9/2/2017 Headache

Headache

Irene Worthington, BScPhm

Date of Revision: August 2017

Introduction
This chapter focuses on 3 of the most common headache disorders: tension-type headache and migraine (primary headache disorders), and medication-overuse headache
(secondary headache disorder). A full list of headache disorders and their classification is published by the International Headache Society (IHS).1

Pathophysiology

Tension-type Headache

Tension-type headache (TTH) is the most common type of headache. It is diagnosed mainly by the presence of a headache lasting 30 minutes to 7 days that has at least
2 of the following criteria: bilateral location, a pressing/tightening quality, mild or moderate intensity, not aggravated by routine physical activity, and an absence of
features found in other types of headache (e.g., migraine). Although mental stress and tension are frequently thought to precipitate TTH, the exact pathophysiology is
unknown. Both peripheral (myofascial tissues) and central mechanisms are thought to contribute to pain in TTH.2 Since there are significant overlapping features, some
headache experts believe that TTH is a variant of migraine; however, epidemiologic studies have concluded that migraine and TTH are different disorders that coexist in
many patients.1 TTH can be episodic or chronic (headache on ≥15 days per month). The lifetime prevalence of TTH is around 80%, and about 3% for chronic TTH. TTH
appears to be more prevalent in women, and declines with age in both women and men.2

Migraine

Migraine is a common, underdiagnosed, often incapacitating neurovascular disorder characterized by recurrent attacks of headache pain (generally moderate to severe),
autonomic nervous system dysfunction, and neurologic symptoms in some patients.3 The IHS describes the diagnostic features of migraine subtypes.1 The 2 most
common are migraine with aura and migraine without aura. The specific cause of migraine is unknown but genetic factors are likely involved. It has been proposed that
specific triggers can provoke CNS dysfunction in susceptible individuals, leading to dilation of intracranial and extracerebral blood vessels and activation of the trigeminal
sensory nerves (resulting in release of vasoactive peptides such as calcitonin gene-related peptide), with subsequent relaying of pain signals to the brain. Migraine
attacks may be episodic or chronic (≥15 days per month). Approximately 15% of patients experience migraine attacks preceded or accompanied by transient focal
neurologic symptoms (usually visual), referred to as an aura. Aura is thought to be caused by neuronal dysfunction, not ischemia or vasoconstriction as previously
believed. Aura can also occur without a subsequent headache. In North America and Western Europe, the 1-year prevalence of migraine is 11% overall: 15–18% among
women and 6% among men. Attacks may last from 4–72 hours.3,4 Status migrainosus is a debilitating migraine attack that lasts more than 72 hours.

Medication-overuse Headache

Medication-overuse headache (MOH) is an under-recognized condition that may occur in patients who suffer from migraines (primarily) or tension-type headaches.
Recognition and treatment of MOH may lead to long-term improvement in headache relief and quality of life for many patients. Frequent use of analgesics or other acute
migraine medications for ≥3 months can lead to MOH (headache present on ≥15 days per month) in patients with migraine/tension-type headaches. MOH can occur in
association with simple analgesics (e.g., acetaminophen, ASA) or, less commonly, with NSAIDs. It is more common with combination products containing barbiturates,
caffeine and/or opioids. Overuse of ergotamine or triptans and withdrawal from substances such as caffeine, opioids and estrogen have also been implicated.1,5

Goals of Therapy
Identify potentially serious causes of headache and refer patient for diagnosis/treatment. Patients with sudden, severe headache should go to an emergency room
Relieve pain and associated symptoms (e.g., nausea/vomiting) so that patient can return to normal functioning
Prevent recurrence of migraine headache
Prevent medication-overuse headache

Patient Assessment
The IHS has established criteria for the diagnosis of various headache disorders.1 There are no diagnostic tests for primary headache disorders (e.g., tension-type
headache, migraine, cluster headache). Diagnosis is based on symptoms, after ruling out any serious underlying disorders.6,7,8,9,10,11 Secondary headache disorders are
those associated with organic causes (e.g., trauma, meningitis, space-occupying lesion). Some medical procedures are associated with headache (e.g., lumbar puncture,
rhinoscopy).

Patients with occasional tension-type headache do not require further assessment unless the headaches become chronic (≥15 days/month). Patients with features of
migraine require assessment, diagnosis and appropriate treatment. Patients with any unusual headache require further assessment; if the headache is very severe, with a
sudden onset, refer immediately to an emergency room (see Red Flags for Serious Headache).

A stepwise approach to headache assessment and treatment is provided in Figure 1.

Common Signs and Symptoms

Table 1 outlines the clinical features of tension-type and migraine headache.

Table 1: Clinical Features of Tension-type Headache and Migraine

Clinical Feature Tension-type Headache Migraine

Quality of headache Pressing/tightening (nonpulsating) Throbbing/pulsating (at least part of the time)

Severity Mild to moderate Usually moderate to severe, although can be mild

Location Bilateral Usually unilateral (can be bilateral, especially in children)

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Clinical Feature Tension-type Headache Migraine

Frequency Episodic (<15 days/month) or chronic (≥15 Episodic (<15 days/month) or chronic (≥15 days/month)
days/month)

Duration 30 min to 7 days 4–72 h

Aggravated by physical activity No Yes

Associated symptoms No nausea/vomiting (anorexia may occur) At least one of the following:
Photophobia or phonophobia but not both 1. nausea and/or vomiting
2. photophobia and phonophobia
May occur with or without aura (usually visual)

Differential Diagnosis

In addition to the primary headache disorders listed in Table 1, other possible etiologies of headache include:1,6,7,8,12

Primary headache types such as benign cough headache, benign exertional headache, cluster headache and other trigeminal autonomic cephalgias, hemicrania
continua, cold-stimulus headache, primary stabbing headache and new daily persistent headache
Infections such as meningitis and encephalitis
Temporal arteritis (an important cause of headache in those over 50 years of age; associated with systemic symptoms and elevated erythrocyte sedimentation rate;
if left untreated, often leads to permanent blindness)
Cerebral ischemia (stroke); cervicogenic headache (originating from the neck); glaucoma; headache following stroke or transient ischemic attack (TIA); space-
occupying lesions (e.g., brain tumour); subarachnoid hemorrhage or intracerebral hemorrhages; subdural hematoma; systemic/CNS vasculitides (e.g., systemic
lupus erythematosus); and others
Note: “sinus” headaches occur only in the presence of a sinus infection (fever, purulent nasal discharge)12
Medications (see Table 2)

Drugs Associated with Headache

Table 2 lists drugs that commonly cause headache as a side effect.

7,13,14,15
Table 2: Drugs Associated with Headache

Drugs associated with intracranial hypertensiona

Antibiotics minocycline, sulfamethoxazole/trimethoprim, tetracycline

Corticosteroids

Other cimetidine, isotretinoin, tamoxifen

Drugs with headache as a side effecta

ACEIs e.g., captopril

Antihypertensives, miscellaneous hydralazine, methyldopa

Beta-blockers e.g., atenolol, propranolol (also used for migraine prophylaxis)

Calcium channel blockers nifedipine

H2 antagonists e.g., cimetidine, ranitidine

Nitrates e.g., nitroglycerin

NSAIDs diclofenac, indomethacin (also used to treat certain types of headache)

Oral contraceptives and HRT (in some patients predisposed to migraine)

SSRIs citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

Other caffeine (especially caffeine withdrawal), cyclosporine, danazol, latanoprost

ophthalmic drops,16 metronidazole

a Most common drug-related causes (not exhaustive).

Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; HRT = hormone replacement therapy; NSAID = nonsteroidal anti-inflammatory drug; SSRI = selective serotonin
reuptake inhibitor

Red Flags for Serious Headache

Severe/abrupt onset (“worst headache ever”)

Onset in middle age or older (>40 years)

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Neurologic signs: stiff neck, focal signs, reduced consciousness
Systemic signs: appears ill, fever, nausea/vomiting (not explained by migraine or systemic illness)
Significant change in pattern of headaches: increased frequency and/or progressive severity
Nocturnal occurrence or on awakening in the morning; if patient consistently has headache on awakening or is awakened by a headache, brain tumour is a possible
cause; however, migraines sometimes occur on awakening
Onset with exercise or sexual activity (may be benign or serious)

Nonpharmacologic Therapy
Patient education is important in the management of headache. Provide patients with an explanation of their headache disorder and use printed materials to reinforce verbal
information. Reassure them (in some cases, once the diagnosis has been confirmed) that they do not have a serious underlying cause for headaches (e.g., brain tumour).
Establish realistic goals and expectations of treatment; explain benefits and limitations of various treatment options in collaboration with the patient's healthcare team.
Patients may also benefit from referral to self-help groups.11,14

Acute/Symptomatic Treatment

During a migraine attack, simple measures such as resting in a dark, quiet room and applying a cold cloth/ice pack to the head are helpful, although not evidence-based.
Sleep often alleviates migraine headaches.

Prevention

Migraine and other headaches are often triggered by 1 or more factors. Triggers vary among individual patients. Advise patients to identify and avoid the triggers
associated with their migraines. Lifestyle changes such as maintaining regular sleeping and eating schedules, reducing stress and limiting caffeine intake may reduce the
frequency of headaches, particularly migraine. A sudden decrease in caffeine consumption may lead to a withdrawal headache; caffeine may help alleviate headache in
some migraine sufferers. Ask patients to maintain a headache diary (available from www.headachenetwork.ca or www.migrainecanada.org), that includes food ingested
within 24 hours prior to an attack, to identify dietary migraine triggers.14 If feasible, discontinue drugs implicated in triggering a headache (see Table 2) on a trial basis.
Common migraine triggers are listed in Table 3.

9,14
Table 3: Migraine Triggers

Types of Triggersa Examples

Chemical Benzene, insecticides, perfumes or other strong odours.

Drugs See Table 2.

Environmental Weather changes (barometric pressure changes), bright/flickering lights, loud noise, strong odours
(e.g., perfume), cigarette smoke, travel across time zones.

Foods and beverages that contain nitrites, Aged cheeses, cured meats (e.g., hot dogs, bacon), chocolate, alcoholic beverages (especially red
monosodium glutamate (MSG), aspartame or wine), caffeine-containing beverages.
neurotransmitter precursors (e.g., tyramine, tyrosine, Missed or delayed meals can also trigger migraine.
phenylalanine)

Hormonal Menstruation, pregnancy (especially in first trimester), perimenopause.

Other Sleep-wake cycle alterations, stress/anxiety (or let-down from stress), intense activity/physical
exertion, sexual activity.

a Most common triggers are listed (not an exhaustive list).

Biobehavioural measures such as biofeedback, relaxation therapy, cognitive behavioural therapy and acupuncture may help to prevent migraine in some individuals.14
While aerobic exercise (e.g., 40 minutes 3 times weekly) may trigger a headache for some patients, in others it may reduce headache frequency and provide an option
for patients who cannot or choose not to take prophylactic medication.17

Controversial measures include chiropractic and other physical therapies, transcutaneous electrical stimulation, hypnosis, occipital or supraorbital nerve blockade and
homeopathic remedies.14,18

Pharmacologic Therapy
For comparative ingredients of nonprescription products, consult the Compendium of Products for Minor Ailments—Analgesic Products: Internal Analgesics and Antipyretics;
Herbal and Natural Health Products: Single Entity; Vitamin and Mineral Products: Single Entity.

Symptomatic Treatment

See Table 4 for information on drug therapy for acute headache.

Tension-type Headaches

Analgesics

Mild tension-type headache may not require treatment. Appropriate doses of simple analgesics (e.g., acetaminophen, ASA) or NSAIDs (e.g., ibuprofen,
naproxen sodium) will often alleviate tension-type headaches.2,11

Migraine Headaches

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The goal of acute drug therapy for migraine headaches is to alleviate pain within 2 hours of treatment.10 Several agents may be tried before finding the most effective
therapy. Patients may need ≥1 medication depending on the migraine severity. Moderate to severe migraine attacks often require the use of triptans with or without
simple analgesics, and possibly antiemetics.10 Consider prophylactic therapy if migraine attacks have a significant impact on quality of life despite appropriate use of
acute medications or if frequency of attacks and reliance on acute medications puts patients at risk of MOH30 (see Preventive Therapy).

Analgesics

Mild to moderate migraine attacks may respond to adequate doses of simple analgesics (e.g., acetaminophen, ASA) or NSAIDs (e.g., ibuprofen, naproxen
sodium).2,11,26,31

There is a lack of evidence of efficacy for codeine (8 mg) in combination with ASA or acetaminophen (plus caffeine) in the treatment of migraine. It may be
considered if other options are ineffective or contraindicated. Recommended dosage is 1–2 tablets Q4H PRN in adults and 1–2 tablets up to QID in adolescents.
Side effects associated with codeine include constipation, sedation, dependence and tolerance. Codeine has been associated with an increased incidence of
congenital anomalies including cleft palate and inguinal hernias.21 To avoid MOH, these combination products should be used <10 days/month. Overuse of
caffeine can lead to withdrawal headache. Use codeine with caution in a breastfeeding mother: choose the lowest effective dose and limit treatment to less than
3–4 days.32 For more information on opioid use in this population, consult the Compendium of Pharmaceuticals and Specialties: Drug Use during Breastfeeding.

Unfortunately many migraine sufferers do not achieve adequate pain relief by relying exclusively on simple analgesics.33,34,35,36,37,38 Furthermore, most
published trials of nonprescription agents in migraine have systematically excluded patients with more severe attacks.

Triptans

Triptans or 5-HT1B/1D receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan) are considered to
be the most efficacious agents for acute migraine treatment.39,40 They alleviate headache pain and migraine-associated symptoms (nausea/vomiting,
photophobia/phonophobia). In randomized controlled trials, all triptans have demonstrated efficacy in the treatment of acute migraine; however, individuals may
differ in their response to a particular triptan. The triptans are available in various formulations: subcutaneous injection (sumatriptan), oral tablets (all), orally
disintegrating tablets (rizatriptan, zolmitriptan) and intranasal (sumatriptan, zolmitriptan).41 If oral agents are not effective or cannot be used due to
nausea/vomiting, consider an intranasal formulation or the triptan showing the greatest efficacy—subcutaneous sumatriptan.10

The combination of an NSAID (e.g., naproxen sodium) and a triptan (e.g., sumatriptan) has better efficacy compared with either agent alone, and reduces
headache recurrence.42,43 A Cochrane review determined that the combination of naproxen sodium (500 mg) and sumatriptan (50 mg or 85 mg) was more
effective than monotherapy with naproxen sodium, sumatriptan or placebo for headache relief and being pain-free after two hours.44 Treating early, while pain was
still mild, was significantly better than treating when pain was moderate or severe;44 thus, encourage patients to treat the migraine as soon as possible. [Evidence:
SORT A] As some of the above formulations or strengths are not available in Canada (e.g., naproxen sodium 500 mg, sumatriptan 85 mg), prescribers should
offer the multi-drug combination of naproxen sodium (550 mg) and sumatriptan (50 mg) to the following patients:
patients whose response to triptan monotherapy is inadequate10,44 [Evidence: SORT A] or
patients who experience frequent headache recurrences after successful treatment with triptan monotherapy10 [Evidence: SORT A]

Ergotamine Derivatives

Nasal or injectable dihydroergotamine (DHE) has been shown to be effective for migraine.10,45 Oral ergot preparations (e.g., ergotamine tartrate; no longer
available in Canada) have limited efficacy and excessive side effects.10,46

Other Agents

In the emergency room, various parenteral agents may be used for treatment of severe migraine. Adjunctive antiemetics (e.g., metoclopramide),
chlorpromazine, prochlorperazine, ketorolac, dexamethasone or opioids (not considered first-line therapy) may be given with other agents such as DHE.10

Butalbital (in combination with ASA, caffeine and/or codeine) is sometimes used in the management of acute migraine, but has a very limited role due to the
potential for dependence, abuse, medication-overuse headache and the possibility of a withdrawal syndrome following discontinuation of high doses.10

Adjunctive drugs for the management of nausea/vomiting associated with migraine include dimenhydrinate (though there is a lack of evidence), domperidone,
metoclopramide or prochlorperazine.10

For further discussion of pharmacologic therapy for migraine, consult the Compendium of Therapeutic Choices: Headache in Adults; Headache in Children.

Medication-overuse Headache

Treatment of medication-overuse headache (MOH) involves discontinuation of the drug(s) that are implicated, relief of withdrawal symptoms, use of migraine-specific
medications (adhering to recommended limits in frequency of use) to treat recurrent headaches, and initiation of prophylactic therapy (e.g., divalproex sodium,
propranolol, topiramate, tricyclic antidepressants). The causative agents are usually stopped abruptly or sometimes tapered, while titrating prophylactic therapy.
Advise patients not to discontinue high doses of butalbital-containing analgesics abruptly, since seizures may occur on withdrawal. Ideally, refer these patients to a
neurologist/headache specialist. Primary care healthcare practitioners can play a key role in preventing and managing MOH. Monitor the patient's use of prescription
and nonprescription medications, counsel on appropriate use of antimigraine medications and provide support to patients who are withdrawing from
medications.47,48,49,50,51,52

Preventive Therapy

Tension-type Headache

Most strategies to prevent tension-type headache are nonpharmacologic (see Nonpharmacologic Therapy). For disabling and/or chronic tension-type headache,
pharmacologic prophylaxis may be considered (e.g., amitriptyline, mirtazapine, nortriptyline, venlafaxine).53

Migraine

Prophylactic therapy is usually administered daily to reduce the frequency and severity of attacks in patients with migraine. Guidelines for migraine prophylaxis are
available from the Canadian Headache Society.30

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Prophylactic migraine therapy is appropriate in the following circumstances:10,11,30

Migraine attacks (any number) that significantly impair normal activity or quality of life despite appropriate use of acute therapies
Optimal acute therapies have failed, are contraindicated or have produced serious side effects
Frequent attacks that result in the potential overuse of acute therapies and may lead to medication-overuse headache.

Prophylaxis is considered successful if headache frequency, or number of days with headache, is reduced by ≥50%. Typically only 1 preventive agent is used at a
time; however, neurologists may prescribe combinations of agents in resistant cases. Start medications at a low dose and titrate to the most effective tolerated dose.
A trial period of at least 2 months is needed to assess the efficacy of most prophylactic medications. If effective, prophylactic agents may be continued for 6–12
months, then tapered gradually (to assess ongoing need and prevent rebound headaches). Prophylactic therapy may be required for prolonged periods in some
patients. Consider the patient's concurrent medical conditions (e.g., hypertension, depression or obesity) and/or drug contraindications (e.g., beta-blockers are
contraindicated in patients with asthma) when selecting a prophylactic agent. Advise patients to keep a headache diary (available from www.headachenetwork.ca or
www.migrainecanada.org) to monitor their response to therapy.30

Preventive Agents

Medications used for migraine prophylaxis include beta-blockers without intrinsic sympathomimetic activity (e.g., propranolol, nadolol, metoprolol), tricyclic
antidepressants (e.g., amitriptyline, nortriptyline), calcium channel blockers (e.g., flunarizine, verapamil), serotonin (5-HT2) receptor antagonists (e.g.,
pizotifen), valproic acid/divalproex sodium, topiramate, candesartan, lisinopril, gabapentin and NSAIDs (e.g., naproxen sodium 550 mg twice daily for 1
week per month for menstrual migraine prophylaxis).10,11,30,53

For more information on preventive therapy, consult the Compendium of Therapeutic Choices: Headache in Adults; Headache in Children.

Natural Health Products

See Table 5 for information on natural health products used for migraine headache prophylaxis.

Butterbur (Petasites hybridus extract) 75 mg, and not 50 mg, was significantly more effective than placebo in a controlled trial that randomized patients with
migraine (n=245) to butterbur 50 mg, 75 mg or placebo twice daily.55 Sixty-eight percent of patients receiving butterbur 75 mg BID achieved ≥50% reduction in
attack frequency after 4 months compared with 49% for the placebo arm. Butterbur was well tolerated; the most frequently reported adverse events included mild
GI events, primarily burping. There have been rare reports of hepatotoxicity.54 Caution patients to avoid consuming any part of the Petasites plant other than
specific commercially prepared products that have had plant carcinogens and hepatotoxic alkaloids removed.

Coenzyme Q10 (300 mg/day) was well tolerated and superior to placebo in a small, randomized, controlled trial of migraine prophylaxis in 42 patients.57 Better
studies are needed to determine the efficacy of coenzyme Q10 in migraine prophylaxis.

The potential role of magnesium deficiency in the pathogenesis of migraine has been investigated. Prophylactic oral magnesium supplementation was effective in
2 double-blind studies. The lack of response in a third study is thought to be due to the poor absorption of magnesium preparation used.58,59,60 In 1 study that
demonstrated the efficacy of magnesium, patients received magnesium 600 mg (24 mmol) daily in the form of trimagnesium dicitrate (not available in Canada; an
alternative may be magnesium citrate).58 More definitive, large-scale studies are needed to assess the role of magnesium in migraine prevention.

Riboflavin (vitamin B2) 400 mg daily for 3 months was compared with placebo for migraine prophylaxis in a randomized, double-blind trial with 55 patients.61
Approximately 50% of patients taking riboflavin had ≥50% reduction in frequency of attacks compared with 15% in the placebo arm. The exact mechanism of
action is not known but may be related to its effects on mitochondrial energy metabolism. It is thought that mitochondrial dysfunction, resulting in impaired oxygen
metabolism, may play a role in migraine pathogenesis. Only minor adverse effects (1 case each of diarrhea and polyuria) were reported in the riboflavin group.
Riboflavin can also cause insignificant yellow discoloration of the urine.61 In a randomized, double-blind study of 48 children with migraine, a high placebo
response rate suggested that riboflavin 200 mg daily is not effective in preventing migraine in children.62 Further large-scale and comparative studies are needed
to determine the efficacy of riboflavin in migraine prophylaxis.

Although feverfew (Tanacetum parthenium) has been used for migraine prophylaxis, evidence for its efficacy is conflicting and it appears to be no better than
placebo. Therefore, it is no longer recommended for migraine prophylaxis in the Canadian guidelines.30 Furthermore, discontinuation of feverfew can result in
post-feverfew syndrome, characterized by severe headache, insomnia, nervousness and joint pain.56

Medication-overuse Headache

To prevent the development of MOH when treating primary headache disorders such as migraine or tension-type headache, use simple analgesics (e.g.,
acetaminophen, ASA) <15 days per month and combination analgesics or opioids <10 days per month. Frequent use (≥10 days per month) of ergot or triptan
medications can also result in MOH. Headache associated with overuse of analgesics tends to resemble a tension-type headache (migraine headaches can also be
superimposed) whereas triptan overuse manifests as increased migraine frequency.47,48,49,50,51,52

Monitoring of Therapy

Acute/Symptomatic Therapy

Ideally, medications should relieve headaches (no pain or mild pain) and associated nausea/vomiting and photophobia/phonophobia within about 2 hours.10 Advise
patients to report any significant adverse effects to their healthcare practitioner (see Table 4 for side effects and drug interactions of nonprescription medications).

Preventive Therapy

Continue prophylactic medications for migraine for at least 2 months to determine efficacy. A ≥50% reduction in the frequency of migraine attacks is considered a good
response. Advise patients to record exercise, food intake, medication use and migraine attacks in a headache diary,4 and to report any medication adverse effects to their
healthcare practitioner (see Table 5 for side effects of natural health products for migraine prophylaxis).

Algorithms

Figure 1: Assessment and Management of Patients with Headache

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a Limit use of simple analgesics (e.g., acetaminophen, NSAIDs) to <15 days/month and combination analgesics (e.g., acetaminophen with codeine) to <10 days/month.
b Limit use of ergot and triptan products to <10 days/month.

Drug Tables
Table 4: Drug Therapy for Treatment of Mild Tension-type and Migraine Headaches

Drug/Costa Dosage Adverse Effects Drug Interactions Comments

Drug Class: NSAIDs

ASA Adult: 975–1000 mg GI upset—usually the Increased risk of bleeding with Use <15 days/month to avoid MOH. Good
Aspirin, Coated pob only more common anticoagulants (e.g., warfarin) or evidence for efficacy in migraine (975–1000
Aspirin, generics Pediatric (≥12 y): adverse effect when antiplatelet drugs (e.g., mg).19
500–650 mg single single doses are used to clopidogrel). A meta-analysis of 3 trials concluded that
$ dose treat acute headache. May decrease effect of effervescent ASA 1000 mg was as effective as
With continuous or antihypertensives. sumatriptan 50 mg for acute migraine.20
frequent NSAID use: May decrease renal clearance
Cardiovascular: MI, Because of the possible risk of Reye's
of lithium; monitor lithium levels syndrome, ASA should not be used in the
stroke, heart failure, fluid when NSAID added.
retention, hypertension. presence of viral illness or fever in children.
Increased risk of GI bleeding Enteric-coated preparations will result in a
CNS: Dizziness, when used with SSRIs.
drowsiness, headache, delayed onset of action.
tinnitus, confusion Pregnancy: Relatively safe in intermittent
(especially in the elderly); doses during first and second trimesters;
CNS effects may be dose avoid use in third trimester (may be
related and respond to associated with prolonged gestation and
decreased dosage. labour, premature narrowing of ductus
GI: Dyspepsia, epigastric arteriosus, persistent pulmonary hypertension
pain, nausea/vomiting, of the newborn).21
diarrhea, gastric and
duodenal ulcers, GI
bleeding.
Nephrotoxicity may occur;
avoid NSAIDs in patients
with severe renal
impairment (ClCr <30
mL/min).
Minor or serious skin
rashes, pruritus.

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Drug/Costa Dosage Adverse Effects Drug Interactions Comments

ibuprofen Adult: 400 mg pob GI upset—usually the Increased risk of bleeding with Use <15 days/month to avoid MOH.
Advil, Advil
Pediatric:
only more common anticoagulants (e.g., warfarin) or Good evidence for efficacy in migraine.22
Children/Pediatric, adverse effect when antiplatelet drugs (e.g.,
Children ≥6 months: A meta-analysis concluded that ibuprofen at
Advil Junior Strength, single doses are used to clopidogrel).
5–10 mg/kg Q6–8H doses of 200 mg or 400 mg is effective in
Advil Liquid Gels, treat acute headache. May decrease effect of
po PRN for symptom rendering migraine sufferers pain-free at 2 h;
Motrin, Motrin With continuous or antihypertensives.
management; however, photophobia and phonophobia
(Children's), Motrin IB, frequent NSAID use: May decrease renal clearance
Motrin Liquid Gels,
maximum 40
Cardiovascular: MI, improved only with the 400 mg dose.23
mg/kg/day; do not of lithium; monitor lithium levels
generics stroke, heart failure, fluid when NSAID added. Pregnancy: Relatively safe in intermittent
exceed adult dose
retention, hypertension. doses during first and second trimesters;
$ Increased risk of GI bleeding avoid use in third trimester (may be
CNS: Dizziness, when used with SSRIs.
drowsiness, headache, associated with prolonged gestation and
tinnitus, confusion labour, premature narrowing of ductus
(especially in the elderly); arteriosus, persistent pulmonary hypertension
CNS effects may be dose of the newborn).21
related and respond to
decreased dosage.
GI: Dyspepsia, epigastric
pain, nausea/vomiting,
diarrhea, gastric and
duodenal ulcers, GI
bleeding.
Nephrotoxicity may occur;
avoid NSAIDs in patients
with severe renal
impairment (ClCr <30
mL/min).
Minor or serious skin
rashes, pruritus.

naproxen Adult: 500 mg pob GI upset—usually the Increased risk of bleeding with Use <15 days/month to avoid MOH.
Naprosyn, only more common anticoagulants (e.g., warfarin) or In studies showing efficacy in migraine,
Pediapharm Naproxen adverse effect when antiplatelet drugs (e.g., prescribed doses of 500–825 mg were
Suspension, generics single doses are used to clopidogrel). used.24
treat acute headache. May decrease effect of
$ Pregnancy: Relatively safe in intermittent
With continuous or antihypertensives.
doses during first and second trimesters;
frequent NSAID use: May decrease renal clearance avoid use in third trimester (may be
Cardiovascular: MI, of lithium; monitor lithium levels associated with prolonged gestation and
stroke, heart failure, fluid when NSAID added. labour, premature narrowing of ductus
retention, hypertension.
Increased risk of GI bleeding arteriosus, persistent pulmonary hypertension
CNS: Dizziness, when used with SSRIs. of the newborn).21
drowsiness, headache,
tinnitus, confusion
(especially in the elderly);
CNS effects may be dose
related and respond to
decreased dosage.
GI: Dyspepsia, epigastric
pain, nausea/vomiting,
diarrhea, gastric and
duodenal ulcers, GI
bleeding.
Nephrotoxicity may occur;
avoid NSAIDs in patients
with severe renal
impairment (ClCr <30
mL/min).
Minor or serious skin
rashes, pruritus.

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Drug/Costa Dosage Adverse Effects Drug Interactions Comments

naproxen sodium Adult: 550 mg pob GI upset—usually the Increased risk of bleeding with Use <15 days/month to avoid MOH.
Anaprox, Aleve, only more common anticoagulants (e.g., warfarin) or In studies showing efficacy in migraine,
Recommended self-
generics adverse effect when antiplatelet drugs (e.g., prescribed doses of 500–825 mg were
care dose: 220 mg
Q12H po
single doses are used to clopidogrel). used.24
$ treat acute headache. May decrease effect of
With continuous or antihypertensives.
frequent NSAID use: May decrease renal clearance
Cardiovascular: MI, of lithium; monitor lithium levels
stroke, heart failure, fluid when NSAID added.
retention, hypertension.
Increased risk of GI bleeding
CNS: Dizziness, when used with SSRIs.
drowsiness, headache,
tinnitus, confusion
(especially in the elderly);
CNS effects may be dose
related and respond to
decreased dosage.
GI: Dyspepsia, epigastric
pain, nausea/vomiting,
diarrhea, gastric and
duodenal ulcers, GI
bleeding.
Nephrotoxicity may occur;
avoid NSAIDs in patients
with severe renal
impairment (ClCr <30
mL/min).
Minor or serious skin
rashes, pruritus.

Drug Class: Simple Analgesics

acetaminophen Adult: 1000 mg pob Potential liver (and rarely Acetaminophen has been Limit use to <15 days/month to avoid MOH.
Atasol Preparations, (do not exceed 4 kidney) dysfunction with reported to increase INR in Effective in childhood migraine.26 In adults, it
Tempra, Tylenol, g/day) chronic use of high doses warfarin-treated patients.25 is considered to be less effective than ASA or
Tylenol Children's, or with acute overdose. Check INR if acetaminophen ≥2 NSAIDs for migraine.10
Pediatric: 10–15
generics g/day is used for ≥3 consecutive 1 g dose shown to be effective for migraine in
mg/kg Q4–6H po
PRN for symptom days. Adjust warfarin dosage as adults, although patients with severe migraine
$ required.
management; were excluded.27,28
maximum 75 Pregnancy: Relatively safe during all
mg/kg/day; do not trimesters; considered to be analgesic of first
exceed adult dose
choice during pregnancy.21,29

a Cost per dose; includes drug cost only.

b In acute migraine, only single doses have been studied in randomized controlled trials.

Abbreviations: MOH = medication-overuse headache; NSAID = nonsteroidal anti-inflammatory drug

Legend: $ <$1
Table 5: Natural Health Products for Prevention of Migraine Headaches

Drug/Costa Dosage Adverse Effects Drug Interactions Comments

Drug Class: Natural Health Products

butterbur Adult: 75 mg BID po Generally well No significant interactions. Good evidence for efficacy in adults.55
Pediatric: No tolerated; mild Derived from Petasites hybridus root
$$$ gastrointestinal extract; product should be standardized to
recommendations; some
evidence for safe use in events (mainly contain a minimum of 15% petasins (e.g.,
children 6–17 y for up to burping). Petadolex—Weber & Weber, GmbH & Co,
4 months Rare reports of Germany).
hepatotoxicity.54 Caution patients against consuming any
part of Petasites plant in any form other
than commercially prepared products, in
which plant carcinogens and hepatotoxic
alkaloids have been removed.
Preparations containing hepatotoxic
alkaloid might be teratogenic and
hepatotoxic.
Safety has not been established in
pregnancy, breastfeeding, or children <6
years.56

coenzyme Adult: 300 mg/day po in Generally well May have additive blood pressure lowering One small trial showed efficacy in adults.57
Q10 3 divided doses tolerated; GI effects effects when used with antihypertensive May take up to 3 months for significant
Pediatric: No (<1%; minimized by agents. benefit.
$$ recommendations; some giving in divided May reduce anticoagulant effects of warfarin.
Insufficient data regarding use in
evidence of efficacy in doses 2 or 3 times Monitor patient's INR closely.
pregnancy.
children who have low daily). May lower efficacy of chemotherapeutic
levels of coenzyme Q10 agents (e.g., doxorubicin; preliminary
evidence).

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9/2/2017 Headache

Drug/Costa Dosage Adverse Effects Drug Interactions Comments

Drug Class: Minerals

magnesium Adult: 300 mg (elemental Generally well May decrease absorption of Conflicting evidence for efficacy.58,59,60
magnesium) BID po tolerated; diarrhea, bisphosphonates (e.g., alendronate, Some magnesium salts are poorly
$ Pediatric: No GI upset. risedronate), tetracyclines or quinolone absorbed; suggest citrate salt.
recommendations; some antibiotics (e.g., ciprofloxacin, levofloxacin,
Considered reasonably safe to use in
evidence of efficacy in moxifloxacin); separate administration by at
pregnancy.
children least 2 h.

Drug Class: Vitamins

riboflavin Adult: 400 mg/day po Generally well No significant interactions. One small trial in adults showed efficacy.61
Pediatric: Insufficient tolerated; yellow Lack of efficacy in pediatric migraine
$ evidence discoloration of urine prophylaxis.62
(benign).
Use in pregnancy: safety of high-dose
therapy not shown to be safe but not
considered teratogenic.

a Cost per month; includes drug cost only.

Legend: $ <$10 $$ $10–20 $$$ $20–30

Resource Tips
Canada. Canadian Headache Society. Available from: www.migrainecanada.org.

Canada. Headache Network Canada. Available from: www.headachenetwork.ca (bilingual—English and French).

Ontario. Help for Headaches. Available from: www.headache-help.org.

U.S. American Committee for Headache Education, American Headache Society. Available from: www.achenet.org.

Suggested Readings
Becker WJ, Findlay T Moga C et al. Guideline for primary care management of headache in adults. Can Fam Physician 2015;61:670-9.

Evers S, Marziniak M. Clinical features, pathophysiology, and treatment of medication-overuse headache. Lancet Neurol 2010;9:391-401.

Purdy RA. Headache in adults. In: Jovaisas B, ed. Compendium of therapeutic choices: CTC 7. 7th ed. Ottawa: Canadian Pharmacists Association; 2014. p. 211-28.

Worthington I. Migraine headache: management strategies and optimizing therapy for acute attacks. Pharm Pract 2014;1:23-9.

Worthington I. Migraine prophylaxis: drug selection and treatment strategies for individual patients. Pharm Pract 2012;28:28-34.

References

1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version).
Cephalalgia 2013;33:629-808.
2. Fumal A, Schoenen J. Tension-type headache: current research and clinical management. Lancet Neurol 2008;7:70-83.
3. Goadsby PJ, Lipton RB, Ferrari MD. Migraine–current understanding and treatment. N Engl J Med 2002;346:257-70.
4. Silberstein SD. Migraine. Lancet 2004;363:381-91.
5. Saper JR, Da Silva AN. Medication overuse headache: history, features, prevention and management strategies. CNS Drugs 2013;27:867-77.
6. Dodick D. Headache as a symptom of ominous disease. What are the warning signals? Postgrad Med 1997;101:46-50, 55-6, 62-4.
7. Clinch CR. Evaluation of acute headaches in adults. Am Fam Physician 2001;63:685-92.
8. Campbell JK, Sakai F. Diagnosis and differential diagnosis. In: Olesen J, Tfelt-Hansen P, Welch KM, eds. The headaches. 2nd ed. Philadelphia: Lippincott William &
Wilkins; 2000. p. 359-63.
9. Worthington I. Migraine headache: management strategies and optimizing therapy for acute attacks. Pharm Pract 2014;1:23-9.
10. Worthington I, Pringsheim T, Gawel MJ et al. Canadian Headache Society Guideline: acute drug therapy for migraine headache. Can J Neurol Sci 2013;40:S1-S80.
11. Purdy RA. Headache in adults. In: Jovaisas B, ed. Compendium of therapeutic choices: CTC 7. 7th ed. Ottawa: Canadian Pharmacists Association; 2014. p. 211-28.
12. Cady RK, Dodick DW, Levine HL et al. Sinus headache: a neurology, otolaryngology, allergy, and primary care consensus on diagnosis and treatment. Mayo Clin
Proc 2005;80:908-16.
13. Silberstein SD. Drug-induced headache. Neurol Clin 1998;16:107-23.
14. Pryse-Phillips WE, Dodick DW, Edmeads JG et al. Guidelines for the nonpharmacologic management of migraine in clinical practice. Canadian Headache Society.
CMAJ 1998;159:47-54.
15. Askmark H, Lundberg PO, Olsson S. Drug-related headache. Headache 1989;29:441-4.
16. Weston BC. Migraine headache associated with latanoprost. Arch Ophthalmol 2001;119:300-1.
17. Varkey E, Cider A, Carlsson J et al. Exercise as migraine prophylaxis: a randomized study using relaxation and topiramate as controls. Cephalgia 2011;31:1428-38.
18. Li Y, Liang F, Yang X et al. Acupuncture for treating acute attacks of migraine: a randomized controlled trial. Headache 2009;49:805-16.
19. Kirthi V, Derry S, Moore RA et al. Aspirin with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2010;(4):CD008041.
20. Lampl C, Voelker M, Diener HC. Efficacy and safety of 1,000 mg effervescent aspirin: individual patient data meta-analysis of three trials in migraine headache and
migraine accompanying symptoms. J Neurol 2007;254:705-12.
21. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 10th ed. Philadelphia: Wolters Kluwer; 2015.
22. Rabbie R, Derry S, Moore RA et al. Ibuprofen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2010;
(11):CD008039.
23. Suthisisang C, Poolsup N, Kittikulsuth W et al. Efficacy of low-dose ibuprofen in acute migraine treatment: systematic review and meta-analysis. Ann Pharmacother
2007;41:1782-91.
24. Suthisisang C, Poolsup N, Suksomboon N et al. Meta-analysis of the efficacy and safety of naproxen sodium in the acute treatment of migraine. Headache
2010;50:808-18.

https://www.myrxtx.ca/print/new/documents/MA_CHAPTER/en/psc1008 9/10
9/2/2017 Headache
25. Lopes RD, Horowitz JD, Garcia DA et al. Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility. Blood 2011;118:6269-73.
26. Whiting S. Headache in children. In: Jovaisas B, ed. Compendium of therapeutic choices: CTC 7. 7th ed. Ottawa: Canadian Pharmacists Association; 2014. p. 229-
39.
27. Lipton RB, Baggish JS, Stewart WF et al. Efficacy and safety of acetaminophen in the treatment of migraine: results of a randomized, double-blind, placebo-
controlled, population-based study. Arch Intern Med 2000;160:3486-92.
28. Derry S, Moore RA, McQuay HJ. Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev
2010;(11):CD:008040.
29. Menon R, Bushnell CD. Headache and pregnancy. Neurologist 2008;14:108-19.
30. Pringsheim T, Davenport W, Mackie G et al. Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci 2012;39:S1-59.
31. Worthington I. Pediatric migraine. Pharm Pract 1999;15:48-57.
32. Sachs HC, Committee On Drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics 2013;132:e796-809.
33. Wenzel RG, Sarvis CA, Krause ML. Over-the-counter drugs for acute migraine attacks: literature review and recommendations. Pharmacotherapy 2003;23:494-505.
34. Rapoport AM. Emerging nonspecific migraine therapies: targets and unmet needs. Headache 1999;39:S27-34.
35. Sheftell FD. Role and impact of over-the-counter medications in the management of headache. Neurol Clin 1997;15:187-98.
36. Lipton RB, Stewart WF, Goadsby PJ. Headache-related disability in the management of migraine. Neurology 2001;56:S1-3.
37. Edmeads J, Findlay H, Tugwell P et al. Impact of migraine and tension-type headache on life-style, consulting behaviour, and medication use: a Canadian population
survey. Can J Neurol Sci 1993;20:131-7.
38. Lipton RB, Stewart WF. Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache 1999;39:S20-266.
39. Gawel MJ, Worthington I, Maggisano A. A systematic review of the use of triptans in acute migraine. Can J Neurol Sci 2001;28:30-41.
40. Ferrari MD, Roon KI, Lipton RB et al. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 2001;358:1668-
75.
41. Worthington I. Delivery systems for acute migraine medications. Can Fam Physician 2001;47:322-9.
42. Brandes JL, Kudrow D, Stark SR et al. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA 2007;297:1443-54.
43. Smith TR, Sunshine A, Stark SR et al. Sumatriptan and naproxen sodium for the acute treatment of migraine. Headache 2005;45:983-91.
44. Law S, Derry S, Moore RA. Sumatriptan plus naproxen for the treatment of acute migraine attacks in adults. Cochrane Database Syst Rev 2016;(4):CD008541
45. Saper JR, Silberstein S. Pharmacology of dihydroergotamine and evidence for efficacy and safety in migraine. Headache 2006;46:S171-81.
46. Tfelt-Hansen P, Saxena PR, Dahlof C et al. Ergotamine in the acute treatment of migraine: a review and European consensus. Brain 2000;123:9-18.
47. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology 2008;71:1821-8.
48. Saper JR, Da Silva AN. Medication overuse headache: history, features, prevention and management strategies. CNS Drugs 2013;27:867-77.
49. Turner CJ, Pryse-Phillips W. Pilot study to improve health outcomes for medication-induced headache sufferers. Can J Clin Pharmacol 1999;6:113-7.
50. Tepper SJ, Tepper DE. Breaking the cycle of medication overuse headache. Cleve Clin J Med 2010;77:236-42.
51. Dodick D. Freitag F. Evidence-based understanding of medication-overuse headache: clinical implications. Headache 2006;46:S202-11.
52. Grazzi L, Andrasik F. Medication-overuse headache: description, treatment, and relapse prevention. Curr Pain Headache Rep 2006;10:71-7.
53. Becker WJ, Findlay T Moga C et al. Guideline for primary care management of headache in adults. Can Fam Physician 2015;61:670-9.
54. Medicines and Healthcare Products Regulatory Agency. Consumers are advised not to take unlicensed Butterbur (Petasites hybridus) herbal remedies. London:
MHRA; 2012. Available from:
webarchive.nationalarchives.gov.uk/20141205150130/http://www.mhra.gov.uk/Safetyinformation/Generalsafetyinformationandadvice/Herbalmedicines/Herbalsafetyupdates/Allherbalsaf
55. Lipton RB, Gobel H, Einhaupl KM et al. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology 2004;63:2240-4.
56. D'Andrea G, Cevoli S, Cologno D. Herbal therapy in migraine. Neurol Sci 2014;35:135-40.
57. Sandor PS, Di Clemente MD, Coppola G et al. Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial Neurology 2005;64:713-5.
58. Mauskop A, Altura BM. Magnesium for migraine: rationale for use and therapeutic potential. CNS Drugs 1998;9:185-90.
59. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-centre, placebo-controlled and double-blind
randomized study. Cephalalgia 1996;16:257-63.
60. Pfaffenrath V, Wessely P, Meyer C et al. Magnesium in the prophylaxis of migraine–a double-blind, placebo-controlled study. Cephalalgia 1996;16:436-40.
61. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology 1998;50:466-70.
62. MacLennan SC, Wade FM, Forrest KM et al. High-dose riboflavin for migraine prophylaxis in children: a double-blind, randomized, placebo-controlled trial. J Child
Neurol 2008;23:1300-4.

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