608

Migraine and Tension-Type Headache

Azmin Kahriman, MD1 Shuhan Zhu, MD1

1 Department of Neurology, Boston Medical Center, Boston, Address for correspondence Shuhan Zhu, MD, 725 Albany Street,
Massachusetts Suite 7B. Boston, MA 02118 (e-mail: shuhan.zhu@bmc.org).

Semin Neurol 2018;38:608–618.

Abstract Migraine and tension-type headache (TTH) are common primary disorders that carry
significant morbidity and socioeconomic effect. In this article, we will review the
epidemiology, presentation, and diagnosis of these disorders. First-line acute treat-
ment for migraine consists of analgesics, triptans, and antiemetics, while nonsteroidal
anti-inflammatory drugs are the mainstay treatment for TTH. Patients with frequent or
chronic headaches warrant prophylactic therapy. For migraine, various classes of
Keywords preventives can be used (β-blockers, tricyclics, antiepileptics, botulinum toxin), with
► migraine the choice of therapy tailored to the patient’s risk factors and symptoms. For TTH,
► tension-type tricyclics have the most evidence as prophylactic therapy. A new class of medication,
headache monoclonal antibodies to calcitonin gene receptor peptide or its receptor, became

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► chronic migraine available in 2018, and is the first class of medication specifically designed to treat
► acute treatment migraine. In addition to pharmacotherapy, we will also review nonpharmacologic
► preventive treatment interventions as well as neuromodulation for migraine.

neurological diseases such as epilepsy, Parkinson’s disease,

Migraine
Epidemiology and Health Impacts
Migraine is a primary neurological condition that is char-
acterized by recurrent episodes of headache with other
associated symptoms such as nausea, vomiting, and sensi-
tivity to sensory stimuli.
The prevalence is variable based on age and gender. Among
preadolescent males and females, the prevalence is quite similar
at approximately 5%. With puberty and adulthood, the preva-
lence increases to a peak of approximately 20% for females in the
third and fourth decades of life, with a corresponding peak of
10% for males.1,2 With middle age, the prevalence begins to
decrease for both sexes, reaching approximately 5% for males
and 5 to 10% for females by the seventh decade.
Approximately 2% of the population is affected by chronic
migraine (CM) with headache
15 days of the month1; for
patients with CM, one in five patients has occupational
disability due to migraine.1 As the highest prevalence is
during early middle age, migraine leads to significant mor-
bidity and disruption of productivity, and impacts not only
the individual but also their families.1 Despite having a
higher burden on disability-adjusted life-years than other
and multiple sclerosis, migraine receives the least National
Institutes of Health research funding.3
Clinical Symptoms
Headache is a prominent feature of migraine, with a wide
range of other associated symptoms that may occur before,
during, and after the headache. In the hours to days before
onset of migraine headache, a majority of patients report
symptoms that may include feelings of fatigue, anorexia or
food cravings, restlessness, and changes in mood.4 The
underlying neurochemical changes leading to these preced-
ing symptoms are not well understood.
Approximately 30% of patients with migraine experience
aura during their lifetime. For most patients, auras are
sporadic and typically do not accompany most migraines.
Migraine aura classically consists of visual phenomena that
begin and evolve over the course of 5 to 20 minutes before
the migraine pain. Patients may describe spots of blurry or
grayed vision that block visual input (scotomas), flashes of
lights, or an arch with “zig zag” lines or jagged edges. During
the course of aura, there is evolution of the phenomenon
with the visual effects growing in size or moving across the

Issue Theme Headache and Pain; Guest Copyright © 2018 by Thieme Medical DOI https://doi.org/
Editors, James A.D. Otis, MD, FAAN, and Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0038-1673683.
Shuhan Zhu, MD New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
 Migraine and Tension-Type Headache Kahriman, Zhu 609

visual field before fading or resolving. Typical duration is 5 to
20 minutes but may be up to 60 minutes; aura may also
overlap with the onset of the headache.
Less common forms of aura include deficits in sensory,
motor, and language function, and may mimic features of
transient ischemic attacks or strokes, requiring appropriate
evaluation to exclude these diagnoses.
Based on animal models and functional imaging studies in
humans, aura is a manifestation of intense cortical neuronal
discharges followed by cortical depression that begins in the
posterior occipital lobe (hence, the visual predominant symp-
toms) and travels anteriorly through the occipital cortex.5–7
This process is termed “cortical spreading depression (CSD)”
and generally involves only the occipital lobes but can continue
to spread anteriorly and lead to the less common sensory and
motor auras. Accompanying CSD, there is release of glutamate
and potassium from glial cells that leads to activation of
trigeminal nerve fibers in brain vasculature and meninges
and subsequent propagation of migraine headache.
The headache of migraine is usually unilateral, gradual in
onset, throbbing in quality, and can be aggravated by routine
activities, light, sound, and smells. The pain severity may be
women. Headache and special considerations in women
are covered in a companion article in this issue of Seminars
in Neurology and should be reviewed for a more in-depth
discussion of this topic.
Diagnosis
Migraine is a clinical diagnosis. A physical examination
should always be performed to look for asymmetry or signs
of raised intracranial pressure, and when indicated, labora-
tory studies and neuroimaging may be helpful to evaluate
for secondary disorders that lead to migrainous pain.
Secondary causes of headache range from benign (caffeine
withdrawal) to potentially catastrophic (cerebral vasospasm,
tumors, hemorrhagic stroke). Therefore, a clear understand-
ing of the patient’s symptoms, medical background, and risk
factors are necessary to guide the evaluation. Various mne-
monics have been created to help clinicians assess for
symptoms that warrant secondary workup. A particular
favorite is the SNOOP4 mnemonic published by Dr. Dodick10
and stands for: systemic symptoms, neurological symptoms,
sudden onset, onset after age 50, pattern change, Valsalva
precipitation, postural aggravation, and papilledema.

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mild to debilitating and can last hours to several days. Muscle
tenderness on the head and neck is also very common with
migraine headache.
Migraine is more prevalent among women and is strongly
influenced by hormonal cycles. In the days before onset of
menses, there is drastic decline in serum levels of both
estrogen and progesterone; the drastic drop in estrogen
levels leads to menstrual migraine for as many as half of
women.8,9 The stability of estrogen levels during pregnancy
(consistently higher) and after menopause (consistently
lower) leads to reduction migraine for the majority of
When secondary disorders are adequately evaluated and
excluded, the International Classification of Headache Disor-
ders, 3rd edition (ICHD-3)11 can be used to help with the
diagnoses of migraine and other primary headache disorders.
►Table 1 shows the diagnostic criteria for migraine and aura
based on the ICHD-3.
Approach to Migraine Management
As for any complex medication condition, both nonpharma-
cologic and pharmacologic managements are required.
Appropriate treatment should take into account the patient’s

Table 1 ICHD-3 diagnostic criteria for migraine with and without aura11

Migraine without aura Migraine with aura

A. At least five attacks fulfilling criteria B–D
B. Headache attacks lasting 4–72 h
(untreated or unsuccessfully treated)
C. Headache has at least two of the following
four characteristics:
1. Unilateral location
2. Pulsating quality
3. Moderate or severe pain intensity
4. Aggravation by or causing avoidance
of routine physical activity
(e.g., walking or climbing stairs)
D. During headache at least one of the following:
1. Nausea and/or vomiting
2. Photophobia and phonophobia
E. Not better accounted for by another
ICHD-3 diagnosis
A. At least two attacks fulfilling criteria B and C
B. One or more of the following fully reversible aura symptoms
1. Visual
2. Sensory
3. Speech and or language
4. Motor
5. Brainstem
6. Retinal
C. At least two of the following four characteristics:
1. At least one aura symptom spreads gradually over
5 min
2. Two or more aura symptoms occur in succession
3. Each individual aura symptom lasts 5–60 min
4. At least one aura symptom is unilateral
5. At least one aura symptom is positive
6. The aura is accompanied, or followed within 60 min, by headache
D. Not better accounted for by another ICHD-3 diagnosis

Abbreviation: ICHD-3, International Classification of Headache Disorders, 3rd edition.

Seminars in Neurology Vol. 38 No. 6/2018

610 Migraine and Tension-Type Headache Kahriman, Zhu
medical comorbidities, preferences and needs, migraine
symptoms, and their frequency, severity, and impact upon
quality of life.
First step in the management of migraine should include
identification and management of migraine triggers such as
sleep deprivation, alcohol, hunger/dehydration, and pro-
longed exposure to strong stimulus (lights, sounds, strong
odors), as well as identification of possible contribution to
headaches from medication overuse (MOH).
Anecdotally, particular foods such as chocolate, aged
cheeses, red wine, monosodium glutamate, and aspartame
have been implicated as migraine triggers, but this is a topic
of great controversy without a consensus. While alcohol is
generally accepted as a migraine trigger,12 studies on other
foods have been conflicting.13–17 There may be a subset of
patients who are particularly affected by certain foods but
the mechanism of association is uncertain. Patients should
identify personal triggers by a careful headache diary.
As for any complex medication condition, both nonpharma-
cologic and pharmacologic managements are required. Appro-
priate treatment should take into account the patient’s medical
comorbidities, preferences and needs, migraine symptoms, and
their frequency, severity, and impact upon quality of life.
As migraine is not a static condition, patients may move in
and out of periods of more severe/frequent migraine and
require different treatment over time. Pharmacotherapy
includes acute and preventive treatments. Acute treatments
are taken during a migraine attack with the goal of quickly
reducing the duration and severity of migraine symptoms.
Preventive treatment medications are meant to be taken
daily with a goal of reducing the frequency/duration/severity
of migraine. Preventive treatments often require several
weeks or longer to exert an effect and cannot substitute for
acute medications. Acute medications also cannot substitute
for preventive medications, as daily use of acute medications
can lead to increased headache frequency, loss of effective-
ness, and other side effects.
Nonpharmacologic techniques include relaxation train-
ing, biofeedback, and cognitive behavioral therapy. For
patients with infrequent episodic migraine that are nondi-
sabling, avoidance of triggers along with acute treatment
during attacks may be sufficient. Patients with disabling
attacks, high-frequency migraine, or CM at
15 headaches
days/month11 may require preventive treatments along with
acute and nonpharmacologic treatments.
Acute Treatment
Acute treatments can be separated into three main classes:
(1) the nonspecific analgesics (e.g., acetaminophen), (2)
migraine-specific analgesics (e.g., triptans and ergots), and
(3) adjunctive treatment for other associated symptoms (e.g.,
antiemetics). ►Table 2 lists some common acute treatments
in each class and the strength of evidence for effectiveness as
acute treatment as established by the American Headache
Society (AHS).18 As reported in further detail in the AHS
publication, level A medications are established as effective
for acute migraine treatment, level B medications are prob-
ably effective, and level C medications are possibly effective.
Seminars in Neurology Vol. 38 No. 6/2018
Table 2 Acute migraine treatments with American Headache
Society recommendations on level of evidence
Level of evidence18
Nonspecific analgesics
Acetaminophen A
Ibuprofen A
Naproxen A
Diclofenac A
Ketorolac B
Migraine-specific analgesics
Triptans (see ►Table 3) A for all triptans
Ergots (nasal spray, injection) A
Adjunctive treatment
Metoclopramide B
Prochlorperazine B
Others
Butalbital-containing compounds C
Opioids C
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Nerve blocks Not rated
Corticosteroids Not rated
Notes: Level A medications are established as effective for acute
migraine treatment, level B medications are probably effective, and
level C medications are possibly effective.
Although butalbital and opioid-containing medications may
have some role in the treatment of acute migraine, especially
if other acute treatments are contraindicated due to comor-
bidities or medication interactions, its routine use is not
generally recommended due to the risk of tolerance, addic-
tion, and potential withdrawal.19
While most neurologists are already quite familiar with
the use of nonspecific analgesics and antiemetics, many
are not as familiar with the use of ergots or all the various
formulations of triptans. Ergots were the first migraine-
specific treatments with agonism at two main serotonin
receptors, 5-HT1B and 5-HT1D. Ergots have largely been
replaced by triptans after their advent in the 1990s. Although
effective for acute migraine, ergots have a more problematic
side effect profile compared with triptans including hyper-
tension, peripheral arterial constriction, and severe nausea
due to its dopaminergic properties. It is also poorly absorbed
as an oral or nasal spray medication and is not available as a
preloaded syringe injection making administration more
difficult for patients. Currently, ergots are largely prescribed
only by headache specialists for patients with severe refrac-
tory migraines.
Triptans, similar to ergots, are also agonists at 5-HT1B and
5-HT1D, which are found on the arterial vasculature and tri-
geminal nerve endings, respectively. Due to its effects at 5-HT1D,
triptans can also cause vasoconstriction and are contraindicated
in those with vascular disease such as coronary artery disease,
ischemic stroke, peripheral arterial disease, and Raynaud’s.
 Migraine and Tension-Type Headache Kahriman, Zhu 611

Subcutaneous sumatriptan was the first triptan formula-
tion to receive U.S. Food and Drug administration (FDA)
approval for acute treatment of migraine in 1993. In the
subsequent decade, the FDA approved rizatriptan, naratriptan,
almotriptan, and others. Currently, there are seven triptans
available in different formulations, from injections to nasal
sprays and oral disintegrating tablets, with half-lives ranging
from 2 to 3 hours to more than 24 hours. Although triptans are
generally quite safe for those without vascular disease, there
are key medication interactions that clinicians should be aware
of. Triptans are contraindicated for use with ergots and mono-
amine oxidase inhibitors (MAOIs) such as phenelzine or selegi-
line due to the serotonergic effects. The use of triptans with
other serotonergic medications such as serotonin reuptake
inhibitors (SSRI) is generally safe; however, for patients on high
doses of fluoxetine or paroxetine which are strong inhibitors of
CYP2D6, using a lower triptan dose and specifically discussing
the additional risk of overuse to include serotonin syndrome
can reduce the risk of severe adverse events.
►Table 3 lists specific details of triptan formulations and
pharmacokinetics along with major pharmacologic interac-
tions.20 Triptans are solely used for acute treatment, with the
treatment. Retrospective data show that it may reduce pain
intensity and medication use but not pain duration.23
Corticosteroids, either through oral dosing (e.g., prednisone
40–60mg for 6–8 days) or single parenteral dosing (e.g.,
dexamethasone 8–10mg), is commonly used for acute treat-
ment of refractory migraine, particularly if patients have not
responded to other treatments. A comprehensive meta-analy-
sis by Woldeamanuel showed reduced risk of headache recur-
rence with generally tolerable adverse side effects.24 Although
steroids may be effective acute treatment, physicians should be
aware of the long-term adverse effects (immunosuppression,
adrenal insufficiency, Cushing’s syndrome, osteonecrosis,
osteoporosis, etc.) and monitor/limit cumulative exposure.
For milder migraine attacks, use of a nonspecific analgesic
may be sufficient. More severe attacks may be treated by
combining medications from two or more classes. Stratifying
the combination of acute medications based on attack sever-
ity has been shown to be more effective than a fixed or
escalating approach, with better 2-hour pain-free response
and lower score on the Migraine Disability Assessment
Scale.25 Use of acute treatments early during the attack
when pain severity is typically lower also results in more

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exception of frovatriptan, which has a relatively long half-life
of more than 24 hours and has been studied as a short-term
preventive medication for up to 6 days at a time for the
treatment of menstrual migraine.21,22
Greater occipital nerve blocks with an anesthetic (typi-
cally 1–2% lidocaine, or 0.25% bupivacaine) with or without
steroids (typically methylprednisolone 20–40 mg) are gen-
erally safe and frequently performed by physicians for acute
treatment of migraine. However, there is a lack of standar-
dization in exact techniques and injectate used, in addition to
a lack of placebo-controlled and sufficiently powered studies
to be able to formulate a level of recommendation for this
effective treatment, as central sensitization may occur with
delayed treatment and lead to poorer response.26–29
Although opioids and butalbital-containing medications
may provide acute pain relief for some patients, nonsteroidal
anti-inflammatory drugs (NSAIDs) and triptans have better
levels of evidence for effectiveness. Opioid and butalbital-
based medications also carry significant risks of dependence
and abuse; therefore, they are not routinely recommended
for acute treatment of migraine. If their use is required for
patients who have contraindications to other acute treat-
ments, the risks should be discussed and the doses should be
appropriately monitored and limited in frequency/duration.

Table 3 Triptan formulations, pharmacokinetics, and use details

Generic Formulations Tmax Half-life Major interactions and clinical notes20

(brand)
Sumatriptan Oral 2.5 h 2h Contraindication with MAOI. Only injectable form of triptan available,
(Imitrex) Intranasal 1–1.5 h 2h most commonly prescribed triptan
Subcutaneous 15 min 2h
injection
Rizatriptan Oral 1–2.5 h 2–3 h Contraindication with MAOI. Levels increased by propranolol,
(Maxalt) use half max daily dose of triptan
Naratriptan Oral 2–3 h 5–8 h No major interactions with MAOI
(Amerge)
Zolmitriptan Oral 2h 2.5–3 h Contraindication with MAOI, levels increased by CYP1A2 inhibitors
(Zomig) Intranasal 2h 2.5–3 h such as cimetidine or ciprofloxacin (use half max daily dose of triptan)
Almotriptan Oral 1–3 h 3–4 h No major interactions with MAOI
(Axert)
Eletriptan Oral 1–2 h 3–4 h No major interactions with MAOI. Levels increased by CYP3A4
(Relpax) inhibitors such as ketoconazole or clarithromycin, wait for 72 h
before triptan exposure
Frovatriptan Oral 2–4 h 26 h Contraindication with MAOI. Levels increased by CYP1A2 inhibitors
(Frova) such as cimetidine or ciprofloxacin (use half max daily dose of triptan)

Notes: Triptans should not be used with ergots. Most triptans are also contraindicated for use with monoamine oxidase inhibitors (MAOI) such as
phenelzine or selegiline due to the serotonergic effects; a wash out period of 2 wk is recommended.

Seminars in Neurology Vol. 38 No. 6/2018

612 Migraine and Tension-Type Headache Kahriman, Zhu
Medication Overuse Headache
It is a generally accepted idea that acute medications used to
treat migraine may cause MOH with overly frequent use in
addition to other side effects such as gastrointestinal injury
(NSAIDs), hepatic toxicity (acetaminophen), and movement
disorder (antiemetics). Medications that have been associated
with MOH include triptans, formulations containing caffeine
(e.g., Excedrin), butalbital (e.g., Fioricet), and opioids. There is
no standardized threshold at which individual patients may
develop MOH. As a general guideline, nonspecific analgesics
should be used no more than 15 days of a month, and triptans
should be limited to no more than 9 days a month.30,31
Although MOH is a generally accepted idea, there are some
controversies as patients may very well have frequent migraine
independent of any medication use and invoking MOH may be
interpreted as laying the blame on patients rather than their
disease. There are no blinded and controlled studies on the
effect of medication withdrawal for suspected MOH and
observational studies are limited by high drop out and con-
founding. A large survey-based longitudinal study as part of the
American Migraine Prevalence and Prevention study32 showed
that over the course of 1 year, of 8,219 patients with episodic
migraine, 209 (2.5%) had transformation to CM. Compared with
patients who used only acetaminophen, those with exposure to
barbiturate or opioid-containing medications were more likely
to have transformation to CM. Triptan, NSAIDs, and caffeine-
containing compounds were not associated with a higher risk
compared with acetaminophen alone.
As observational studies are limited by confounding, some
animal models of MOH have been used. A study of triptans
showed that rats exposed to 6 days of subcutaneous suma-
triptan had lowered threshold of electrically inducible CSD
which was blocked by coadministration of topiramate.33 A
rat study with acetaminophen exposure for 30 days also
showed an increase in CSD frequency with KCl induction,
whereas acute administration did not change CSD fre-
quency.34 Relationship between caffeine and headache in
general is complex. While caffeine has been shown to have
efficacy as an adjuvant to analgesic for treatment of acute
headache treatment, caffeine overuse and withdrawal from
caffeine can trigger migraines.35 Caffeine produces a vaso-
constrictive effect on cerebrovascular by antagonism of
adenosine A2 receptor and withdrawal can lead to change
in vascular tone and headache.36,37
When MOH is suspected to play a role in the frequency of
headache, cessation of the drug may require initiation of a
prophylactic medication and/or a corticosteroid burst or taper
of 60 mg prednisone over 6 to 8 days.38 Butalbital-containing
analgesics deserve a specific mention as withdrawal from high
daily doses may cause to delirium and seizure. Cessation may
require inpatient monitoring for withdrawal symptoms and
administration of oral phenobarbital whose long-life allows for
slow tapering and prevention of withdrawal symptoms.39 A
commonly used “conversion” is phenobarbital 30 mg/day in
place of 100 mg/day of butalbital followed by gradual taper of
the phenobarbital over weeks to a month.
Chronic opioid medication use is associated with many
other potential adverse effects in addition to possible MOH.
Seminars in Neurology Vol. 38 No. 6/2018
The interaction of physical and psychologic addiction may
make opioid cessation a particularly difficult process to
manage for patients and treating physicians and is out of
the scope of this publication to review in detail.
Preventive Pharmacologic Treatment
Patients with migraines that are refractory to acute treat-
ment, high-frequency episodic migraine, or CM may require
preventive pharmacologic treatments along with acute and
nonpharmacologic treatments.
Multiple classes of oral medications have been used as
migraine preventives, including blood pressure agents, anti-
depressants, antiseizure medications, and nutraceuticals.
Onabotulinum toxin A, injected to cranial/head and neck
muscles via the PREEMPT protocol every 12 weeks, received
FDA approval as a preventive agent for CM in 2010.40–42
►Table 4 reviews the most commonly used preventive agents
along with their classification for level of effectiveness based
on guideline publications from the American Academy of
Neurology.43–45
Selection of an appropriate preventive medication requires
review of each patient’s medical background, comorbidities,
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and health concerns. In women, it is also important to take into
account possible family planning goals to reduce the risk of fetal
exposure, particularly to agents such as valproate and topira-
mate, which are pregnancy category X and D, respectively.
Preventives may take weeks to several months to exert a
therapeutic effect, which requires patience on behalf of both
patients and providers. Medications should be started at low
dose and gradually increased based on clinical response and
tolerability.
The natural history of migraine is to vary over time in
frequency and severity, such that during periods of relatively
quiesce, a preventive may not be necessary. For many patients,
if migraines are well controlled for 6 months, then preventives
may be gradually tapered and stopped. In a randomized and
placebo-controlled trial, patients were treated with topira-
mate for 6 months and then randomized to either continue
therapy or placebo for another 6 months. Although patients
randomized to placebo had more headache days and more
acute medication use than those who remained on topiramate,
some maintained a therapeutic benefit despite cessation.46
Nonpharmacologic Treatment
Nonpharmacologic treatment is an important aspect of
treating any complex disorders, especially for patients who
may want to minimize exposure to pharmacologic therapy.
These forms of treatment take time to develop and require
commitment from both the patient and physician.
One component of nonpharmacologic treatment includes
reducing exposure to common migraine triggers such as
sleep deprivation, alcohol, hunger, and dehydration. Redu-
cing these exposures generally requires a step-by-step
adjustment in lifestyle over a period of time. Other non-
pharmacologic therapies include cognitive behavior therapy,
relaxation training, and exercise.
Stress is a very common trigger for migraine.47 With high
stress, maladaptive responses such as catastrophizing and
 Migraine and Tension-Type Headache Kahriman, Zhu 613

Table 4 Migraine preventives with American Academy of Neurology (AAN) recommendations on level of evidence

Level of Clinical notes

evidence43–45
Beta blocker
Propranolol A Beta-blocker is the commonly used class of preventive. They are relatively
Metoprolol A contraindicated in the presence of severe lung disease such as asthma or chronic
Timolol A obstructive lung disease, peripheral vascular disease, and Raynaud’s disease
Atenolol A
Nadolol A
Antidepressant
Amitriptyline B Common side effects of tachycardia, dry mouth, constipation, and sexual side effects
Venlafaxine B
Antiepileptic drug
Valproate A Teratogenic with pregnancy category rating of D (topiramate) and X (valproate)
Topiramate A
Botulinum toxin A Generally requires diagnosis of chronic migraine for insurance coverage. Injected into
cranial and neck muscles via PREEMPT protocol every 12 wk41,42
Nutraceutical
Magnesium Not rated The 2012 AAN nutraceuticals guidelines were withdrawn in 2015 due to safety concerns
Riboflavin Not rated regarding petasites (butterbur). These safety concerns do not involve magnesium,
Coenzyme Q10 Not rated riboflavin, or coenzyme Q10 and they may be used for patients with contraindications

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or intolerance to other preventives

Notes: Level A medications are established as effective. Level B medications are probably effective. Level C medications are possibly effective. Of
note, the nutraceuticals of magnesium and riboflavin were previously given level B classification and coenzyme Q10 level C; these guidelines were
withdrawn as a whole in 2015 due to safety concerns regarding the petasites (butterbur) nutraceutical.

anxiety may develop which then lead to further functional
impairment and suffering for patients with migraine. Meth-
ods such as relaxation training, cognitive behavioral training
(CBT), and biofeedback aim to provide tools for effective
management of stress.
Relaxation training with breathing exercises, guided
imagery, or meditation can be used to help reduce the
physiologic activation that contributes to headache activa-
tion. Patients are trained to master the practice of brief
stress-reducing methods multiple times a day and reduce
stress.48
CBT has been used in the treatment of multiple other
disorders such as panic attacks, depression, and posttrau-
matic stress disorder to modify beliefs and thoughts which
are sources of stress. In a trial with pediatric and adolescent
migraine sufferers, CBT in combination with amitriptyline
was more effective than headache education and medication
in reducing headache frequency.49
Biofeedback uses electronic devices to inform the patient
about physiological processes associated with headache such
as muscle tension, blood pressure, heart rate changes, and
brain activity, with the goal of helping the patient modulate
these physiologic responses to reduce or prevent head-
aches.50,51 All of the behavioral therapies have evidence for
efficacy alone or in combination with pharmacologic agents,
but are not necessarily widely available due to a paucity of
trained providers and cost. Acupuncture has had conflicting
evidence for efficacy in migraine and is not generally recom-
mended,50 though it is not contraindicated should a patient
express interest.
Emerging Therapies and Neuromodulation
There is high excitement among neurologists as an entirely
new class of migraine preventives, the monoclonal antibo-
dies (MABs) to the calcitonin gene receptor peptide (CGRP)
or its receptor, became available in May 2018. This is the first
class of medications specifically designed for migraine.
CGRP is a potent vasodilator, and human cerebral arteries
are innervated by CGRP-active nerve fibers.52,53 CGRP levels
are increased during a migraine attack and normalize with
injection of sumatriptan; furthermore CGRP infusions can
provoke migraine.54 Past studies have shown that small
molecule CGRP receptor antagonists have good efficacy in
the acute treatment of migraine,55–57 though this class of
small molecule drugs did not reach the market due to
unacceptably high rates of transaminitis. MABs are more
specific than small molecule drugs, are not associated with
adverse hepatic effects, and have been used extensively in the
treatment of other diseases.
Erenumab, a monthly injectable, is a CGRP receptor
antagonist and received FDA approval as a migraine preven-
tive in May 2018. Three other MABs, all CGRP ligand antago-
nists, are in clinical trials for migraine or other primary
headache disorders (fremanezumab, eptinezumab, and gal-
canezumab). One advantage of MABs seems to be that their
efficacy occurs early in treatment (as early as the first week),
compared with other current therapies.58
As a potent vasodilator, CGRP may have a protective role
in cardiac and cerebral ischemia, and the blockade theore-
tically could cause unfavorable effects. Furthermore, the long
half-life of MABs could potentially cause prolonged damage

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614 Migraine and Tension-Type Headache Kahriman, Zhu
as there are no means of reversal.59 Preliminary data pre-
sented at the International Headache Conference in 201760
showed that intravenous erenumab in those with stable
angina did not cause significant differences in exercise
duration or time to onset of angina and/or ST-segment
depression; however, clarification of the long-term cardiac
and cerebrovascular safety will require additional studies,
including close post-marketing follow-up.
Noninvasive neuromodulation for treatment of migraine
and other headache disorders is also an emerging area of
research and development. This field employs technologies
such as transcutaneous nerve stimulation, transcranial mag-
netic stimulation (TMS), noninvasive vagal nerve stimulation
(nVNS), and direct current stimulation (DCS).
Supraorbital transcutaneous stimulation (STS) is com-
mercially available as Cefaly (Grâce-Hollogne, Belgium). A
randomized controlled trial of 67 subjects showed a 30%
reduction in headache days/month (6.94 vs. 4.88; p ¼ 0.054)
during the third month of daily use, although this finding was
not a prespecified primary outcome and average number of
headache days averaged over the total 3 months was not
significantly different between the two groups.61 Transcu-
taneous occipital nerve stimulation (ONS) with a transcuta-
neous electric nerve stimulation (TENS) device was studied
in an RTC of 110 subjects randomized into five different
groups (three receiving different frequencies, sham, and
Topiramate).62 The treatment group with higher frequency
(100 Hz) and the topiramate group showed significant
decreases in migraine frequency compared with sham. A
common criticism of transcutaneous stimulation-based
technologies is loss of blinding due to strong paresthesia
associated with verum stimulation.
A randomized controlled trial of 164 patients studied TMS
for treatment of acute migraine with aura, and showed that
39% of subjects in treatment group achieved pain freedom at 2
hours compared with 22% in sham group with the first treated
attack.63 An open-label post-marketing study of the
SpringTMS device (eNeura, Baltimore, MD) showed significant
reduction in headache days and pain relief.64 Both SpringTMS
and Cefaly have U.S. FDA approval for treatment of migraine
and are available for purchase with a prescription.
nVNS was studied for migraine after anecdotal improve-
ment in patients who had VNS implanted for refractory
epilepsy. Although some open-label studies showed promis-
ing results, RCT studies of nVNS for acute and preventive
migraine treatment did not reach primary end points.65–67
The gammaCore device is a handheld nVNS (electroCore LLC,
Basking Ridge, NJ) that has received FDA approval for both
migraine and cluster headache treatment.
Several other noninvasive and invasive neuromodulators,
including direct DCS, percutaneous mastoid stimulation, and
brachial electric stimulation, have been studied, though
currently no commercially available devices exist for these
technologies. Although neuromodulation technologies avoid
some of the side effects of prescription medications, the data
for their effectiveness are not robust and cannot be recom-
mended as the standard of care currently. Their use is further
curtailed due to limited access, as they are typically not
Seminars in Neurology Vol. 38 No. 6/2018
covered by insurance, and lack of clinicians who are familiar
with these devices. Further studies of neuromodulation
technologies will be necessary to show their potential effec-
tiveness and mainstream them into clinical practice.
Tension-Type Headache
Epidemiology and Impact
TTH is a primary headache disorder that often coexists with
migraine, and differentiating between TTH and milder forms
of migraine without aura often represents a diagnostic
challenge. Although more common than migraine, with a
prevalence anywhere from 30 to 70%, TTH is less likely than
migraine to cause severe pain and functional impairment.
While sufferers of migraine are more likely to miss work,
more lost work days are actually attributable to TTH as it is a
more common disorder.68
Clinical Symptoms and Diagnosis
The symptoms, diagnosis, and treatment of TTH significantly
overlap with migraine. Much like migraine, diagnosis of TTH
also requires exclusion of secondary causes; here, the
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SNOOP4 mnemonic is equally applicable.10
The pathophysiology of TTH is poorly understood, and, in
the past, has had psychogenic association, which is implied
in the previous names: muscle contraction headache, psy-
chomyogenic headache, stress headache, ordinary headache,
essential headache, idiopathic headache, and psychogenic
headache.11 One of the characteristic physical exam findings
in TTH patients is increased tenderness to palpation of
pericranial myofascial tissues. Electromyography (EMG) stu-
dies have shown that patients with TTH have decreased
relaxation of pericranial muscles at rest.69 Activation of
peripheral pericranial myofacial nociceptors are thought to
be at least partially responsible for episodic TTH, and sensi-
tization of pain pathways in the CNS is responsible for
conversion of episodic to chronic TTH.70 Palpation of peri-
cranial myofacial tissues for tenderness should be included
in the physical exam and used along with the ICH-3 diag-
nostic criteria to make a clinical diagnosis of TTH.
TTH characteristically presents as bilateral mild to moder-
ate pain of pressing or tightening quality, in contrast to
unilateral pulsating pain of the migraine. Patients often report
the feeling of wearing a tight band around their head or
heaviness of the head. The headache starts at some point
during the day and commonly persists the reminder of the
day with possible aggravation toward the end of the day.
Frequency of headache subdivides TTH into three major
categories: infrequent episodic, frequent episodic, and chronic
(►Table 5). While photophobia and phonophobia can often be
present, only one is allowed by the diagnostic criteria for
episodic TTH. Mild nausea is allowed to take the place of
photophobia or phonophobia in the diagnosis of chronic TTH,
but not episodic TTH. One distinguishing feature between
migraine and TTH is that migraine usually worsens with
common physical activities of daily living, whereas TTH does
not. Precipitating and aggravating factors of TTH match those
of migraine and it is not useful to differentiate the two.

Table 5 ICHD-3 diagnostic criteria for TTH11
Infrequenta or frequentb TTH
a
A. At least 10 episodes of headache fulfilling criteria B–D
B. Lasting from 30 min to 7 d
C. At least two of the following four characteristics
1. Bilateral location
2. Pressing or tightening (nonpulsatile) quality
3. Mild or moderate pain intensity
4. Not aggravated routing physical activity
such as walking or climbing stairs
D. Both of the following
1. No nausea and/or vomiting
2. No more than one of photophobia or phonophobia
E. Not better accounted for by another ICHD-3 diagnosis
Abbreviations: ICHD-3, International Classification of Headache Disorders, 3rd edition; TTH, tension-type headache.
a
Infrequent TTH is defined as pain on <1 d/mo on average.
b
Frequent TTH is defined as pain on 1–14 d/mo on average for >3 mo.
Treatment
Most individuals affected by infrequent episodic TTH do not
come to the attention of medical providers as the headaches
are infrequent and respond to over-the-counter NSAIDs. For
frequent episodic TTH, NSAIDs are also the mainstay treat-
ment, but patients with frequent and chronic TTH may
warrant prophylactic treatment, which may consist of both
pharmacologic and nonpharmacologic therapies.
For acute treatment of TTH, simple analgesics and NSAIDs
may be sufficient. Acetaminophen, ibuprofen, and aspirin have
all been shown to be superior to placebo; higher dosing with
acetaminophen 1,000 mg, ibuprofen 400 to 800 mg, or aspirin
500 to 1,000 mg may be more effective than lower doses,71–74
and NSAIDs may be more effective than acetaminophen.75,76
Overall, the response to NSAIDs in patients with severe pain
is modest; according to a systemic review, number needed to
treat (NNT) to achieve pain free at 2 hours for ibuprofen
400 mg is 14, and for acetaminophen 1,000 mg it is 22.77,78
There is no evidence for using triptans, opioids, or muscle
relaxants for treatment of TTH. The data point to NSAIDs to be
the treatment of choice for acute attacks of TTH. Caution
should be exercised to prevent MOH and rebound headache.
The first step in headache prophylaxis should be identifica-
tion of headache triggers and correction of behavior, and a
headache diary may be helpful for this task. Triggers reported
are very similar to those of migraines and include but are not
limited to stress, poor sleep, inadequate/excessive sleep, vari-
able sleeping patterns, disrupted dietary patterns, excessive
caffeine, poor ergonomic conditions, physical exertion, eye
strain, noise, lights, odors, etc.79 Amitriptyline is the TCA with
the most evidence as a preventive treatment in TTH.80 It is
important to advise patients that this medication has tradi-
tionally been used as an antidepressant, but that it has an
independent pain effect and is used at a different dosage for
pain. Amitriptyline should be started at 10 mg nightly and
Migraine and Tension-Type Headache Kahriman, Zhu 615
Chronic TTH
A. Headache occurring on
15 d/mo on average for >3 mo
(
180 d/y), fulfilling criteria B–D
B. Lasting hours to days, or unremitting
C. At least two of the following four characteristics
1. Bilateral location
2. Pressing or tightening (nonpulsatile) quality
3. Mild or moderate pain intensity
4. Not aggravated routing physical activity such
as walking or climbing stairs
D. Both of the following
1. No more than one of photophobia, phonophobia,
or mild nausea
2. Neither moderate or severe nausea nor vomiting
E. Not better accounted for by another ICHD-3 diagnosis
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increased by 10 mg/weekly until a therapeutic effect is
achieved. Patients should be advised to take it 1 to 2 hours
before bed time or 8 to 9 hours before desired wake up time to
avoid undesired effects of sedation. The usual effective main-
tenance dose is 30 to 70 mg daily; patients without benefit on
a maintenance dose for 3 to 4 weeks should be switched to an
alternative agent.80 Common side effects of amitriptyline
include dry mouth, drowsiness, dizziness, constipation, and
weight gain, so patients should be counseled appropriately.
Other TCAs have not been adequately studied, but in clinical
practice, nortriptyline is often used as it may be less sedating
than amitriptyline.
While SSRIs have not been found to be effective in the
prophylaxis of TTH, for patients with comorbid depression,
the use of mirtazapine 30 mg/day81 or venlafaxine 150 mg/
day82 to treat an underlying mood disorder may also be
helpful for TTH. Topiramate 100 mg daily was reported to be
effective for TTH prophylaxis in an open-label study.83
Botulinum toxin injections have not been shown to reduce
the frequency of chronic TTH.84 Use of myofascial trigger point
injections is widely practiced in patients with pericranial
muscle tenderness, although evidence of efficacy is limited.
Injections are usually given in the muscles where palpation
produces tenderness, and include frontal, temporal, masseter,
sternocleidomastoid, semispinalis capitis, trapezius, and sple-
nius capitis muscles.85 Greater occipital nerve block has not
shown benefit in TTH. Tizanidine, propranolol, and valproic
acid are not recommended for prophylaxis of TTH.80
Besides identification of headache triggers, other nonphar-
macologic treatment of frequent episodic and chronic TTH
include physiotherapy, acupuncture, EMG biofeedback, myo-
fascial trigger point-focused massage, muscle relaxation ther-
apy, cognitive behavioral therapy, and mindfulness stress
reduction. Myofascial trigger point–focused massage was no
better than placebo in reducing headache frequency.86 EMG
Seminars in Neurology Vol. 38 No. 6/2018
616 Migraine and Tension-Type Headache Kahriman, Zhu
feedback trains patients to relax muscles by providing con-
tinuous feedback about muscle activity. Relaxation training
focuses on patients’ recognition and control of tension as it
occurs. Physical therapy focuses on posture, relaxation, heat/
cold application, ultrasound, and electric stimulation; these
methods are widely used but have not been standardized for
TTH, and thus are difficult to establish a level of evidence. CBT
aims to train patients to recognize beliefs and thoughts that
generate stress and provide alternative coping mechanisms.
Nonpharmacologic therapy may increase effectiveness of
pharmacologic therapy and help improve patients’ function-
ality and quality of life.
Conclusion
Multiple new therapies are in development, and trials for
treatment of headaches, from targeted antibody-based infu-
sions to noninvasive neuromodulation. These efforts provide
a hopeful future in terms of better understanding of disease
pathophysiology and better treatment to reduce the impact
of headache disorders on patients and society.
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