laryngospasm, and rhinorrhea). The mechanism is not
immunologically mediated. Risk factors for serious aspirin intolerance include
chronic urticaria for the cutaneous type and asthma with nasal polyps for the
respiratory type. Ten percent of people diagnosed with asthma have aspirin
sensitivity.46 The degree of intolerance is variable, ranging from minor to severe.
Patients with aspirin intolerance generally are advised to avoid NSAIDs. However, the
nonacetylated salicylates (magnesium salicylate) and acetaminophen are
considered safe.46

Nonprescription salicylates interact with several other important drugs and drug
classes. Clinically important drug interactions of salicylates are listed in Table 5–5.
When monitoring therapy in patients who are taking high-dose salicylates, health
care providers should review current drug interaction references for newly identified
interactions.

Aspirin ingestion may produce a positive result on fecal occult blood testing, so its
use should be discontinued at least 3 days before testing. Similarly, aspirin should be
discontinued 2–7 days before surgery and should not be used to relieve pain after
tonsillectomy, dental extraction, or other surgical procedures, except under the close
supervision of a primary care provider. Aspirin can potentiate bleeding from
capillary-rich sites such as the GI tract, tonsillar beds, and tooth sockets.

Because of its effect on hemostasis, aspirin is contraindicated in patients with

hypoprothrombinemia, vitamin K deficiency, hemophilia, history of any bleeding
disorder, or history of peptic ulcer disease. In patients with compromised renal
function, renal excretion of magnesium may be decreased, allowing accumulation of
toxic levels with regimens including magnesium salicylate. The maximum 24-hour
dose of magnesium salicylate delivers 400 mg of magnesium.

All salicylates should be avoided in patients with a history of gout or hyperuricemia

because of dose-related effects on renal uric acid handling. In such patients, taking
low-dose aspirin for 2 consecutive days is associated with increased risk for onset or
reemergence of gout. Serum urate monitoring should be considered in patients with
gout who are receiving aspirin therapy.47
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Reye syndrome is an acute illness occurring almost exclusively in children and

teenagers.48 The cause is unknown, but the use of salicylates to treat viral illnesses
has been associated with the syndrome. Onset usually follows a viral infection with
influenza (type A or B) or varicella (chickenpox). Reye syndrome is characterized by
progressive neurologic damage, fatty liver with encephalopathy, and hypoglycemia.
Neurologic manifestations may start with lethargy and progress to delirium,
confusion, and seizures. The mortality rate may be as high as 50%.

The American Academy of Pediatrics, FDA, the Centers for Disease Control and
Prevention, and the Surgeon General have issued warnings that aspirin and other
salicylates (including bismuth subsalicylate and nonaspirin salicylates) should be
avoided in children and teenagers who have influenza or chicken-pox. The following
statement is included in the Electronic Code of Federal Regulations48 and is required
on labeling for nonprescription aspirin and aspirin-containing products:

Reye’s syndrome: Children and teenagers who have or are recovering from
chickenpox or flu-like symptoms should not use this product. When using
this product, if changes in behavior with nausea and vomiting occur,
consult a doctor because these symptoms could be an early sign of Reye’s
syndrome, a rare but serious illness.

Although a simple viral upper respiratory infection does not contraindicate aspirin
use, differentiation of its symptoms from those of influenza and chickenpox can be
difficult. Many health care providers recommend a conservative approach of
avoiding aspirin whenever influenza-like symptoms are present. Use of aspirin as a
pediatric antipyretic and reports of Reye syndrome have all but ceased in the United
States.

All nonprescription analgesic and antipyretic products for adult use bear a warning
regarding alcohol use. Use of aspirin with alcohol intake increases the risk of adverse
GI events, including stomach bleeding. Patients who consume three or more
alcoholic drinks daily should be counseled about the associated risks and referred to
their primary care provider before they use aspirin.

Mild salicylate intoxication (salicylism) occurs with chronic toxic blood levels,
generally achieved in adults who take 90–100 mg/kg per day of a salicylate for at
least 2 days. Symptoms and signs of salicylate toxicity include headache, dizziness,
tinnitus, difficulty hearing, dimness of vision, mental confusion, lassitude,
drowsiness, sweating, thirst, hyperventilation, nausea, vomiting, and occasional
diarrhea. These clinical abnormalities all can be reversed by lowering the plasma
concentration to a therapeutic range. Tinnitus, typically an early manifestation,
should not be used as a sole indicator of salicylate toxicity.

Acute salicylate intoxication is categorized as mild (associated with ingestion of <150

mg/kg), moderate (with ingestion of 150–300 mg/kg), or severe (with ingestion of
>300 mg/kg). Clinical manifestations depend on the plasma drug concentration and
may include lethargy, nausea, vomiting, dehydration, tinnitus, hemorrhage,
tachypnea and pulmonary edema, convulsions, and coma. Acid-base disturbances
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are prominent and range from respiratory alkalosis to metabolic acidosis. Initially,
salicylate affects the respiratory center in the medulla, producing hyperventilation
and respiratory alkalosis. In severely intoxicated adults and in most salicylate-
poisoned children younger than 5 years, respiratory alkalosis progresses rapidly to
metabolic acidosis. Children are more likely than adults to exhibit high fever in
salicylate poisoning. Hypoglycemia resulting from increased glucose utilization may
be especially serious in children. Bleeding may occur from the GI tract or mucosal
surfaces, and petechiae are a prominent feature at autopsy in fatal cases.

Emergency management of acute salicylate intoxication is directed at preventing

absorption of salicylate from the GI tract and providing supportive care. Activated
charcoal should be used at home only if recommended by poison control center or
emergency medical services personnel. In a hospital emergency department setting,
GI tract decontamination with gastric lavage or activated charcoal may be
undertaken. Enhancing renal elimination can be accomplished through
alkalinization of the urine. Dosing recommendations for the use of activated
charcoal are included in Chapter 21.

Combination Products
Many nonprescription analgesics are available in combination products (Table 5–8).

Table 5–8 Selected Nonprescription Combination Analgesic Products

Trade Name Primary Ingredient(s)

Acetaminophen-Containing Products

Excedrin Tension Headache caplet Acetaminophen 500 mg; caffeine 65 mg

Excedrin PM Headache caplet Acetaminophen 250 mg; aspirin 250 mg;

diphenhydramine 38 mg

Goody’s Headache Relief Shot Liquid Acetaminophen 1000 mg; caffeine 65 mg

Percogesic Original Strength tablet Acetaminophen 325 mg; diphenhydramine 12.5 mg

Percogesic Extra Strength tablet Acetaminophen 500 mg; diphenhydramine 12.5 mg

Sudafed PE Pressure + Pain caplet Acetaminophen 325 mg; phenylephrine 5 mg

Tylenol PM caplet Acetaminophen 500 mg; diphenhydramine 25 mg

Tylenol Sinus + Headache caplet Acetaminophen 325 mg; phenylephrine 5 mg

Tylenol Sinus Severe caplet Acetaminophen 325 mg; phenylephrine 5 mg;

guaifenesin 200 mg

Nonsalicylate NSAID-Containing Products

Advil Cold & Sinus tablet (behind the counter) Ibuprofen 200 mg; pseudoephedrine 30 mg

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Trade Name Primary Ingredient(s)

Advil Allergy and Congestion Relief coated tablet Ibuprofen 200 mg; phenylephrine 10 mg;
chlorpheniramine maleate 4 mg

Advil Sinus Congestion and Pain tablet Ibuprofen 200 mg; phenylephrine 10 mg

Aleve-D Sinus & Headache caplet (behind the counter) Naproxen sodium 220 mg; pseudoephedrine 120
mg

Motrin PM caplet Ibuprofen 200 mg; diphenhydramine 38 mg

Sudafed 12 Hour Pressure + Pain Extended Release Naproxen sodium 220 mg; pseudoephedrine 120
tablet (behind the counter) mg

Aspirin-Containing Products

Anacin Regular Strength tablet Aspirin 400 mg; caffeine 32 mg

Bayer Cafiaspirina caplet Aspirin 500 mg; caffeine 40 mg

Excedrin Migraine caplet Aspirin 250 mg; acetaminophen 250 mg; caffeine
65 mg

Goody’s Cool Orange Powder Aspirin 500 mg; acetaminophen 325 mg; caffeine
65 mg

Goody’s Extra Strength Headache Powder Aspirin 520 mg; acetaminophen 260 mg; caffeine
32.5 mg

Key: NSAID = Nonsteroidal anti-inflammatory drug.

Caffeine is used as an adjunct to analgesics for tension-type and migraine

headaches. It also may have its own analgesic properties, and curbing or ceasing
caffeine consumption is known to cause withdrawal headache when it is taken
regularly. Clinical trials have suggested that combining caffeine with analgesics may
result in better efficacy.49 Of note, however, caffeine itself may be a trigger for
migraines, and withdrawal of caffeine, as stated, may result in headache.
Combination dosage formulations containing a decongestant and either
acetaminophen or an NSAID also are available. Use of such combinations appears to
be logical in sinus headaches or other indications for which both analgesia and
decongestion are needed.

Combinations of NSAIDs such as aspirin and/or acetaminophen may achieve goals of

pain relief with lower doses of the individual agents; however, insufficient evidence is
available to support the safety and effectiveness of this practice. Dosing limits for
combination products should be closely monitored.

Pharmacotherapeutic Comparison

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Aspirin Versus Nonacetylated Salicylates

Although definitive clinical data are lacking, aspirin and non-acetylated salicylates
are believed to be of equal anti-inflammatory potency; however, aspirin is thought to
be a superior analgesic and antipyretic. With all analgesics, individual patients may
respond better to one agent than to another.

Aspirin Versus Acetaminophen

Numerous controlled studies have demonstrated the equivalent analgesic efficacy

of aspirin and acetaminophen on a milligram-for-milligram basis; however, statistical
methods used to compare effectiveness among different studies show that
acetaminophen may not be as effective in some types of pain in which an
inflammatory component predominates.50 A recent systematic review found a lack
of evidence for effectiveness of acetaminophen for osteoarthritis.51

Aspirin Versus Nonsalicylate NSAID

Ibuprofen has been shown to be at least as effective as aspirin in treating various

types of pain, including dental extraction pain, dysmenorrhea, and episiotomy pain.
Because aspirin must be dosed at levels near the self-care maximum to achieve anti-
inflammatory effects, nonsalicylate NSAIDs may be preferred for self-treatment of
inflammatory disorders such as rheumatoid arthritis or acute muscle injury.50
Nonsalicylate NSAIDs have a safety advantage of lower toxicity in overdose.

NSAID Versus Acetaminophen

For episodic tension-type headache, acetaminophen 1000 mg appears to provide

relief equivalent to that achieved with naproxen 375 mg.52 For moderate to severe
dental or sore throat pain in children, single doses of acetaminophen 7–15 mg/kg
produced pain relief similar to that with ibuprofen 4–10 mg/kg. Ibuprofen was a more
effective antipyretic, and both drugs were well tolerated.53 A review of evidence
comparing ibuprofen with acetaminophen for headache treatment in children and
adults found that only two trials had shown a modest advantage for ibuprofen, and
the researchers concluded that the two agents should be considered equally
effective.54 Acetaminophen does not have anti-inflammatory properties, which limits
its effectiveness in inflammatory conditions, including dysmenorrhea and
osteoarthritis.50 NSAIDs are less toxic than acetaminophen in the case of an
overdose.

Naproxen Versus Ibuprofen

Naproxen sodium 220 mg and ibuprofen 200 mg appear to have similar efficacy. The
time to onset of activity also is similar for these two NSAIDs. Duration of action of
naproxen is longer than that of ibuprofen, with a dosing schedule of every 8–12 hours
versus ibuprofen’s dosing schedule of every 4–6 hours. Individual patients may
report a better response to one NSAID than to another, for reasons that are unclear.

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Product Selection Guidelines

Special Population Considerations

Age is an important consideration in the selection of an appropriate nonprescription

medication for self-treatment for headache.

Parents of children younger than 8 years should consult a pediatrician before giving
their children nonprescription medications. After appropriate evaluation, children 2
years and older may use acetaminophen or ibuprofen. Children 12 years and older
may use naproxen. To decrease the risk of Reye syndrome, parents should not use
aspirin or aspirin-containing products in children and teenagers unless directed to
do so by a primary care provider.

Older patients are at increased risk for many adverse effects of salicylates and
NSAIDs. Comorbid conditions, impaired renal function, and concurrent use of other
medications contribute to the increased risk. These patients are more vulnerable to
serious GI toxicity and the hypertensive and renal effects of salicylates and NSAIDs.
Acetaminophen may be the safest alternative in the geriatric population.

Many safety considerations have been raised regarding the use of these medications
in patients who are pregnant or breastfeeding; however, no such considerations
apply for males and females of reproductive potential in general. (See the Preface for
a detailed explanation of the pregnancy data.) Acetaminophen crosses the placenta
but is considered safe for use during pregnancy. Acetaminophen appears in breast
milk, producing a milk-to-maternal plasma ratio of 0.5:1. A maternal dose of 1 g
correlates with an estimated maximum infant dose that is 1.85% of the maternal
dose. The only adverse effect reported in infants exposed to acetaminophen through
breast milk is a rarely occurring maculopapular rash, which subsides upon drug
discontinuation. Acetaminophen use is considered compatible with breastfeeding.55

No evidence exists that NSAIDs are teratogenic in either humans or animals. Use of
these agents is contraindicated during the third trimester of pregnancy, however,
because all potent prostaglandin synthesis inhibitors can cause delayed parturition,
prolonged labor, and increased postpartum bleeding. These agents also can have
adverse fetal cardiovascular effects (e.g., premature closure of the ductus arteriosus)
when used in pregnancy (particularly in late pregnancy). Reproductive animal
studies have not shown evidence of harm to the fetus; however, adequate studies to
verify safety have not been conducted in humans. Use in pregnancy should be
limited to clinical situations in which the potential benefit justifies potential risk to
the fetus.55,56

Ibuprofen is considered the safest analgesic for use by nursing mothers. This
designation is based on the low concentration of ibuprofen in breast milk and the
lack of reported ill effects with use of ibuprofen in infants. The concentration of
ibuprofen found in breast milk has been found to be less than 1% of the
recommended infant dose.24 Nursing mothers should not use naproxen, however.
The naproxen anion has been measured in human milk, where it accumulates at a
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level of 1% of the maximum plasma concentration for naproxen. Prostaglandin-

inhibiting drugs have the potential to cause harm in neonates; therefore, this level of
exposure in milk has led to the labeling statement to avoid use during lactation.56

Aspirin should be avoided during pregnancy, especially during the last trimester, and
during breastfeeding. Its ingestion during pregnancy may be associated with
maternal adverse effects such as anemia, antepartum or postpartum hemorrhage,
and prolonged gestation and labor. Regular aspirin ingestion during pregnancy may
increase the risk for complicated deliveries, including unplanned cesarean section,
breech delivery, and forceps delivery. Definitive data supporting these concerns,
however, are lacking.

Aspirin readily crosses the placenta and can be found in higher serum
concentrations in the neonate than in the mother. Salicylate elimination is slow in
neonates because of the liver’s immaturity and underdeveloped capacity to form
glycine and glucuronic acid conjugates and because of reduced urinary excretion
resulting from low glomerular filtration rates.

Fetal effects from in utero aspirin exposure include intrauterine growth retardation,
congenital salicylate intoxication, decreased albumin-binding capacity, and
increased perinatal mortality. In utero death results, in part, from antepartum
hemorrhage or premature closure of the ductus arteriosus. In utero aspirin exposure
within 1 week of delivery can result in neonatal hemorrhagic episodes and/or pruritic
rash. Reported neonatal bleeding complications include petechiae, hematuria,
cephalhematoma, subconjunctival hemorrhage, and increased bleeding after
circumcision.55 An increased incidence of intracranial hemorrhage in premature or
low-birth-weight infants associated with maternal aspirin use near the time of birth
also has been reported.55 An association between maternal aspirin ingestion and
oral clefting and congenital heart disease has been noted. The relationship between
maternal aspirin ingestion and congenital malformation remains unresolved,
however, and studies have failed to confirm a relationship between maternal
ingestion of aspirin and increased risk of fetal malformation.

Aspirin and other salicylates are excreted into breast milk in low concentrations.
After single-dose oral salicylate ingestion, peak milk levels occur at approximately 3
hours, producing a milk-to-maternal plasma ratio of 3:8. Although no adverse effects
on platelet function in nursing infants exposed to aspirin via breast milk have been
reported, these agents still must be considered to carry a risk for such effects.55

For patients with renal impairment, caution is indicated with use of salicylates and
other NSAIDs. Clinically important alterations in renal blood flow that result in acute
reduction in renal function can result from even short courses of salicylates. Referral
for medical evaluation for assistance in selecting an analgesic is appropriate.

For patients with hepatic impairment, caution is warranted with use of

acetaminophen. Presence of active liver disease is a risk factor for hepatic injury
from this drug. Patients with hepatic impairment of any degree should use the

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smallest dose for the shortest duration possible. Prolonged use of this drug at high
doses should be avoided.

Patient Factors

Nonprescription analgesics are available in a number of dosage forms. During

patient assessment, the health care provider should determine which dosage form
will provide an optimal clinical outcome. If rapid response is desired, then
immediate-release oral dosage forms are preferred over coated or extended-release
forms. For patients experiencing migraine headache with severe nausea, rectal
dosage forms may be needed. Liquid dosage forms often are used in children or
adult patients who have difficulty swallowing tablets or capsules. Information
regarding the FDA requirements for dispensing devices included in liquid
nonprescription products is located in Chapter 11, under “Special Populations.”

Use of ibuprofen in the pediatric population is complicated by the availability of two

liquid formulations of different strengths. Unintended over- or underdosing can
occur when parents switch between the concentrated drops (50 mg/1.25 mL) and
the suspension (100 mg/5 mL). In addition, rapidly growing infants quickly outgrow
previous dose requirements. Therefore, recalculation of the pediatric dose according
to present age and body weight is recommended at the time of each treatment
course.

Patients whose lifestyle encompasses significant alcohol ingestion (three or more

drinks per day) should avoid self-treatment with nonprescription analgesics.

Patients with intolerance to aspirin also may experience cross-reactions with other
chemicals or drugs. Up to 15% of aspirin-intolerant patients may exhibit signs of
cross-reaction when exposed to tartrazine (a dye designated by the FDA-
administered Food, Drug, and Cosmetic Act as FD&C Yellow 5), which can be found
in many drugs and foods. Among persons documented to have the respiratory type
of aspirin sensitivity, rates of cross-reaction between aspirin and acetaminophen,
ibuprofen, and naproxen are 7%, 98%, and 100%, respectively. High cross-reaction
rates also are reported with some prescription NSAIDs. The proposed mechanism of
cross-sensitivity between aspirin and other NSAIDs involves shunting arachidonic
metabolism down the lipoxygenase pathway (consequent to inhibition of the COX-1
enzyme pathway), resulting in accumulation of leukotrienes, which can cause
bronchospasm and anaphylaxis. Acetaminophen and nonacetylated salicylates are
weak inhibitors of COX-1 at moderate doses. Patients with a history of aspirin
intolerance should therefore be advised to avoid all aspirin- and other NSAID-
containing products, and to use acetaminophen or a nonacetylated salicylate, with
the caveat that acetaminophen does not offer anti-inflammatory properties.

Patient Preferences

Consideration of dosing frequency in product selection may lead to improved

outcomes for individual patients. Naproxen can be taken 2 or 3 times daily, which
may improve patient adherence to the medication regimen. By contrast, immediate-
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release products of acetaminophen, ibuprofen, and salicylates may require dosing as

frequently as every 4 hours. Acetaminophen 650 mg in extended-release form is
given every 8 hours.

Complementary Therapies
Butterbur, feverfew, riboflavin, and coenzyme Q10 are commonly used for the
prevention of migraine headaches and are discussed in depth in Chapter 51. These
natural products have limited efficacy for the treatment of other types of headaches.
Essential oil remedies include application of peppermint oil to the forehead and
temples for treatment of tension headache and inhalation of aromatized lavender oil
to relieve migraine. Recent and well-designed trials to further clarify the efficacy and
safety of essential oils are lacking. Magnesium and omega-3 polyunsaturated fatty
acid supplementation for headache prevention also has been considered.20

Acupuncture has been used to prevent migraine and tensiontype headache.

Evaluation of acupuncture is complicated by difficulties in blinding of study
participants and investigators and by differences in identifying acupuncture points.
Overall, results have been variable, but several randomized, placebo-controlled trials
found acupuncture to be effective in reducing frequency and severity of headache.56
Methods focusing on stress relief and relaxation techniques such as massage, yoga,
and biofeedback therapy may be useful for the prevention and treatment of
headache.20 Some of these methods are discussed in more depth in Chapter 52.

Assessment of Headache: A Case-Based

Approach
Before self-treatment of headache can be recommended, the health care provider
must assess the patient’s headache complaint to determine type, severity, location,
frequency, intensity over time, and age at onset. The next step is to obtain a medical
and psychosocial history. All current medications should be inventoried, and all past
and present headache treatments should be reviewed, with emphasis on
determining which treatments, if any, were successful or preferred.

Secondary headaches, other than minor sinus headache, are excluded from self-
treatment. Headache associated with seizures, confusion, drowsiness, or cognitive
impairment may be a clinical indicator of brain tumor, ischemic stroke, subdural
hematoma, or subarachnoid hemorrhage. Headache accompanied by nausea,
vomiting, fever, and stiff neck may indicate brain abscess or meningitis. Headache
with night sweats, aching joints, fever, weight loss, and visual symptoms (e.g.,
blurring) in patients with rheumatoid arthritis may indicate cranial arteritis.
Headache associated with localized facial pain, muscle tenderness, and limited
motion of the jaw may indicate temporomandibular joint disorder.

Cases 5–1 and 5–2 illustrate assessment of two different patients with headache.

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Patient Counseling for Headache

To optimize outcomes from therapy, the health care provider should instruct
patients to take an appropriate dose of analgesic early in the course of the headache.
The use of nonprescription analgesics to preempt or abort migraine headaches
should also be explained to patients with migraines whose headaches are
predictable. Patients for whom headache is a relatively common occurrence should
be encouraged to keep a log of their headache episodes to document triggers,
frequency, intensity, duration of episodes, and response to treatment. This record
may also be helpful in identifying factors that can improve headache prevention and
treatment. Patients should be advised that continuing or escalating pain can be a
sign of a more serious problem and that such pain warrants prompt medical
attention. Appropriate drug and nondrug measures for treating headaches should
be explained in appropriate detail. Frequent use of nonprescription analgesics is not
advisable because of the risk for medication overuse headache. The health care
provider should convey the message that nonprescription analgesics are potent
medications with accompanying potential adverse effects, interactions, and
precautions and warnings. The box “Patient Education for Headache” lists specific
information for patient counseling.

Evaluation of Patient Outcomes for Headache

Appropriate follow-up evaluation will depend on headache frequency and severity,
as well as patient factors. Headache pain relief should begin within 30 minutes and
peak at 2 hours after administration of an over-the-counter analgesic. Patients
should seek medical attention if headaches persist longer than 3 days or worsen
despite self-treatment. For patients with episodic headaches, a trial of 6–12 weeks
may be needed to assess efficacy of treatment. For chronic headache, follow-up
evaluation after 4–6 weeks should be adequate to assess treatment efficacy. Patients
with migraine headaches who do not obtain adequate relief with self-treatment
should be referred for medical evaluation, because effective prescription therapies
are available to substantially limit pain and disability.

Case 5–1

Relevant Evaluation Scenario/Model Outcome

Criteria

Collect

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Relevant Evaluation Scenario/Model Outcome

Criteria

1. Gather essential
information about the
patient’s symptoms and
medical history, including

a. Description of The patient describes a dull ache in her forehead. She said it started a
symptom(s) (i.e., nature, few hours ago and is interfering with her ability to concentrate on
onset, duration, severity, studying for an upcoming exam. It seems to feel worse when she tries to
associated symptoms) think and study for the exam. Headaches are generally uncommon for
her but seem to increase in frequency during final exams.

b. Description of any Closing her eyes and resting seem to help relieve the pain.
factors that seem to
precipitate, exacerbate,
and/or relieve the patient’s
symptom(s)

c. Description of the Other than closing her eyes, the patient has not tried anything else to
patient’s efforts to relieve relieve pain.
the symptoms

d. Patient’s identity Cynthia Marshall

e. Patient’s age, gender, 20 years, female, 5 ft 3 in., 130 lb

height, and weight

f. Patient’s occupation Student

g. Patient’s dietary habits Breakfast bar for breakfast, salad from the school cafeteria for lunch, and
dinner varies daily depending on schedule. She does not consume
alcohol and has a single cup of coffee most mornings.

h. Patient’s sleep habits Reports sleeping 6–7 hours nightly.

i. Concurrent medical Multivitamin

conditions, prescription
and nonprescription
medications, and dietary
supplements

j. Allergies None

k. History of other adverse None

reactions to medications

l. Other (describe) _______ n/a

Assess

2. Differentiate patient’s Ms. Marshall is experiencing a dull ache in her forehead consistent with a
signs/symptoms and tension-type headache. This is likely a response to the stress of school.
correctly identify the
patient’s primary
problem(s).

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Relevant Evaluation Scenario/Model Outcome

Criteria

3. Identify exclusions for None

self-treatment.

4. Formulate a Options include

comprehensive list of (1) Refer Ms. Marshall to an appropriate HCP.
therapeutic alternatives for
the primary problem to
(2) Recommend self-care with a nonprescription analgesic
determine whether referral
and nondrug measures.
to a health care provider is
required, and share this
(3) Recommend self-care until Ms. Marshall can see an
information with the
appropriate HCP.
patient or caregiver.

(4) Take no action.

Plan

5. Select an optimal Ms. Marshall should use a nonprescription analgesic and nondrug
therapeutic alternative to measures to treat her problem.
address the patient’s
problem, taking into
account patient
preferences.

6. Describe the “Acetaminophen, ibuprofen, and naproxen are all appropriate options.
recommended therapeutic Correct dosing for the selected medication is essential, with careful
approach to the patient or attention to not take more than the recommended daily amount.
caregiver. Additional stress relief measures should be used when needed.”

7. Explain to the patient or “Tension-type headache can be effectively treated with nonprescription
caregiver the rationale for medications. Because stress is a likely trigger for the headache, it is
selecting the important to focus on stress-relieving activities as well. If the medication
recommended therapeutic chosen does not relieve the pain or if the pain worsens, you should see a
approach from the health care provider.”
considered therapeutic
alternatives.

Implement

8. When recommending The specific administration of the medication is determined by the

self-care with specific analgesic chosen. Most pain relievers will start working within
nonprescription about 30 minutes, and pain relief duration will depend on the analgesic
medications and/or used. The pain should be gone or noticeably diminished by the
nondrug therapy, convey analgesic. Adverse effects will depend on the product chosen. All
accurate information to the medications should be kept in a cool, dry place and out of reach of
patient or caregiver. children. A headache diary will help keep track of headache frequency
and help identify possible triggers.

Solicit follow-up questions “Is it possible to not have these headaches while I’m in school?”
from the patient or
caregiver.

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Relevant Evaluation Scenario/Model Outcome

Criteria

Answer the patient’s or “Various methods to reduce stress may help decrease the frequency of
caregiver’s questions. the headaches. Stress reduction measures will include appropriate study
strategies and adequate sleep.”

Follow-up: Monitor and

Evaluate

9. Assess patient outcome. Follow-up with the patient should occur in 4–6 weeks. Owing to the
episodic nature of this headache, 6 weeks may be necessary to fully
evaluate the treatment.

Key: HCP = Health care provider; n/a = not applicable.

Case 5–2

Relevant Evaluation Criteria Scenario/Model Outcome

Collect

1. Gather essential information about the

patient’s symptoms and medical history,
including

a. Description of symptom(s) (i.e., nature, The patient approaches the pharmacy wearing her
onset, duration, severity, associated sunglasses. She says that she is experiencing
symptoms) throbbing pain on one side of her head. She is feeling
a bit nauseous as well and says the pain started
about 30 minutes ago.

b. Description of any factors that seem to She said that light makes the pain worse, which is
precipitate, exacerbate, and/or relieve the why she is wearing sunglasses. She also said that she
patient’s symptom(s) is sensitive to sound. The only relief seems to come
from resting in a dark, quiet room.

c. Description of the patient’s efforts to relieve She has tried going to a dark and quiet location, but
the symptoms the pain continued. She also tried a cold towel on her
face, but the pain still continued.

d. Patient’s identity Betsy Ogaku

e. Patient’s age, gender, height, and weight 34 years, female, 5 ft 6 in., 150 lb

f. Patient’s occupation Real estate agent

g. Patient’s dietary habits Egg white wrap for breakfast, salad with grilled
chicken for lunch, and a well-rounded dinner each
evening.

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Relevant Evaluation Criteria Scenario/Model Outcome

h. Patient’s sleep habits About 7 hours each evening

i. Concurrent medical conditions, prescription Citalopram 20 mg once daily for depression

and nonprescription medications, and dietary Levothyroxine 137 mcg for hypothyroidism Tums as
supplements needed for occasional heartburn No dietary
supplements

j. Allergies Penicillin

k. History of other adverse reactions to None

medications

l. Other (describe) _______ n/a

Assess

2. Differentiate patient’s signs/symptoms and Mrs. Ogaku is suffering from unilateral, throbbing
correctly identify the patient’s primary pain associated with sensitivity sound and light. She
problem(s). additionally is experiencing nausea. These symptoms
are caused by migraine.

3. Identify exclusions for self-treatment. Symptoms consistent with migraine, but no formal
diagnosis of migraine headache.

4. Formulate a comprehensive list of Options include

therapeutic alternatives for the primary (1) Refer Mrs. Ogaku to an appropriate HCP.
problem to determine whether referral to a
health care provider is required, and share this (2) Recommend self-care with a
information with the patient or caregiver. nonprescription analgesic and nondrug
measures.

(3) Recommend self-care until Mrs. Ogaku

can see an appropriate HCP.

(4) Take no action.

Plan

5. Select an optimal therapeutic alternative to Mrs. Ogaku should see a health care provider.
address the patient’s problem, taking into
account patient preferences.

6. Describe the recommended therapeutic “You should see your primary care provider for
approach to the patient or caregiver. treatment.”

7. Explain to the patient or caregiver the “This option is best because you are experiencing a
rationale for selecting the recommended migraine headache. Self-treatment with over-the-
therapeutic approach from the considered counter medications is not recommended for a
therapeutic alternatives. migraine until you have been evaluated and
diagnosed by your primary care provider.”

Implement

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Relevant Evaluation Criteria Scenario/Model Outcome

8. When recommending self-care with “Work with your primary care provider to determine
nonprescription medications and/or nondrug the cause of this migraine. Try to implement lifestyle
therapy, convey accurate information to the changes to prevent a future occurrence.”
patient or caregiver.

Solicit follow-up questions from the patient or “Does this mean that I will continue to have this
caregiver. problem in the future?”

Answer the patient’s or caregiver’s questions. “The frequency of migraine headache varies for each
affected person. A thorough understanding of the
cause of your migraine will help you try to prevent
another in the future.”

Follow-up: Monitor and Evaluate

9. Assess patient outcome. Contact the patient the following day to ensure that
she made an appointment with a primary care
provider.

Key: HCP = Health care provider.

Patient Education for Headache

The objectives of self-treatment are (1) to relieve headache pain, (2) to prevent
headaches when possible, and (3) to prevent medication overuse headaches by
avoiding chronic use of nonprescription analgesics. Carefully following product
instructions and the self-care measures listed here will help ensure optimal
therapeutic outcomes.

Tension-Type Headaches

Nonprescription pain relievers (analgesics) are usually effective in relieving

tension-type headaches. However, consult your primary care provider
before using such medications for chronic tension-type headaches that
occur 15 days per month or more often over a 3-month period.
If nonprescription pain relievers are used for chronic headaches, keep
records of how often they are used, and share this information with your
primary care provider.

Migraine Headache

Avoid substances (food, caffeine, alcohol, medications) or situations (stress,

fatigue, oversleeping, fasting, missing meals) that you know can trigger a
migraine.
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Use the following nutritional strategies to prevent migraine:

Avoid foods or food additives known to trigger migraines, including
red wine, aged cheese, aspartame, monosodium glutamate, coffee,
tea, cola beverages, and chocolate.
Avoid foods to which you are allergic.
Eat regularly to avoid hunger and low blood sugar.

If onset of migraines is predictable (e.g., occurrence of headache during

menstruation), take aspirin, ibuprofen, or naproxen to prevent the
headache. Start taking the analgesic 2 days before you expect the
headache and continue regular use during the time the headache might
start.
Try to stop a migraine by taking an NSAID such as aspirin or
acetaminophen at the onset of headache pain.
If desired, rest in a quiet, dark room and use an ice bag or cold pack applied
with pressure to the forehead or temples to reduce the pain associated
with acute migraine attacks.

Sinus Headache

Consider using a combination of a decongestant and a nonprescription

analgesic to relieve the pain of sinus headache.

Precautions for Nonprescription Analgesics

If you are pregnant or breastfeeding, consult your primary care provider

before taking any nonprescription medications.
If you have a medical condition or are taking prescription medications,
obtain medical advice before taking any of these medications.
Nonprescription analgesics are known to interact with several medications.
Do not take nonprescription analgesics more often than 3 days per week
unless a health care provider has recommended prolonged use.
Do not take these medications if you consume three or more alcoholic
beverages daily.
Do not exceed recommended dosages.
Products containing aspartame and/or phenylalanine (usually chewable
tablets) should not be given to persons with phenylketonuria.

Salicylates (Aspirin and Magnesium Salicylate) and Other NSAIDs (Ibuprofen

and Naproxen)

Do not take salicylates or nonsalicylate NSAIDs during the last 3 months of

pregnancy unless a primary care provider is supervising such use.
Unsupervised use of this medication could harm the unborn child or cause
complications during delivery.
Do not give aspirin or products that contain aspirin to children and
teenagers who have or are recovering from chickenpox or influenza-like

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symptoms. To avoid the risk of Reye syndrome, a rare but potentially fatal
condition, use acetaminophen for pain relief.
Do not take aspirin or other NSAIDs if you are allergic to aspirin or have
asthma and nasal polyps. Take acetaminophen instead.
Do not take aspirin or other NSAIDs if you have stomach problems or
ulcers, liver disease, kidney disease, or heart failure.
Do not take NSAIDs if you have or are at high risk for heart disease or stroke
unless the use is supervised by a health care provider.
Do not take aspirin if you have gout, diabetes mellitus, or arthritis unless
the use is supervised by a health care provider.
Do not take salicylates or other NSAIDs if you are taking anticoagulants.
Do not take magnesium salicylate if you have kidney disease.
Do not give naproxen to a child younger than 12 years.

When to Seek Medical Attention

Stop taking salicylates or other NSAIDs and seek medical attention if any of
the following signs and symptoms are noted:
Headache, dizziness, ringing in the ears, difficulty in hearing, dimness
of vision, mental confusion, lassitude, drowsiness, sweating, thirst,
hyperventilation, nausea, vomiting, or occasional diarrhea. These signs
and symptoms indicate mild salicylate toxicity.
Dizziness, nausea and mild stomach pain, constipation, ringing in the
ears, or swelling in the feet or legs. These signs and symptoms are
common adverse effects of salicylates and other NSAIDs.
Rash or hives, or red, peeling skin; swelling in the face or around the
eyes; wheezing or trouble breathing; bloody or cloudy urine;
unexplained bruising and bleeding; or signs of stomach bleeding such
as bloody or black tarry stools, severe stomach pain, or bloody vomit
(see the box “A Word About NSAIDs and Stomach Bleeding”). These
signs and symptoms warrant immediate medical attention.

Acetaminophen

To avoid possible damage to the liver, do not take more than 4 g of

acetaminophen a day (total dose from all nonprescription and prescription
single-ingredient or combination products containing acetaminophen).
Do not drink alcohol while taking this medication.
Follow dosage instructions for acetaminophen carefully if you have
glucose-6-phosphate dehydrogenase deficiency.

When to Seek Medical Attention

Stop taking acetaminophen and seek medical attention if you develop

nausea, vomiting, drowsiness, confusion, or abdominal pain.

Key: NSAID = Nonsteroidal anti-inflammatory drug.

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Key Points for Headache

➤ Most tension-type, migraine, and sinus headaches are amenable to
treatment with nonprescription medications.

➤ Patients with signs and symptoms suggestive of secondary headaches

(except for minor sinus headache) or of undiagnosed migraine
headaches should be referred for medical evaluation.

➤ Many patients with frequent headaches may experience improvement

after identifying and modifying environmental, behavioral, nutritional,
or other triggers for their headaches.

➤ The choice of nonprescription analgesic depends on patient

preferences, presence of precautionary or contraindicating conditions,
concomitant medications, cost, and other factors.

➤ Pharmacists have been identified as key sources of information on

nonprescription analgesics to reduce risk for acetaminophen-induced
hepatotoxicity and NSAID-induced GI bleeding, cardiovascular events,
and nephrotoxicity.

➤ Use of nonprescription analgesics for headache should be limited to 3

days per week to prevent medication overuse headache.

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