PRIMER

Tension-type headache
Sait Ashina   1,2 ✉, Dimos D. Mitsikostas3, Mi Ji Lee   4, Nooshin Yamani5,
Shuu-Jiun Wang   6, Roberta Messina   7, Håkan Ashina8, Dawn C. Buse9,
Patricia Pozo-Rosich10,11, Rigmor H. Jensen   8, Hans-Christoph Diener   12 and
Richard B. Lipton9,13
Abstract | Tension-type headache (TTH) is the most prevalent neurological disorder worldwide
and is characterized by recurrent headaches of mild to moderate intensity, bilateral location,
pressing or tightening quality, and no aggravation by routine physical activity. Diagnosis is based
on headache history and the exclusion of alternative diagnoses, with clinical criteria provided
by the International Classification of Headache Disorders, third edition. Although the biological
underpinnings remain unresolved, it seems likely that peripheral mechanisms are responsible for
the genesis of pain in TTH, whereas central sensitization may be involved in transformation from
episodic to chronic TTH. Pharmacological therapy is the mainstay of clinical management and
can be divided into acute and preventive treatments. Simple analgesics have evidence-based
effectiveness and are widely regarded as first-line medications for the acute treatment of TTH.
Preventive treatment should be considered in individuals with frequent episodic and chronic
TTH, and if simple analgesics are ineffective, poorly tolerated or contraindicated. Recommended
preventive treatments include amitriptyline, venlafaxine and mirtazapine, as well as some
selected non-pharmacological therapies. Despite the widespread prevalence and associated
disability of TTH, little progress has been made since the early 2000s owing to a lack of attention
and resource allocation by scientists, funding bodies and the pharmaceutical industry.

Photophobia
Tension-type headache (TTH) is the most prevalent
Sensitivity to light. neurological disorder worldwide1–3. This primary head-
ache is characterized by recurrent headaches of mild to
Phonophobia moderate pain intensity. The headaches tend to be bilat-
Sensitivity to sound.
eral and are sometimes described as of a ‘hatband’-like
pattern, although pain can also occur in the forehead,
posterior head regions and neck. The headaches are also
characterized by the absence of accompanying symptoms
such as photophobia, phonophobia and nausea4.
Diagnosis of TTH is based on clinical criteria in
the third edition of the International Classification of
Headache Disorders (ICHD-3), which divides TTH
into three subtypes based on headache frequency:
infrequent episodic TTH (ETTH; headaches for
<1 day/month on average or <12 days/year), frequent
ETTH (headaches for 1–14 days/month or ≥12 and
<180 days/year) and chronic TTH (CTTH; headaches
for ≥15 days/month or ≥180 days/year)4 (Box 1). These
distinctions are important, as infrequent ETTH has
minimal effects on individuals and rarely requires use
✉e-mail: sashina@ of health-care services, whereas CTTH is associated
bidmc.harvard.edu with considerable disability and is often difficult to
https://doi.org/10.1038/ treat1–3,5. The ICHD-3 also subclassifies TTH as asso-
s41572-021-00257-2 ciated or not associated with pericranial tenderness,
which may have implications for pathophysiology and
treatment4. TTH management can be conceptualized
within a biopsychosocial framework, which acknowl-
edges that biological, psychological and environmental
factors all have substantial and interactive roles in the
development, maintenance and successful management
of this disorder.
This Primer provides an overview of the epidemiol-
ogy, pathophysiology and diagnosis of TTH. In addition,
recommended practices for clinical management and
future research directions are discussed.
Epidemiology
In epidemiological studies, a diagnosis of TTH is estab-
lished by meeting the diagnostic criteria of the ICHD;
this information may be captured by interviews con-
ducted by trained clinicians, in-person lay interviews
based on semi-structured diagnostic questionnaires,
validated telephone interviews or self-reported question-
naires. A two-step survey can also be used, in which a
screening tool survey is followed by a case-ascertainment
interview with clinicians. Self-reported medical diagno-
sis is not used as a case definition in epidemiological
studies owing to under-diagnosis.

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Author addresses Data on the prevalence of TTH in children and

adolescents are relatively sparse, with available studies
1
BIDMC Comprehensive Headache Center, Department of Neurology and Department reporting a wide range in estimates, from 9.8% in Sweden
of Anesthesia, Critical Care and Pain Medicine, Harvard Medical School, Beth Israel to 72.3% in Brazil14. However, one study in rural Tanzania
Deaconess Medical Center, Boston, MA, USA. found a very low prevalence for TTH of 0.04% in individ-
2
Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen,
uals 0–10 years of age and 1.3% in people 11–20 years of
Copenhagen, Denmark.
3
First Neurology Department, Aeginition Hospital, Medical School, National and age16. The 2017 GBD study found a global prevalence
Kapodistrian University of Athens, Athens, Greece. of TTH in individuals aged 5–9, 10–14 and 15–19 of
4
Department of Neurology, Samsung Medical Center, Sungkyunkwan University 12.1%, 35.7% and 35.8% in women/girls and 11.7%,
School of Medicine, Seoul, South Korea. 34.5%, and 34.0% in men/boys, respectively17. In com-
5
Headache Department, Iranian Center of Neurological Research, Neuroscience parison with 2007, there was an increase in prevalence
Institute, Tehran University of Medical Sciences, Tehran, Iran. of 0.5–1.0% among women/girls and of 0.9–1.3% among
6
Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, men/boys at different age groups17.
Brain Research Center, National Yang-Ming University, Taipei, Taiwan. The global prevalence of CTTH is ~2–3% in most
7
Neuroimaging Research Unit and Neurology Unit, IRCCS San Raffaele Scientific population studies13,18–22 although values range from
Institute, Milan, Italy.
0.2% to 4.8%23. This variation might be due to differ-
8
Danish Headache Center, Department of Neurology, University of Copenhagen,
Rigshospitalet Glostrup, Glostrup, Denmark. ences in study samples based on age profiles, ethnicity
9
Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA. and environment as well as data collection methodology.
10
Headache Unit, Neurology Department, Vall d’Hebron University Hospital, In most studies, the prevalence of CTTH is higher in
Barcelona, Spain. women/girls than in men/boys (range 3.0–3.9% versus
11
Headache and Neurological Pain Research Group, Vall d’Hebron Research 1.1–2.0%, respectively)19,21. CTTH is rare in young ado-
Institute, Departament de Medicina, Universitat Autònoma de Barcelona, lescents and the prevalence increases until age 39 and
Barcelona, Spain. then declines23. One large survey of 7,900 children in
12
Faculty of Medicine, Institute for Medical Informatics, Biometry and Epidemiology, Taiwan found the prevalence of CTTH as 1.0% in ado-
University Duisburg-Essen, Essen, Germany. lescents aged 12–14 years (ref.24). However, one survey in
13
Montefiore Headache Center, Bronx, NY, USA.
an elderly cohort in Kinmen, Taiwan, found a prevalence
of 2.7% for chronic daily headache (CDH)20,25.
Incidence The prevalence of infrequent ETTH and probable TTH
Data from the Global Burden of Disease (GBD) study were rarely surveyed in populations until recently. The
estimated that there were 882.4 million new cases of average estimated prevalence of infrequent ETTH is
TTH globally in 2017 (ref.2). In this study, there were 8.4% (range 3.3–17.7%), and the average estimated
~63.6 million new cases in the European Union and prevalence of probable TTH is 9.9% (range 0.4–27.3%)23.
~44.5 million new cases in the USA2,3. In a 12-year lon- Most of these studies showed a similar prevalence in
gitudinal study in Denmark, the incidence of frequent male and female subjects.
ETTH and CTTH was 14.2 per 1,000 person-years in
a random sample of the general population6. Incidence Risk factors
was 2.6 times higher in women than in men6. In a similar Risk factors for TTH have been studied in cross-sectional
study in Taiwan, in which adolescents aged 13–14 years and longitudinal studies. A positive association between
were followed for 12–24 months, the reported incidence educational level and prevalence of ETTH has been
was 3.9 per 1,000 person-years, with a 4.6-fold higher reported12, although an inverse relationship was found
incidence in female than in male subjects7. for CTTH, which was more prevalent in groups with
lower levels of education. In another study, TTH was
Prevalence associated with fatigue and, among women, a lack of
Prevalence estimates vary between studies and regions ability to relax after work26.
of the world owing, in part, to differences in case defi- In a longitudinal study from Denmark, using multi-
nitions and study methods as well as differences in variable models, young age, female sex, poor self-rated
Chronic daily headache ethnicity and other demographic characteristics of health, not being able to relax after work and sleep-
Primary or secondary populations1–3. Data from the GBD study estimated ing few hours per night were associated with incident
headache, defined as the that in 2017 there were ~2.33 billion people with TTH TTH6. Risk factors for incident CTTH in a study of
presence of a headache worldwide2,8, with 121.6 million in the USA3,9. Prevalence adolescents in Taiwan were baseline frequent headache
on ≥15 days/month for
at least 3 months, which may
increased by 31.7% in the USA from 1990 to 2017 (ref.3). (that is, headache for ≥7 days/month) and female sex7.
include chronic tension-type In the European Union, the prevalence of TTH was In an elderly cohort in Taiwan (≥65 years with mean age
headache, chronic migraine, ~173.7 million in 2017 (ref.2). 75.0 ± 7.9 years), overuse of acute headache medications,
new daily persistent headache, The estimated 1-year prevalence of TTH in popu- a history of migraine and depression severity were risk
medication overuse headache
lation studies was 10.8% in China10, 36.1% in Jordan11, factors for CTTH, and medication overuse was a poor
or other disorders with
headaches. 38.3% in the USA12, ~80% in European studies and prognostic factor for predicting the persistence of CDH
86.6% in Denmark13,14. In a population-based Danish in 2 years20.
Probable TTH twin registry, the 1-year prevalence of TTH among indi- In a 2-year follow-up study in adolescents with CDH,
Tension-type headache viduals aged 12–41 was 86%15. In another Danish study, mostly CTTH (61%), factors associated with persistence
(TTH) that is missing one of
the features required to fulfil
59% of individuals had infrequent ETTH. TTH has a of CDH in 2 years were baseline major depression and
all ICHD-3 criteria for a type female preponderance with a sex prevalence ratio of medication overuse27. In a Danish study, poor progno-
or subtype of TTH. 1.2:1, far lower than the 3:1 ratio that typifies migraine14. sis of TTH (defined as ≥180 days with TTH per year at

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follow-up due either to increased frequency from ETTH
at baseline into CTTH or to persistent CTTH) was asso-
ciated with baseline CTTH, coexisting migraine, being
unmarried and sleeping problems28. Another study with
similar definitions for poor outcome29 found that unilat-
eral headache, nausea and individual headache attack
duration of ≥72 h were nonsignificantly associated with
poor outcome of individuals with TTH alone.
Burden and impact
Based on the GBD study, TTH is ranked as the second
most common cause of chronic disease and injury
globally30. The most burdened age groups in terms of
years of life lived with disability (YLD) for TTH were
between 15 and 49 years. However, as TTH had a
much lower disability weight than migraine, overall, it
caused 7.1 million YLD compared with 47.2 million for
migraine globally in 2017 (ref.2). In a clinic-based study
on disease burden, patients with ETTH reported an
average of 2.3 work days and 1.6 household work days
lost in the last 3 months, whereas patients with CTTH
reported a mean of 8.9 work days and 10.3 days of house
activity lost in the last 3 months31. In the Danish popu-
lation, 12% of employed participants with TTH, repre-
senting 9% of the general employed population, lost one
or more working days in the preceding year owing to
headache, and the mean number of absence days from
Box 1 | Diagnostic criteria for tension-type headache according to the ICHD-3
Infrequent ETTH
Meeting the following criteria A and B, in addition to criteria C–E, below.
A. Frequency: at least 10 headache episodes occurring on average <1 day/month
(that is, <12 days/year)
B. Duration: 30 min to 7 days
Frequent ETTH
Meeting the following criteria A and B, in addition to criteria C–E, below.
A. Frequency: at least 10 headache episodes occurring on average 1–14 days/month
for >3 months (≥12 and <180 days/year)
B. Duration: 30 min to 7 days
CTTH
Meeting the following criteria A and B, in addition to criteria C–E, below.
A. Frequency: headache occurring on ≥15 days/month on average for >3 months
(≥180 days/year)
B. Duration: hours to days, or unremitting
C. At least two of the following four characteristics:
1. bilateral location
2. pressing or tightening (non-pulsating) quality
3. mild or moderate intensity
4. not aggravated by routine physical activity such as walking or climbing stairs
D. Both of the following:
for infrequent and frequent ETTH:
1. no nausea or vomiting
2. no more than one of photophobia or phonophobia
for CTTH:
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
CTTH, chronic tension-type headache; ETTH, episodic tension-type headache; ICHD-3,
International Classification of Headache Disorders, third edition. Data from ICHD-3 (ref.4).
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work was estimated to be 820 days per 1,000 patients32.
The corresponding amount for migraine headache was
270 work days per 1,000 employed people with migraine.
Sickness absence rate in both groups was higher in
women than in men. Approximately 60% of patients
with TTH reported impaired social activities and work-
ing ability33. ETTH in Brazilian university students was
noted to have significant impact on physical activity and
productivity34.
Limitations of epidemiological studies
The definition of TTH in epidemiological studies is
challenging for several reasons. First, infrequent ETTH
is common and may not be accurately recalled and
reported in epidemiological studies. Second, the inci-
dence of frequent ETTH or CTTH may represent an
exacerbation of a pre-existing disorder rather than new
onset of a distinct condition. Third, TTH can coexist
with migraine in the same person and diagnostic rules
for coding migraine and TTH vary between studies.
When this occurs, suggestions from the ICHD-3 are to
code all present conditions; however, attacks of pheno­
typic TTH in patients with migraine may be mild
migraine, and coding these headaches as TTH may be
incorrect35,36. By contrast, other studies may code these
individuals as having migraine only. Biomarkers to dif-
ferentiate between phenotypic TTH and mild migraine
are not available, but would be useful for this purpose.
Comorbidities
TTH can co-occur with several disorders that may
affect the choice of therapy37. Population-based data
have shown that anxiety, depression and sleep distur-
bances (including insomnia) are more prevalent in
individuals with TTH than in the non-headache general
population38–42. Depression and anxiety are also associ-
ated with the frequency and severity of TTH attacks43.
However, it is not possible to ascertain a causal relation-
ship based on cross-sectional data. One longitudinal
study showed possible bidirectional effects between
pain and emotional factors on the burden of CTTH44.
However, these associations could be influenced by
coexisting migraine, which is highly comorbid with
depression and anxiety45,46.
TTH is also associated with other pain disorders,
including migraine. Indeed, one population-based study
found that 83% of people with migraine within the past
year also had TTH13. TTH has been found to be asso-
ciated with comorbid neck pain and low back pain47–49.
Almost 90% of people with TTH have comorbid neck
pain49, and ~80% of individuals with TTH have low
back pain48. Moreover, TTH frequency positively cor-
relates with the frequency of comorbid neck pain and
low back pain48,49.
Mechanisms/pathophysiology
The potential pathophysiological mechanisms of TTH
can be divided into three broad categories: genetic
factors, myofascial mechanisms (including myofascial
nociception) and mechanisms of chronification (includ-
ing central sensitization and altered descending pain
modulation) (Fig. 1).
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Myofascial mechanisms Genetic disposition

• Increased tenderness • 5-HTTLPR polymorphism
• Increased hardness • Val158Met COMT polymorphism
• Local inflammation • APOE-ε4 polymorphism
• Local ischaemia

Tension-type
Peripheral headache
sensitization

Vascular mechanisms Central mechanisms

• Increased blood flow in cerebral arteries • Central sensitization
• Abnormal carotid artery blood flow • Dysfunction in descending
• Abnormal extracranial vascular response pain modulation

Fig. 1 | Pathophysiology of tension-type headache. The potential pathophysiological mechanisms of tension-type

headache involve possible genetic factors, peripheral and central mechanisms. Peripheral mechanisms, including
myofascial and to a lesser degree vascular factors, may lead to peripheral sensitization of nociceptors. Central
mechanisms involve central sensitization of nociceptive pathways and altered descending pain modulation. 5-HTTLPR,
5-hydroxytryptamine (serotonin)-transporter-linked-gene-linked polymorphic region; APOE, apolipoprotein;
COMT, catechol-O-methyltransferase.

Genetic factors Peripheral mechanisms

Two registry-based twin studies have investigated the
influence of genetic factors on TTH50,51 and found that
heritability estimates vary with the presence of concom-
itant migraine. In those with migraine, the heritability
of TTH was 19% in one study, whereas heritability of
TTH was 48% in male twins and 44% in female twins
in those without migraine50,51. The difference in con-
cordance rates of monozygotic twins and same-sex dizy-
gotic twins was ~5% and ~10% in infrequent ETTH and
frequent ETTH, respectively. This finding may suggest
that the genetic effects were more substantial in frequent
ETTH than in infrequent ETTH, although a direct com-
parison between the two conditions was not carried
out52. For CTTH, heritability could not be estimated
from twin studies owing to small sample sizes, but a
family aggregation study found a threefold increased
risk of CTTH in first-degree relatives of patients with
CTTH53. Of note, this study should be interpreted
with caution because concomitant migraine was not
evaluated.
The specific genes that are causative of TTH are
unknown. Studies have found a possible contribu-
tion of the 5-HTT-gene-linked polymorphic region
(5-HTTLPR) genotype and Val158Met COMT (encoding
catechol‐O‐methyltransferase) polymorphism in the risk
of CTTH or its phenotype54–56. By contrast, the APOE-ε4
gene was suggested as protective against TTH57.
Myofascial mechanisms. Tenderness of pericranial
muscles is common in patients with TTH during the
acute headache phase and, in some patients, outside
of headache periods, pointing to a potential role of
myofascial tissues in the pathophysiology of TTH58,59.
Manual palpation is the most common method used for
the evaluation of tenderness, and tenderness is quan-
tified using a subjective pain scoring system60. Both
pericranial muscles and tendon insertions have higher
tenderness scores in patients with ETTH and CTTH
than in controls60,61. Whether muscular tenderness is a
consequence of the pain or contributes to the develop-
ment of TTH attacks is still debated62. In one study with
30 min tooth clenching (a stimulus known to induce
headache), muscle tenderness preceded the headache
in patients with ETTH or CTTH63. Similarly, increased
muscle tenderness anticipated a lower pain threshold in
patients who developed frequent ETTH over 12 years
of follow-up in a population-based study64. Pericranial
tenderness is exacerbated during the acute headache
phase and increases with the severity and frequency of
TTH attacks, supporting the presence of more severe
tenderness in individuals with CTTH than in those
with ETTH61,63,65. By contrast, other studies have found
increased muscular tenderness and stiffness in patients
with either ETTH or CTTH when they are headache-free
compared with healthy individuals66,67. Along with

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increased tenderness, pericranial muscles are ‘harder’
in patients with ETTH and CTTH66,68. Muscle hardness
can be investigated using the hardness meter, a reliable,
quantitative measurement method. Muscle hardness
was increased in patients with CTTH both on days with
and on days without TTH66. Of note, inhibiting nitric
oxide synthase (NOS) with NG-monomethyl-l-arginine
hydrochloride (l-NMMA) leading to decreased nitric
oxide (NO) levels reduced pain and muscle hardness in
patients with CTTH69,70, supporting a role for NO in pain
modulation in TTH.
Myofascial trigger points, hyperirritable spots asso-
ciated with a taut band (a band of muscle fibres with
increased tone) in skeletal muscles that elicit local and
referred pain when compressed, may be important in
the pathophysiology of TTH. The referred pain from
muscles in the head, neck and shoulder regions can
mimic the pain pattern of TTH71,72. Several studies have
found a high relative frequency of myofascial trigger
points in patients with ETTH or CTTH compared with
controls73,74. In addition, increased nociception at myo-
fascial trigger points could lead to sensitization of cen-
tral nociceptive pathways in individuals with ETTH and
CTTH75,76. However, data on the association of myofas-
cial trigger points and the severity and frequency of TTH
attacks have been inconsistent74. Moreover, prospective
studies evaluating the role of myofascial trigger points in
the evolution of ETTH to CTTH are needed71. Methods
used to investigate the role of peripheral mechanisms in
TTH pathophysiology (such as manual palpation and
palpometer for measuring muscle tenderness, and sur-
face versus needle electromyography (EMG) for meas-
uring muscle activity) have varied, and might contribute
to variation in results between studies77.
Myofascial nociception is mediated by thin myeli-
nated (Aδ) and unmyelinated (C) fibres that are activated
by noxious and innocuous stimuli, including muscle
strain or contraction, inflammation and ischaemia62.
Sustained contraction of head, shoulder and neck mus-
cles was believed to contribute to the onset of pain in
TTH by the sensitization of peripheral nociceptors.78
However, interestingly, many studies have found normal
global EMG activity in most patients with ETTH, with
small areas, such as trigger points, with increased EMG
activities in patients with CTTH62,79,80.
Physiologically, stress can trigger or aggravate the
headache by increasing muscle contraction, by releas-
ing catecholamines and cortisol, by peripheral sensi-
tization and/or by affecting central pain processing81.
Long-term corticosteroid release in those with stress
may cause tissue damage leading to pain and increased
pain perception82,83. In TTH, stress has been shown
to trigger higher pericranial muscle pain ratings in
patients with TTH than in controls84. However, there
is no evidence supporting a link between stress and
increased peri­cranial EMG activity, and its role in TTH
pathophysiology remains unclear84,85.
Muscle nociceptors can be activated by several
inflammatory mediators (such as serotonin, brady-
kinin, substance P and calcitonin gene-related peptide
(CGRP)), resulting in activation and sensitization of
peripheral sensory afferents86. Patients with frequent
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ETTH have increased pain sensitivity after intramuscu-
lar infusion of inflammatory substances compared with
controls87, which could be related to central sensitiza-
tion (increased excitability of the central nervous system)
and peripheral sensitization (reduced thresholds and
increased responsiveness of peripheral nociceptors)88 of
myofascial sensory afferents, and is likely caused by the
release of endogenous inflammatory mediators in tender
muscles87. Further studies are needed to clarify the rela-
tionship between muscle tender points and myofascial
trigger points, and their role in TTH pathophysiology78.
Some evidence suggests an association between myo-
fascial pain and local muscle ischaemia (likely caused
by sustained muscle contraction, alterations in metab-
olism, microcirculation and mitochondrial function) in
the tender areas in TTH and in other myofascial pain
disorders89. A few studies have reported increased lev-
els of substances involved in pain and inflammation,
such as IL-6, bradykinin and serotonin in the blood
and myofascial trigger points of patients with TTH73,90.
By contrast, one study found normal interstitial levels
of inflammatory mediators (such as bradykinin, aden-
osine 5-triphosphate, glutamate and prostaglandin E2)
in tender points of the trapezius muscle in patients with
CTTH, suggesting that these points do not have per-
sistent inflammation in patients with TTH91. Using the
133xenon clearance technique, one study92 found nor-
mal resting blood flow and relative flow increase dur-
ing isometric work in large areas of temporal muscle in
patients with CTTH92. In addition, normal muscle blood
flow and lactate levels were found in tender points in
patients with CTTH during static exercise, suggesting
that muscle ischaemia may not contribute to the onset
of TTH93.
Vascular factors
In contrast to migraine, cerebral vascular input is of
minor importance in TTH94. Haemodynamic changes
in the cerebral vasculature could activate trigeminal
nociceptors and lead to headache pain95. In support
of this, patients with ETTH have increased blood flow
velocities in the anterior, middle and posterior cerebral
arteries, whereas patients with CTTH had alterations of
the blood flow velocities of the basilar and middle cere-
bral arteries, compared with controls96–98. These findings
could be explained by the vasodilator activity of CGRP
and NO, or by impaired sympathetic function; how-
ever, although increased NO levels have been found in
patients with CTTH, further studies are needed to clarify
the role of CGRP and the sympathetic system in TTH
pathophysiology99. Cranial haemodynamics in patients
with CTTH has been studied during nitroglycerin and
head down tilt headache provocation100, both of which
induced a significant increase in the severity of head-
ache in patients with CTTH, but not in controls. Both
patients with CTTH and controls had similar changes in
the carotid artery blood flow after nitroglycerin admin-
istration, but higher carotid artery blood flow was found
in patients with CTTH compared with controls during
head down tilt, probably due to distention of intracranial
veins100. Some evidence suggests a failure of dilatation of
temporal arteries in response to exercise in patients with
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Motor cortex (M1/M2) Somatosensory cortex (S1/S2)

Descending input from the motor cortex modulates motor Ascending input from thalamo-cortical projections
neurons leading to maladaptive changes in muscle fibres increases somatosensory cortical levels of glutamate

Thalamus
Ascending inputs
from spinal trigeminal
nucleus and dorsal
horns at C3–C4 levels
lead to sensitization
Limbic system of third order neurons
The limbic system in thalamus mediated by
modulates the nitric oxide and glutamate
motor cortex,
decending
pathways modulate
the periaqueductal
grey and rostral
ventromedial
medulla PAG

PAG and RVM

Muscle fibres Sensory afferents
Increased muscle hardness and C fibres, Aδ fibres
sustained contraction leads to and Aβ fibres (become
local ischaemia and inflammation pro-nociceptive
or pain simulatory)
transmit peripheral
nociceptive input
from muscles and
blood vessels to the
Blood vessels
trigeminal and
Increased blood flow in cerebral
C1–C4 dorsal
arteries, abnormal cartoid artery
root ganglions
blood flow, and abnormal
extracranial vascular response
Trigeminal
ganglion
Decreased inhibition
(PAG) and increased
facilitation (RVM) of
nociceptive transmission
at the level of trigeminal
nucleus caudalis and
dorsal horns at C3–C4
RVM levels lead to sensitization
STN
DH C3–C4
Medulla and upper cervical spinal cord
Increased afferent nociceptive input leads
Dorsal root to sensitization of second order neurons
ganglion in spinal trigeminal nucleus and
of C1–C4 dorsal horns at C3–C4 levels mediated by
nitric oxide and glutamate

Fig. 2 | Proposed mechanisms of chronification of tension-type headache. Abnormal input from myofascial structures
in the head and neck and, to a lesser degree, from vascular structures, results in sensitization of peripheral nociceptors.
This increased nociceptive input leads to sensitization of second order neurons in the spinal trigeminal nucleus and dorsal
horns of the spinal cord at levels C1 to C4. Aβ fibres, which normally only respond to innocuous stimuli, become pro-
nociceptive or pain stimulatory. Dysfunction of descending modulatory pain pathways results in decreased inhibition and
increased facilitation of nociceptive transmission. This leads to increased nociceptive input to the thalamus and sensitization
of third order neurons, which send impulses to the cortex. The result is increased pain perception and chronification of
tension-type headache. DH, dorsal horn; M1, primary motor cortex; M2, supplementary motor area; PAG, periaqueductal
grey; RVM, rostral ventromedial medulla; S1, primary somatosensory area; S2, secondary somatosensory area; STN, spinal
trigeminal nucleus (comprising pars caudalis, pars interpolaris and pars oralis; pars caudalis extends from C2 to the obex).

CTTH, supporting an abnormal extracranial vascular thalamus, limbic system, motor cortex and somatosensory
response in TTH101. cortex (Fig. 2).

Central factors Central sensitization. Several early studies found nor-

The transformation of ETTH into CTTH remains
incompletely understood. The mechanism of chronifi-
cation of TTH may include sensitization of second-order
neurons in the dorsal horn of the spinal cord or the
spinal trigeminal nucleus, sensitization of supraspinal
neurons, and decreased antinociceptive or modulat-
ing activity from supraspinal structures, such as the
mal pressure pain detection thresholds in patients with
ETTH61,102–104; however, these studies were performed
before the separation of infrequent and frequent TTH in
ICHD-2 (ref.105), which may explain these data. Indeed,
when infrequent ETTH was separated from frequent
ETTH, abnormal or low pain detection thresholds were
found in patients with frequent ETTH in the cephalic

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region but not in patients with infrequent ETTH61,106,107.
In addition, patients with CTTH had lower pain detec-
tion thresholds and tolerance thresholds to pressure,
electrical and thermal stimuli in cephalic and extra-
cephalic regions compared with controls77,102,103,108–111.
In patients with CTTH, alterations in pain sensitiv-
ity were more evident using suprathreshold stimuli,
which may be more clinically relevant than threshold
measurements112,113.
Studies of temporal summation with repetitive pain-
ful stimuli in patients with CTTH provided inconsistent
results, probably owing to the application of different
types of stimulation (electrical versus mechanical stim-
ulation). Compared with controls, patients with CTTH
had higher pain ratings from repeated pressure stim-
uli, and nonsignificant temporal summation changes
to electrical stimuli have been observed112,114. In con-
trast to electrical stimuli, which stimulate nerve fibres
directly, pressure pain stimulation activates both noci-
ceptors and central mechanisms. Abnormal temporal
summation in patients with CTTH might, therefore,
result from an altered response in both peripheral and
central mechanisms.
Overall, pain perception studies support the pres-
ence of hyperalgesia (increased sensitivity to painful
stimuli) and allodynia (pain elicited by stimuli that are
normally not painful) in patients with frequent ETTH
or CTTH48,62,75,102,106,110,112. The nonspecific and wide-
spread nature of pain hypersensitivity in these patients
suggests the involvement of sensitization of central pain
processing regions62,108,115.
In support of a role of central sensitization in TTH
chronification, several studies have found an associa-
tion between central pain sensitization and more fre-
quent TTH attacks77,116. In addition, one longitudinal,
population-based study found normal pain thresholds
at baseline in patients with ETTH, but reduced thresh-
olds in patients who developed CTTH after 12 years64.
Sensitization of both supraspinal and spinal nociceptive
pathways might explain the increased muscle tenderness
in patients with TTH. The pain response to mechanical
pressure applied to tender muscles is quantitatively and
qualitatively different in patients with CTTH from that
in controls106,113. Palpation pressure elicited a stronger
pain response in patients with CTTH, as represented by
a steeper stimulus–response function, compared with
controls113. These findings seem to be explained by cen-
tral sensitization at the dorsal horn of the spinal cord and
trigeminal nucleus108,113. A moderate correlation between
cortical pain hypersensitivity and myofascial tenderness
has been found in patients with CTTH117.
NO may be involved in the pain pathways of the
spinal cord and the central sensitization at the spinal
level118. The role of NO has been investigated in CTTH.
Increased NOS activity in platelets was found in patients
with CTTH, reflecting central upregulation of NOS
activity in neurons in the spinal dorsal horn, trigeminal
nucleus and supraspinal structures99. In a provocation
study using glyceryl trinitrate (GTN), which is an NO
donor, patients with CTTH had an immediate headache
and a delayed headache the latter of which resembled
TTH, whereas controls developed immediate mild
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headaches only119. This biphasic response occurred in
a similar manner in patients with migraine, and where
migraine-like attacks were induced. These findings
may suggest that NO-related central sensitization is an
important common denominator of primary headache
disorders118.
Glutamate, a neuroexcitatory amino acid, has been
investigated in several studies on migraine but only in
two studies in patients with CTTH. Data from these
studies are conflicting: normal plasma glutamate levels
were found in one study and increased platelet glutamate
levels were found in the other99,120.
Comorbid conditions may alter pain sensitivity
in individuals with TTH. In patients with TTH and
migraine, the presence of back pain was associated with
increased central sensitization and muscular tender-
ness compared with individuals without headache48.
Whether central sensitization facilitates the onset of
back pain in patients with TTH or vice versa or whether
it might be the consequence of comorbidity is unclear48.
Fibromyalgia is also an important comorbidity of TTH,
with a twofold increased prevalence in patients with
CTTH compared with those with ETTH, implying a
shared mechanism between the two conditions, such as
central sensitization121. In addition, the increased prev-
alence of temporomandibular disorder symptoms in
patients with TTH also suggests increased pain percep-
tion associated with TTH, although it is unclear whether
the mechanisms linking the two conditions is central
sensitization from TTH or peripheral sensitization from
temporomandibular disorder122.
Personality traits and psychological comorbidities
may affect patients’ vulnerability to and coping strat-
egy for pain. For example, high levels of depression and
neuro­ticism were associated with increased pain sensi-
tivity in cephalic and extracephalic regions in individuals
with TTH and migraine, suggesting that pain percep-
tion and modulation may be influenced by negative
appraisals of pain38. Sleep disturbances are common in
patients with TTH. This association might be explained
by the involvement of common neurotransmitters and
brain networks, including the hypothalamus and brain-
stem, in the pathophysiology of the two diseases123. The
inadequate sleep may lead to central sensitization as
demonstrated by lower pain thresholds in individuals
with CTTH124,125.
Neuroimaging studies have found functional126 and
structural127,128 alterations in cortical regions involved
in pain processing in patients with TTH. For example,
decreased grey matter volume of areas of the limbic
system, such as the insula and anterior cingulate cor-
tex, were found in patients with CTTH and those with
chronic migraine, compared with patients with episodic
TTH and patients with episodic migraine128. In addition,
decreased grey matter volume of limbic areas in patients
with ETTH and CTTH was significantly associated with
longer disease duration. Furthermore, structural brain
alterations of the insula, cingulate and somatosen-
sory cortex change dynamically between the pain and
pain-free phases in patients with ETTH127,129. Thus,
imaging findings might be a consequence of frequent
peripheral nociceptive inputs and central sensitization.
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Some central mechanisms related to CTTH are simi-
lar to those found in chronic migraine (such as increased
pain perception, NO-related mechanisms, comorbidi-
ties and brain structural and functional abnormalities).
Whether chronic migraine and CTTH are two different
conditions or a single process in which two primary
headaches converge is debated. Considering the shared
pathophysiological mechanisms, it can be suspected that
central sensitization is a key factor in the chronification
of the two disorders, whereas the difference in clinical
phenotypes between migraine and TTH suggest that
they are two different entities.
Dysfunction in descending pain modulation. Deficiency
of the descending pain modulatory system may con-
tribute to the increased pain sensitivity and central
sensitization in CTTH. Neurophysiological studies
investigating the activity of inhibitory brainstem neu-
rons in patients with TTH have provided inconsistent
results, perhaps owing to methodological issues such as
the use of different recording systems117,130. Conversely,
many studies have pointed to dysfunction of the dif-
fuse noxious inhibitory controls (DNICs)77, which com-
prises the inhibition of spinal and trigeminal neurons
by nociceptive stimulation applied to spatially distant
regions of the body. This phenomenon is usually regu-
lated by supraspinal descending projections. Compared
with controls, patients with CTTH had facilitation
of the nociceptive flexion reflex, which is a polysyn-
aptic spinal withdrawal reflex that may be depressed
by supraspinal descending projections and DNICs131.
Impaired inhibition of repeated nociceptive inputs
was also found in patients with CTTH117,132. Negative
findings were found regarding a possible influence of
stress on temporal summation or DNICs114. In contrast,
greater levels of physical activity have been shown to
be associated with less pain facilitation and more pain
inhibition133.
Serotonin. The monoamine serotonin (5-hydroxy­
tryptamine; 5-HT) has been investigated in several
early studies of TTH. Although these studies used
hetero­geneous methods and yielded conflicting results,
it is widely accepted that patients with ETTH have
increased platelet and plasma serotonin levels, and
decreased platelet serotonin uptake compared with
controls134,135. By contrast, platelet and plasma serotonin
levels were either normal or decreased in patients with
CTTH, and platelet serotonin uptake was also normal
compared with controls136,137. In addition, 5-HTTLPR
polymorphism may be associated with CTTH risk54.
When the increased levels and decreased uptake of ser-
otonin are regarded as a physiological antinociceptive
reaction to pain, those findings may suggest that patients
with CTTH have a deficiency in the ability to increase
plasma serotonin in response to peripheral nociceptive
inputs, which may predispose to dysfunctional pain
processing or modulation108. Serotonin acts on central
antinociceptive mechanisms along with other neuro-
transmitters such as noradrenaline and adenosine138,
which may explain why stronger serotonin reuptake inhi-
bition by a selective serotonin reuptake inhibitor (SSRI)
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(citalopram) did not achieve better treatment outcome
compared with non-selective agents (amitriptyline)139,140.
Endogenous opioids. Endogenous opioids have an
important role in modulating nociceptive information141.
Opioid receptors are found in central or peripheral
nociceptive afferent fibres, and in regions involved in
descending pain modulation, such as the periaqueductal
grey, nucleus raphe magnus and dorsal raphe in the
rostral ventral medulla141. There is no compelling evi-
dence of impaired endogenous opioid system in TTH,
although the number of studies is small. Two studies
found normal β-endorphin levels in peripheral blood
and cerebrospinal fluid (CSF) in patients with ETTH or
CTTH142,143. In ETTH, reduced β-endorphin levels were
observed and correlated with pressure pain threshold144.
In addition, plasma and CSF met-enkephalin levels are
increased in patients with CTTH145,146, with a small but
significant decrease in CSF dynorphin levels in patients
with CTTH compared with controls147.
Neuropeptides
CGRP is one of the important neurotransmitters of
trigeminal nociceptive signalling148. In migraine, the
finding of increased plasma levels of CGRP during
and outside of migraine attacks has led to the success
of modern CGRP-targeting treatments149,150. However,
in TTH, studies have consistently found normal CGRP
concentrations in cranial and peripheral blood and CSF
in patients with ETTH and CTTH147,151,152, which did not
increase during spontaneous or induced attacks151,153.
Of note, owing to methodological issues of in vitro meas-
urement of CGRP, it is difficult to draw a firm conclu-
sion that CGRP is not involved in the pathophysiology
of TTH.
In addition to CGRP, nerve fibres containing sub-
stance P, neuropeptide Y (NPY) and vasoactive intesti-
nal peptide (VIP) are found in extracranial cutaneous,
muscular and perivascular tissues, suggesting a poten-
tial role of these peptides in the pathophysiology of
headaches, including TTH154. However, plasma levels
of substance P, NPY and VIP were normal in cranial
and peripheral blood of patients with CTTH, irrespec-
tive of headache status155. In a study of individuals with
ETTH, substance P was reduced in platelets from patients
with ETTH compared with controls, and levels of sub-
stance P were negatively correlated with pressure pain
threshold144. Normal plasma levels of NPY were noted
during and between attacks in patients with ETTH156.
Of note, assay methodology should be considered when
interpreting these study results.
Diagnosis, screening and prevention
Clinical presentation
Episodic tension-type headache. TTH is sometimes
described as a ‘featureless headache’ because it lacks the
associated features of migraine (such as nausea, photo­
phobia and phonophobia) or trigeminal autonomic
cephalalgias (such as lacrimation and conjunctival
injection (enlargement of conjunctival blood vessels))5.
Most individuals with ETTH rarely, if ever, seek medical
care despite the widespread prevalence in the general

Medication overuse
headache
Secondary headache
characterized as headache
occurring on ≥15 days/month
that is attributed to regular
overuse of analgesics or
migraine-specific acute
medications (on ≥10 or
≥15 days/month, depending
on the medication) in
individuals with a pre-existing
headache disorder such
as tension-type headache
or migraine.
NATURE REVIEWS | DISEASE PRIMERS | Article citation ID:
population32, which has resulted in a scarcity of litera-
ture related to clinical features of ETTH157,158. Much of
the available data come from a Danish population-based
cohort13. Based on these data, ETTH is bilateral in 90%
of occurrences, of pressing or tightening quality in 78% of
occurrences, of mild or moderate pain intensity in 99%
of instances and is not aggravated by routine physical
activity in 74% of instances13. In another report from the
same cohort, episodes of headache in individuals with
frequent ETTH lasted between 30 min and 24 h in 83%
of instances29.
Chronic tension-type headache. TTH is often described
as ‘graded’, as the intensity of pain increases with the
frequency of headache158. In CTTH, headaches are
more frequent, more severe and more likely to require
medical care than in ETTH19,32. CTTH typically devel-
ops gradually in individuals with ETTH4. Clinical fea-
tures of CTTH have been examined in only a very few
studies13,19 but are similar to those reported in individ-
uals with ETTH, except for an increased intensity of
pain13. In a population-based sample of persons with
CTTH, pain is of bilateral location in 88% of instances, of
pressing or tightening quality in 83% of occurrences,
of mild or moderate pain intensity in 96% of instances
and is not aggravated by routine physical activity in 71%
of cases13. Furthermore, 58% of individuals with CTTH
did not report nausea, photophobia or phonophobia as
accompanying symptoms13. Pericranial tenderness is
the most common abnormal finding with CTTH, and
is more common in those with CTTH than in patients
with ETTH or migraine or in healthy volunteers without
headache61,159.
Diagnostic work-up
TTH is diagnosed on the basis of headache history and
the exclusion of other disorders that may mimic TTH.
Diagnostic criteria are provided by ICHD-3 (ref.4) (Box 1).
TTH should be suspected in any individual who
reports recurrent headache of mild or moderate inten-
sity. The diagnosis is most probable in patients whose
headache is bilateral and tightening or pressing in qual-
ity. A typical description of TTH is the sensation of a
tightening rubber band around the head. Appropriate
clinical evaluation is needed to establish diagnosis, and
a review of medical history must account for onset, dura-
tion and frequency of headache, as well as pain features,
accompanying symptoms and aggravating and relieving
factors157,158. Assessment of accompanying symptoms
are mostly used to differentiate TTH from migraine,
which is the most common and important differential
diagnosis160.
Diagnostic headache diaries are the best available
assessment tool for TTH and can be used to support
diagnosis and guide clinical decision-making. Headache
diaries enable patients to report clinical headache features
(such as frequency and characteristics) and accompany-
ing symptoms. The benefits of headache diaries are multi­
fold and include better differentiation of ETTH from
CTTH compared with clinical evaluation alone. Indeed,
patients tend to over-report their headache frequency
during an initial clinical evaluation when compared with
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data gathered by prospective diary entries161. In addition,
diagnostic headache diaries can help to differentiate
CTTH from other headache disorders, mainly migraine
and medication overuse headache (MOH)162.
Physical examination is carried out in all patients
with suspected TTH and includes fundoscopic, general
and neurological examinations (comprising mental sta-
tus, cranial nerve, motor and sensory function, balance
and coordination, reflexes and gait assessment). This
is often normal aside from possible pericranial ten-
derness, which is assessed by manual palpation61,157,158.
Fundoscopic examination is performed to rule out pap-
illoedema, which can be a sign of idiopathic intracranial
hypertension, or other causes of increased intracranial
pressure.
Comorbid disorders should also be assessed by
detailed medical history and physical examination at the
initial clinical evaluation. Such assessment is likely to
inform better practices and individualize approaches
to clinical management.
Differential diagnosis
A wide range of headache disorders can mimic the
clinical features of TTH160; careful exclusion of these
disorders relies on a thorough review of medical his-
tory and an adequate physical examination. On this
basis, further diagnostic tests might be required if a
patient has red flags that are suggestive of secondary
headache causes163,164 (Box 2). Further tests may include
Box 2 | Secondary headache disorders: red flags
Intracranial space-occupying lesion
Red flags:
• progressively worsening headache
• headache brought on by sneezing, coughing or exercise
Subdural haematoma
Red flags:
• head trauma
Secondary headache
Red flags:
• headache associated with weight loss and/or change
in memory or personality
• headache onset >50 years of age
• focal neurological symptoms
• weight loss
• impaired memory and/or altered consciousness
or personality
Meningitis
Red flags:
• unexplained fever
• neck stiffness
Intracranial hypertension or hypotension
Red flag:
• headache aggravated by posture or manoeuvres that
raise intracranial pressure
Subarachnoid haemorrhage
Red flag:
• neck stiffness
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New daily persistent

headache
Primary headache disorder
characterized by unremitting
pain within 24 h of a clearly
remembered onset and
for >3 months.
neuroimaging, blood sampling, lumbar puncture and
polysomnography. Systematic testing of all patients with
TTH (for example, neuroimaging) should be avoided
and does not appear to improve quality of life or mitigate
health concerns in the long term165.
Migraine is the common and important differential
diagnosis of TTH30,160,166. It is not uncommon for clini-
cians to conflate TTH and migraine, as individuals with
migraine have coexisting TTH with a similar prevalence
to that seen in the general non-migraine population167.
Indeed, the 1-year prevalence of frequent ETTH was 56%
in individuals with migraine in one population-based
study168. Differentiating migraine and CTTH is difficult,
as CTTH often manifests with headache episodes of at
least moderate pain intensity19 that are comparable to
those seen in individuals with migraine19. Migraine may
also be conflated with CTTH in those with overuse of
analgesics. One point that merits special emphasis is the
exclusion of a secondary diagnosis of TTH in individuals
who meet the diagnostic criteria for chronic migraine, as
defined by the ICHD-3 (ref.4). Indeed, it is very common
for individuals with chronic migraine to experience at
least some headache days with clinical features that fulfil
the diagnostic criteria for TTH.
No biomarkers can differentiate between TTH,
migraine and other headache disorders, therefore, cli-
nicians can benefit from the use of diagnostic head-
ache diaries, in which clinical features are prospectively
recorded.
Clinicians should also consider MOH as an addi-
tional diagnosis in individuals with CTTH4,169. Another
differential diagnosis to CTTH is new daily persistent
headache (NDPH)4. NDPH is a rare headache disorder in
the general population, with an estimated prevalence of
0.03–0.1%170. Of note, NDPH is reported by 11% of head-
ache centre patients with CDH171 and in 21% of adolescent
patients with CDH172.
Brain tumours often present with headache that most
often has features of TTH rather than migraine173. Other
differential diagnosis of TTH includes a range of sec-
ondary headache disorders, such as headache attributed
to traumatic brain injury, idiopathic intracranial hyper-
tension, low CSF pressure, sleep apnoea and recurrent
rhinosinusitis160. These disorders may have features sug-
gestive of TTH and clinicians should, therefore, become
suspicious if red flags are raised by the medical history
and/or physical examination (Box 2). In such instances,
neuroimaging is often recommended to confirm or
exclude underlying causes.
Management
Multimodal treatment should be tailored for each
patient with TTH and may include pharmacotherapy,
interventional medicine, behavioural therapies, physi-
cal and occupational therapies, exercise, healthy lifestyle
habits and stress management (Fig. 3). Infrequent TTH
can be managed primarily with acute pharmacological
treatment and lifestyle modifications but frequent ETTH
or CTTH may require preventive pharmacotherapy
and/or behavioural interventions.
A mainstay of clinical management of TTH is phar-
macotherapy. Educating patients about TTH triggers,
natural history and treatment options and goals is essen-
tial. Decision-making requires consideration of patients’
preferences and comorbidities. As the evidence base is
less well developed for TTH than for migraine, clinical
experience has a larger role in making treatment choices
for TTH. In this context, comorbidities should also be
considered in the decision-making. Patients should
also be educated to know that the goal of the medical
interventions is not to cure TTH but to help patients
to manage the condition. Alignment on both the goals
of treatment and the approach to treatment improves
outcomes174. In addition, unless the patient’s individual

Management of TTH

Patient education and trigger management

Prophylactic:
Prophylactic: pharmacological
Symptomatic non-pharmacological
In case of high-frequency 1st option:
1st option: amitriptyline
ETTH, or CTTH, or when • Bio-behavioural therapies
aspirin and/or
acetaminophen symptomatic treatment (CBT, biofeedback,
fails, or comorbidities relaxation)
• Physical and/or 2nd option:
require chronic
mirtazapine
2nd option: management of the occupational therapy
caffeine condition, initiate • Acupuncture
combinations prophylactic treatment • Lifestyle modification 3rd option:
or NSAIDs (including sleep hygiene) venlafaxine

Fig. 3 | Management of tension-type headache. Management of tension-type headache (TTH) starts with patient education
and management of known headache triggers. Symptomatic treatment is required for mild to severe headaches, or when
headaches affect function. Non-pharmacological treatments can be used concurrently with pharmacological therapies
(including symptomatic and/or prophylactic) or as stand-alone therapies. Of note, multiple non-pharmacological
therapies can be combined. When prophylactic treatment is needed, starting with non-pharmaceutical interventions is
recommended unless the patient prefers pharmacological therapy. After 6 months of successful management (defined as a
≥50% reduction in headache frequency), treatment may be paused to see whether TTH relapses or worsens. CBT, cognitive
behavioural therapy; CTTH, chronic TTH; ETTH, episodic TTH.

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Box 3 | Management of TTH in specific populations
Children and adolescents
There is some evidence only for acetaminophen267 in the acute treatment of tension-
type headache (TTH) and amitriptyline268,269 for prevention, whereas non-pharmacological
and multidisciplinary interventions216,270–272 have stronger evidence and should be
preferable or used in combination with amitriptyline when needed.
Elderly individuals
First-choice treatment is non-pharmacological intervention (such as biofeedback or
relaxation techniques) whenever accessible and accepted by patients. Acetaminophen
is the drug of first choice for acute treatment (NSAIDs should be avoided) and
amitriptyline for prevention of TTH, followed by venlafaxine and mirtazapine.
Close monitoring is required owing to the risk of adverse effects181,199,273. Notably, TTH
may be a risk factor for dementia274.
Pregnancy and lactation
Pharmacological treatment should be offered and not be postponed when needed275.
Acetaminophen is the first-choice drug for symptomatic treatment but combinations
with caffeine or NSAIDs should be avoided275. Amitriptyline is preferred for the
prevention of TTH, followed by venlafaxine and mirtazapine (same FDA classification
as for pregnancy — C class)275.
needs and preferences are considered, treatment adher-
ence is very low175; thus, shared decision-making is
indispensable176. Potential nocebo-producing behav-
iours (such as frequent previous experiences of severe
subjective adverse events or frequent previous treatment
discontinuations owing to safety reasons) should also be
taken into account, in order to recruit tailored strategies
to limit it177. In addition, the potential role of medication
overuse in exacerbating headache should be emphasized
along with clear guidance about limits on weekly or
monthly use of acute treatments178 (Box 3).
Acute treatment
Simple analgesics. Both acetaminophen and aspirin
have been investigated for the symptomatic treatment of
TTH179,180 (Table 1). Both treatments have a good safety
profile. The serious adverse events include liver dys-
function for acetaminophen and bleeding with aspirin.
The European Federation of Neurological Societies Task
Force (EFNS-TF) recommends the oral use of acetami-
nophen and aspirin for the acute treatment of TTH with
level A recommendation181. Notably, the effectiveness of
symptomatic medication is associated with better head-
ache parameters (history, frequency and duration) and
lower emotional burden182.
Of the NSAIDs, ibuprofen183 and ketoprofen184 have
the highest efficacy for the acute treatment of TTH.
Other NSAIDs that have a lower evidence of efficacy
contain naproxen185 and diclofenac186,187, yet are common
in practice (Table 1). NSAIDs inhibit the cyclooxygen-
ase pathway and may be associated with gastric, hepatic
and kidney adverse events, blood pressure elevation and
increased risk of bleeding. EFNS-TF recommends
the oral use of ibuprofen, ketoprofen, naproxen and
diclofenac for the acute treatment of TTH with level A
recommendation181.
Combination analgesics. Although caffeine alone was
not effective for TTH treatment in a placebo-controlled
study188, there is evidence that the combination of caf-
feine with acetaminophen, aspirin or ibuprofen improves
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the efficacy of the analgesics for the acute treatment of
TTH189. Indeed, in a meta-analysis of four trials189, the
fixed combination of aspirin, acetaminophen and caf-
feine was superior to paracetamol alone or placebo, with
limited adverse effects reported. The most common
adverse events of these combinations were nervousness
(in 6.5% of participants), nausea (4.3%), abdominal
pain or discomfort (4.1%) and dizziness (3.2%)190,191. In
addition, rebound headache after caffeine withdrawal
may occur192. Caffeine may increase the antinocice-
ptive effects of analgesics by promoting their gastric
absorption190. EFNS-TF recommends the oral use of
caffeine combinations for the acute treatment of TTH
with level B recommendation181. There is some evidence
that local application of peppermint oil in an ethanol
solution may be helpful in TTH relief193,194.
Medications to avoid. Opioids are best avoided owing
to the risk of MOH and the potential for misuse169,195.
Triptans have not shown efficacy for symptomatic
treatment of TTH and might be avoided unless head-
ache attacks have features of migraine181. Of note,
sumatriptan gave only modest headache relief for
CTTH compared with placebo but the study may have
been underpowered196. Muscle relaxants are not recom­
mended for symptomatic TTH treatment owing to low
efficacy. In some individuals, such as children, preg-
nant or breast-feeding women and elderly patients,
the use of NSAIDs or combinations of caffeine with
aspirin or acetaminophen should be avoided for safety
reasons (Box 3).
Preventive treatment
Preventive treatment is recommended only for patients
with frequent ETTH and CTTH. Infrequent TTH does
not require preventive treatment unless there are specific
comorbidities (such as depression or fibromyalgia), if
symptomatic treatment fails or daily functioning is
affected by TTH.
Deciding the duration of TTH prophylaxis remains an
active challenge. All studies lasted 2–6 months, but many
patients may require longer treatment. Comorbidity,
response to treatment, patient characteristics, previ-
ous headache history, patient preferences and lifestyle
choices should be considered in deciding how long to
continue treatment. In those with an excellent response
(such as 50–75% reduction in monthly headache days)
pausing the treatment after 3 or 6 months and monitor-
ing for any recurrence of the headache is a widely used
approach, unless other comorbidities, such as depression
or anxiety disorders, require longer treatment.
Amitriptyline. Level of evidence of efficacy of amitrip-
tyline (tricyclic antidepressant) in TTH prevention is
moderate to high in several studies supporting its level A
rating by EFNS-TF181,197 (Table 2). The analgesic effect of
amitriptyline is related to, for example, noradrenaline
reuptake inhibition, N-methyl-d-aspartate (NMDA)
receptor antagonism, blockade of muscarinic recep-
tors and ion channels140, or modulation of the seroto-
ninergic and noradrenergic descending pain inhibitory
system198. Common tolerability issues include drowsiness,
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Table 1 | A selection of acute medications for TTH tested in randomized placebo-controlled trials
Drug by type of study Route NNT NNH Quality of Ref.
evidence
Meta-analysis
Aspirin PO 6 (4.2–12)a No difference Low 180

Paracetamol/acetaminophen PO 22 (15–40)a No difference High 179

Ibuprofen PO 14 (8.4–47)a NA Moderate 183

Ketoprofen PO 9.0 (4.8–72)a 15 (8.7–15) Low 184

Aspirin + paracetamol + caffeine PO 6 (4.8–6.5)b 41 High 189

Single studies
Diclofenac sodium PO 7 (4.5–14.7)a 50 Low 186

Diclofenac sodium PΟ 10 (5.7–33.9)a 122 Low 186

Naproxen PO 18c 53 Low 185

Metoclopramide + diphenhydramine IV 6 (3–66)d NA Low 264

Pethidine IM 7 (4.5–14.7)a NA Low 265

Chlorpromazine IV 2 (1.4–3.5)e NA Low 265

Metoclopramide IV 2 (1.3–2.6)e No difference Low 265

Quality of evidence is based on the results of the meta-analyses, otherwise calculated as follows: one positive RCT = low, two
positive RCTs = moderate, three or more positive RCTs = high-quality evidence). IM, intramuscular; IV, intravenous; NA, not
applicable; NNT, number of patients needed to treat for a patient to have a beneficial outcome; NNH, number of patients needed
to treat for a patient to have an adverse event; PO, per os; RCT, randomized controlled trial; TTH, tension-type headache. aPain
free at 2 h post-dose was the beneficial outcome. bNNT is the number of headache attacks that are needed to treat for a headache
attack to have a complete pain-free outcome. cWhen NNTs or NNHs extend from a negative absolute risk reduction the 95%
confidence intervals are not presented. dNNT is the number of patients who would need to be treated with the more efficacious
medication (metoclopramide + diphenhydramine) instead of the ketorolac for a single patient to achieve headache freedom in
the emergency department without requiring rescue medication and maintain headache freedom for 24 h. ePrevention of the
use of a rescue medication 2 h post-dose was the beneficial outcome.

weight gain, dry mouth, dizziness, sweating, constipation
and increased appetite. Amitriptyline is the first-choice
drug for the prevention of TTH in elderly and younger
patients, following the same guidelines, although indi-
viduals with cardiac arrhythmias may be excluded. All
elderly patients need to be monitored with electrocardi-
ography at baseline, with every dosage adjustment and
at their yearly examination, along with monitoring for
potential anticholinergic adverse effects199. In addition,
amitriptyline may cause cognitive impairment or urinary
retention. An observational clinic-based study found that
patients using prophylactic amitriptyline for TTH had
higher headache frequency, higher headache burden,
worse sleep quality and more severe depression than
those who did not receive medicinal prevention, because
patients with these particular features considered them-
selves to benefit more200. By comparison, lower effec-
tiveness of prophylactic amitriptyline was reported by
patients with TTH with widespread pain hyperalgesia200.
Mirtazapine. Two randomized controlled trials (RCTs)201,202
have evaluated the efficacy of mirtazapine (a serotoninergic/
noradrenergic antidepressant) for TTH prevention, sup-
porting its level B rating by EFNS-TF181. The efficacy of
mirtazapine was comparable to that of amitriptyline in
one study202 and significantly superior to placebo in the
other one201. The mechanism of action remains unclear
and may involve the inhibitory descending noradren-
ergic and serotoninergic pathways201. Common adverse
effects include drowsiness, weight gain and somnolence
but mirtazapine has a better tolerability profile than ami-
triptyline or other tricyclic antidepressants and may be
recommended in specific subpopulations, such as elderly
patients.
Venlafaxine. The evidence for efficacy of venlafaxine
(serotonin–noradrenaline reuptake inhibitor) for TTH
prevention is low, with only one small RCT evaluating
this drug for TTH203 and supporting its level B rating
by EFNS-TF181. As with mirtazapine, the mechanism of
action of venlafaxine is uncertain, but the drug works
independently of depression comorbidity and the
mechanism is likely similar to that of of mirtazapine181.
Nausea, vomiting, dizziness and abdominal pain are the
most common adverse events, although this drug has
better tolerability than amitriptyline181.
Other agents. Third-line treatments with label B reco­
mmendation by EFNS-TF are clomipramine (tricyclic
antidepressant), maprotiline (tetracyclic antidepressant)
and mianserin (atypical antidepressant)181. One system-
atic meta-analysis revealed limited scientific evidence
for the use of SSRIs and venlafaxine for the prevention
of TTH in adults197,204. In addition, tizanidine (a muscle
relaxant) has been tested for CTTH prophylaxis in two
placebo-controlled studies205,206, but contradictory results
were reported, probably because of the strong placebo
response in the negative study206. Thus, tizanidine might

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 Primer

Cognitive behavioural
therapy
A time-limited
psychotherapeutic approach
that focuses on assessing
and modifying dysfunctional
moods and thoughts (cognitive)
and actions and behaviours
(behavioural) and replacing
them with strategies to help
patients reach their goals.
Biofeedback
A psychotherapeutic approach
in which physiological data are
fed back to the user in the form
of visual and auditory stimuli,
and in the case of tension-type
headache there is a focus on
recognizing activation of the
nervous system and learning
techniques to calm and relax
the nervous system.
Relaxation therapy
A psychological intervention
that teaches various
approaches to relaxing the
nervous system including
paced diaphragmatic
breathing, imagery,
distraction and meditation.
be useful in practice for the prevention of CTTH when
other agents fail.
One trial207 evaluated the combination of pindolol
(a β-blocker) and amitriptyline compared with placebo
or amitriptyline alone, and found a higher effectiveness
with pindolol and amitriptyline combination therapy
than with placebo, but no higher effectiveness than
amitriptyline207. Topiramate, valproate and buspirone
were effective in individual open label studies208–210, and
may serve as alternative medicinal options for CTTH
prevention when other agents have failed, were poorly
tolerated or were contraindicated. Evidence suggests that
botulinum toxin type A and ibuprofen are ineffective or
even harmful for the prevention of CTTH181.
Medication overuse
Medication overuse and MOH can occur in those with
TTH, although at a lower prevalence than in those
with migraine, complicating the headache features
and worsening the prognosis. Up to 20% of patients
with MOH have TTH as underlying primary headache
disorder28,169,211,212. In those with MOH and TTH, the key
elements of management may include patient education
and cognitive behavioural approaches both to educate
the patient and to help manage anxiety, management
of risk factors for MOH (such as high frequency of
headache attacks, comorbidity with anxiety disorders
and depression, and the use of specific medications for
acute treatment)169, withdrawal of overused medica-
tions and prophylactic treatment along with manage-
ment of the potential comorbidities195,213. Withdrawal
of the overused medications can be abrupt or gradual
depending on the drug used (for example, opioids and
opioid-containing analgesics should be gradually dis-
continued whereas simple analgesics and NSAIDs can be
abruptly discontinued), patient preferences and idiosyn-
crasy, and comorbidities211. The use of pharmaceutical
preventive treatment at the start of withdrawal therapy
increases the chance of MOH cure214. Regardless of
the type of treatment, 25–35% of patients with MOH
relapse, requiring special care and careful monitoring
for prevention215. Patients who relapse, those with exces-
sive medication overuse or those with use of opioid or
opioid-containing analgesics should be managed by a
multidisciplinary team including headache specialists,
physiotherapists and psychiatrists or psychologists,
while hospitalization for detoxification may be needed
in some severe cases169,195.
Non-pharmacological treatments
All individuals with TTH benefit from education includ-
ing education about healthy lifestyle habits that help
TTH management. Additional non-pharmacological
therapies with good evidence and safety for the man-
agement of TTH include physical and occupational ther-
apies, behavioural therapies (cognitive behavioural therapy
(CBT), biofeedback and relaxation therapy), complemen-
tary and integrative medicine (acupuncture and massage)
and lifestyle enhancements, including management of
sleep, healthy diet and hydration, stress management and
regular exercise216. EFNS guidelines recommend that
non-pharmacological treatments are considered before
pharmacological therapy181. Non-pharmacological ther-
apies should be considered as appropriate based on the
evidence, patient preference and in situations where
some pharmacological options are contraindicated
(such as during pregnancy or lactation). They can be
combined with pharmacotherapy or administered on
their own, and multiple non-pharmacological therapies
can be administered concurrently or sequentially.
Behavioural therapies. Biobehavioural therapies (that
is, CBT, biofeedback and relaxation therapy) are effec-
tive and safe treatment options for TTH217. Indeed,

Table 2 | A selection of prophylactic treatments for TTH tested in randomized placebo- or sham-controlled trials
Treatment by study Route NNT NNH Overall quality Refs
of evidence
EFNS Task Force study
Amitriptyline PO NA (30% reduction)a 3 (1.6–3.9) High 181

Amitriptyline PO 12b 2 (1.6–2.6) High 139,181

Single studies
Mirtazapine PO NA (34% reduction)a 4 (2.4–13.0) Moderate 201,266

SMT NA 18b No difference Low 218

Amitriptyline + SMT NA 3 (1.9–6.0)c 2 (1.6–2.6) Low 218

Venlafaxine PO 4 (2.0–14.2)d 6b Low 203

Meta-analysis
Acupuncture NA 11 (5.8–41.5)d 20b High 238

Quality of evidence is based on the results of the meta-analyses, otherwise calculated as follows: one positive RCT = low, two positive
RCTs = moderate, three or more positive RCTs = high quality of evidence. EFNS, European Federation of Neurological Societies;
NA, not applicable; NNH, number of patients needed to treat for a patient to have an adverse event; NNT, number of patients needed
to treat for a patient to have a beneficial outcome; PO, per os; RCT, randomized controlled trial; SMT: stress management treatment,
or cognitive behavioural treatment; TTH, tension-type headache. aNNT cannot be calculated, reduction of the area under the curve
vs placebo was the beneficial outcome. bWhen NNTs or NNHs extend from a negative absolute risk reduction the 95% confidence
intervals are not presented. c>50% reduction of the headache index after treatment was the beneficial outcome. d>50% reduction
in monthly headache days after treatment was the beneficial outcome.

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Primer
Stress management therapy
A combination of relaxation
with cognitive coping skills for
preventing and managing
stress and headaches.
Headache triggers
Factors associated with an
increased probability of
headache over a relatively
short, clinically relevant
time period.
14 | Article citation ID:
one meta-analysis including 53 studies of biofeedback
for TTH among adults, adolescents and children found
a significant medium-to-large effect size (Cohen’s d 0.73;
95% CI 0.61–0.84) that improved the frequency of head-
ache episodes, muscle tension, self-efficacy, symptoms
of anxiety and depression, and analgesic medication
intake over an average follow-up phase of 15 months.
Stress management therapy showed strong evidence of
efficacy in a randomized and placebo-controlled study,
and seemed to have equivalent efficacy to amitripty-
line or nortriptyline for CTTH prevention218. A com-
bination of the two therapies (stress management plus
either amitriptyline or nortriptyline) may improve the
outcome of monotherapy218. Maladaptive coping strat-
egies such as catastrophizing and avoidance are more
common in patients with TTH than in controls, with
a higher frequency in patients with CTTH than in
those with ETTH219,220. These are addressed by CBT221.
Additionally, long-term group behavioural treatment
(psychoeducation, progressive muscle relaxation, cop-
ing strategies for pain and stress, and goal-setting skills)
with pharmacotherapy showed promising results in
reducing headache frequency and related disability
in patients with TTH222. Evidence is growing for the use
of mindfulness-based therapies (including mindfulness
based cognitive therapy (MBCT) and mindfulness based
stress management, which combine the mindful practice
of focused attention without judgement, mindfulness
meditation and cognitive therapy, relaxation therapy
and stress management therapy techniques) and accept-
ance and commitment therapy (a form of behavioural
therapy that combines mindfulness skills with the devel-
opment of psychological flexibility and the practice of
self-acceptance)223.
Trigger management/prevention
Some patients and clinicians search for headache triggers
that can be used as therapeutic strategy by recommend-
ing avoidance behaviour. Triggers are typically identi-
fied by patient self-report. One study of 344 people with
TTH in China found that 67.4% of patients reported
trigger factors, of which the most common were sleep
disturbance, negative affect and sunlight exposure224.
Other frequently reported triggers are stress, distur-
bances in self-care and routines, dehydration, certain
foods and drinks (such as alcohol), travel, high alti-
tude, activity or exertion (for example, various specific
movements or postures) and other activities that disrupt
healthy equilibrium225.
Patient-reported triggers rely on patient beliefs but
not on an actual association between the trigger and the
onset of headache. Headache triggers are best studied
using electronic diaries or in randomized trials226. With
electronic diaries, exposure to triggers is recorded before
the onset of headache, and the risk of headache follow-
ing the trigger is compared with headache risk at other
times. In randomized trials, the probability of headache
following blinded exposure to the trigger is compared
with blinded exposure to the placebo. However, there is
a scarcity of studies that have ascertained whether some
factors are headache triggers in susceptible individuals
with TTH. Thus, clinicians are encouraged to inform
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their patients that excessive reliance on trigger factors
is not evidence based and could result in unnecessary
avoidance behaviour.
Advice about trigger management (which is different
from the traditional advice to avoid all triggers), as well
as therapy with graduated exposure to selected triggers to
promote desensitization (known as learning to cope with
triggers, or LCT therapy) are also effective in reducing
monthly headache days in patients with TTH221.
Growing evidence highlights the association of
TTH with various sleep disorders, including exces-
sive daytime sleepiness, insomnia, poor sleep quality,
insufficient sleep and shift work28,123,227,228. This comor-
bidity increases the risk of TTH chronification and it
is more prevalent in CTTH than in ETTH123. Thus,
it is plausible that improving sleep quality will subse-
quently reduce headache activity. One meta-analysis
of three trials found that psychological sleep interven-
tions (for example, sleep restriction/bed restriction,
stimulus control and sleep hygiene, which encom-
passes optimal lifestyle and environmental factors
for sleep) improve headache frequency and sleep,
although the effect on headache intensity differs
between studies229. In addition to these interventions,
medications that improve sleep — such as amitriptyline
or mirtazapine — may be considered for patients who
report sleep disturbances200.
Physical therapies. Physical therapy, aerobic exercise,
strength training, massage and cervical manipulation
in particular may be beneficial in the management
of TTH230–233. In an open randomized trial, strength
training with patient education decreased the average
monthly headache frequency from 24.5 to 20.5 days in
female adolescents with TTH, but no significant dif-
ferences between treatment groups were detected230.
In another controlled trial, treatment with manipula-
tion and massage or massage alone significantly reduced
the Headache Disability Inventory score (a 25-item
headache disability inventory assessing the impact
of headache in daily living) in patients with TTH233,
and combined treatment significantly decreased head-
ache frequency compared with the massage-only group.
Several meta-analyses have found that patients with
TTH benefit from physical therapy234–237.
Acupuncture. One systematic meta-analysis found
that acupuncture is an effective and safe treatment for
frequent ETTH or CTTH (leading to a reduction of
monthly headaches by >50% reported by 51% of patients
treated with acupuncture versus 43% of patients treated
with sham acupuncture), although further trials com-
paring acupuncture with other treatment options are
needed238. Despite several methodological shortcom-
ings related to placebo effect and blinding of the trials,
which are applicable to all RCTs to some extent, the qual-
ity of evidence for acupuncture is moderate to high, as
with amitriptyline. Acupuncture has a clear advantage
over amitriptyline in terms of the safety profile, with the
number of patients needed to treat for a patient to have
an adverse event of 20 with acupuncture versus 2–4 for
amitriptyline (Table 2).

Transformed migraine
Subtype of the chronic daily
headache, not defined by
ICHD, that initially begins as
episodic migraine and then
evolves over months or years
to daily or near-daily
headaches resembling a
mixture of tension-type
headache and migraine.
NATURE REVIEWS | DISEASE PRIMERS | Article citation ID:
Interventional therapies. Anaesthetic injections at peric-
ranial myofascial trigger points may also be effective for
TTH in terms of reducing monthly painful days239. In
addition, there is moderate evidence that myofascial
trigger point dry needling is effective in patients with
chronic TTH (in terms of a reduction in headache
intensity, frequency and duration, or improvement in
functional and sensory outcomes)240,241. Dry needling,
or intramuscular stimulation, is an alternative medicine
technique, adapted from acupuncture, that is designed
to stimulate trigger points or muscles that are irrita-
ble by inserting needles into the skin and thus treat
dysfunction of skeletal muscle and connective tissue
(American Physical Therapy Association).
Pharmacoeconomics
The indirect and direct costs of TTH owing to medical
services and medications have been investigated in only
a few studies. In the Eurolight project study, the indirect
and direct average annual costs per person were €303 for
TTH in Europe (of which indirect costs contributed to
92% of the estimate) and the total annual cost of TTH
amongst adults aged 18–65 years was €21 billion242.
Compared with migraine, patients with TTH may
seek medical attention less frequently to manage their
headache. Indeed, the consultation rate (the proportion
of individuals with a given disease consulting or seek-
ing care from a physician) in TTH is between 16% and
44%32,243–246. In a Danish population study, only 16%
of patients with TTH contacted their general practi-
tioner, compared with 56% of people with migraine32.
However, when corrected for the higher prevalence
of TTH, the total health-care utilization was found to
be 54% higher for TTH compared with migraine32,247.
In a community-based population study from Chile, the
consultation rate in individuals with TTH was 39% com-
pared with 63% in those with migraine245. Younger age
and moderate to severe headache intensity were associ-
ated with likelihood of consultation245. Of note, the head-
ache consultation rate in individuals with pure frequent
TTH (not coexistent with migraine) in 2001 (44%) was
higher than in 1989 (33%) in a longitudinal Danish popu­
lation study244. The proportion of individuals with TTH
using prescription medications increased from 2.2% in
1989 to 7% in 2001, but the proportion of individuals
using over-the-counter medications (OTC) remained
high (93% in 1989 versus 90.4% in 2001) 244. Only
~1% of individuals with TTH were given preventive
medications244. OTC simple analgesics and NSAIDs are
the most frequently used acute headache-abortive med-
ications in TTH owing to the absence of disease-specific
treatments32,243,244,247. Although these therapies can pro-
vide symptomatic relief, they may lead to MOH when
used frequently, and subsequently increase health-care
utilization and medical costs for the individual with
TTH and indirect costs for society247,248.
Quality of life
Health-related quality of life
Although TTH is the most common neurologi-
cal disorder worldwide, its effects on health-related
quality of life (HRQOL) have been under-studied249.
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Primer
The consequences of TTH have received less attention
than those of migraine owing to the greater burden of
migraine at the individual level, although the very high
prevalence of TTH amplifies its effects from a soci-
etal perspective248. While migraine-specific HRQOL
scales have been developed to measure the effect of
migraine on a patient’s life, no disease-specific HRQOL
measures for TTH are available. The consequences of
TTH on the individual include impaired HRQOL,
psychological comorbidities, loss of productivity and
economic costs249,250.
Previous studies have found that patients with
CTTH have a poor quality of life with a generalized
impairment in functioning compared with the gen-
eral population and patients with episodic migraine251.
Similarly, global impairment measured by General
Health Questionnaire-28 was greater for CTTH than for
ETTH31. Moreover, headache frequency is associated with
reduced HRQOL and disability248. A population-based
survey in the Republic of Georgia, using the Short Form
(36) Health Survey (SF-36), found that people with-
out headache had higher scores on all eight subscales
indicating Physical Component Summary (PCS) and
Mental Component Summary (MCS) than those with
episodic headache (coexistent migraine and TTH) or
chronic headache (unspecified headache for ≥15 days/
month)252. However, no differences were found between
respondents with episodic headache and those with
chronic headache or between individuals with migraine
and those with TTH252. In another population-based
study from Spain, using SF-36, no difference in HRQOL
was found between CTTH and transformed migraine25,253.
Of note, as HRQOL declines with age and the CTTH
group was older, age could confound this finding. In a
population study from Denmark, using the SF-12 sur-
vey, both PCS and MCS scores were lower for individ-
uals with coexistent headache (TTH and migraine),
followed by pure TTH and pure migraine than for those
without headache when adjusted for age, sex and educa-
tion level254. Moreover, both PCS and MCS scores were
lower for patients with CTTH followed by ETTH, than
for the no headache group. Lower PCS scores in TTH
were associated with age, female sex and poor self-rated
health, and lower MCS-12 scores in TTH were associated
with depression254.
Patients with CTTH had numerically lower SF-36
scores in six out of eight domains than those with
migraine, indicating worse HRQOL, in a large study
in an outpatient tertiary headache clinic in Taiwan255.
HRQOL scores were generally higher for CTTH than for
transformed migraine (patients who met the criteria
for both CTTH and transformed migraine were classi-
fied as transformed migraine in the study). In another
study of 209 patients from a tertiary headache clinic256
using the SF-20 survey, ‘poor health’ was associated with
social functioning, and mental health scales were greater
for TTH than for migraine257.
Disability
Owing to the moderate severity of headache in the
majority of patients with CTTH, impaired function
may not lead to absenteeism; only a minority of patients
15
Primer
Box 4 | Patient advocate perspective
A lack of understanding is the lived reality of most people who are disabled by headache
disorders, such as tension-type headache (TTH). Why would you want to tell your family
and co-workers that you are disabled (temporarily or more persistently), if you have
come to learn that you will be immediately dismissed as a complainer? This stigma has
a profound negative effect and often negates the plea from patients that more research
and better care are warranted. We do not want to miss out on life. We do not get to
choose when to feel well and when to spend our days in bed. We dream of contributing
to society without having to be disabled by recurrent episodes of headache.
Thus, we need more research into the biological underpinnings of TTH. This will
facilitate identification of targeted therapies that are effective, well-tolerated and safe.
We need policy-makers and funding bodies to acknowledge individuals living with
headache diseases and to better appreciate the considerable socioeconomic impact
of TTH. As a patient advocate myself, I try to impart to people who are disabled by
headache disorders the importance of speaking up and speaking out. The negative
effects and the personal stories must be shared to break down the ingrained inter-personal
and structural stigma. This will ultimately result in allocation of more resources for
research, which is integral to the development of better therapies, pharmacological as
well as lifestyle-based.
Katie MacDonald, Alliance for Headache Disorders Advocacy
with CTTH report their work performance and social
functioning to be severely impaired258,259. Accordingly,
although patients with migraine probably report
more actual lost workdays than those with TTH, TTH
accounts for a considerable loss of work effectiveness
due to headache32,247.
The effect of TTH is higher for those with TTH
with substantial and complicating comorbidities such
as anxiety and depression than for patients without
comorbidities37,248,250. Although comorbid depression
can generally be mild to moderate, patients with TTH
might have high levels of anxiety, which substantially
impairs functioning258. Indeed, in a small study with
25 patients with CTTH referred from a neurology clinic,
anxiety had a mediating effect and depression had a
modulating effect between headache frequency and
intensity, and reduced QOL (mental health and social
functioning) measured with SF-36 (ref.250). However,
a major limitation of this study was the highly selective
study samples and the small sample size. In another
small study of 89 patients with TTH, depression scores
positively correlated with poor QOL in patients with
CTTH. In addition, patients with CTTH scored lower
on the Nottingham Health Profile (NHP), an everyday
life questionnaire than patients with ETTH220. However,
patients in the CTTH group in this study were older than
those in the ETTH group.
Outlook
Despite advances in basic and clinical research in TTH,
this primary headache remains neglected (Box 4). There
are many unanswered questions about the epidemiol-
ogy, impact, diagnosis, pathophysiology and treatment
of TTH. Answering these questions may lead to the
development of more effective and mechanism-based
treatments.
Epidemiology
Future epidemiological studies should use rigorous
methodology, and better and uniform definitions of
TTH, including the use of ICHD criteria. Migraine
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frequently coexists with TTH, and this interaction
needs to be studied further in epidemiological studies167.
Moreover, more studies on the incidence of TTH and
associative and influencing factors are warranted. The
identification of risk factors for transformation from
ETTH to CTTH is important. In particular, modifi­able
risk factors are of great value and can help to inform
better clinical practice260. Together, incidence and prog-
nostic longitudinal studies can help us to develop pre-
ventive measures for TTH. Epidemiological studies
should also quantify indirect consequences of TTH to
provide accurate total cost estimates, which may include
effect on family life (for example, partner relation-
ships and childcare) and career potential (such as sick
days and productivity losses at work).
Pathophysiology
Future work should also target candidate genes asso-
ciated with various TTH phenotypes. Studies of larger
samples of carefully phenotyped groups with TTH
using unbiased approaches such as whole-genome
sequencing, whole-exome sequencing or genome-wide
association studies may generate additional insights
into the genetic basis of TTH. Roles of other neuro-
chemical peptides in the pathophysiology of TTH are
still inconclusive. Future investigations should take
the type of TTH (infrequent ETTH, frequent ETTH
or CTTH) and the effect of comorbid migraine into
consideration. How emotional factors (such as psycho-
logical stress) can activate the mechanisms of head pain
is unclear, and future studies are warranted. Moreover,
firm evidence is needed to better understand the role
of peripheral myofascial factors in the genesis of pain
in TTH. Further research, including larger samples of
patients with TTH, is also needed to better elucidate
the role of vascular inputs in TTH pathophysiology.
These studies should include provocation studies
with neurochemical signalling compounds, MRI and
angiography to explore differences between those
with frequent ETTH and those with migraine, as well
as healthy non-headache controls. This may help us
to determine whether some patients have a predom-
inantly myofascial TTH pathophysiology, while oth-
ers have a predominantly vascular/neuronal TTH
pathophysiology.
Diagnosis
The diagnosis of TTH is still purely clinical, as reliable
and robust biomarkers are lacking. Similar to migraine,
there is a growing urge to identify reliable serum and
clinical biomarkers useful to diagnose primary head-
aches including TTH, monitor their activity and deter-
mine the response to treatment. Circulating serum
biomarkers such as CGRP have been proposed as
diagnostic and therapeutic tools in primary headaches.
CGRP is thought to be a potential and promising bio-
marker of migraine and cluster headache261. Prospective
daily headache diary studies in patients with TTH are
needed for better characterization of the disease and
identification of clinical biomarkers, and would also be
valuable in ascertaining how often patients with CTTH
have a secondary diagnosis of MOH.
 Primer

Management pharmacological and non-pharmacological therapies

The treatment of TTH remains mainly disease non-
specific. There has been interest in the design of NOS
inhibitors with therapeutic purposes and these drugs
may be tested in CTTH. Future studies should eluci-
date the role of triptans in CTTH, as triptans may block
central sensitization262. CGRP monoclonal antibodies
should be investigated for TTH prevention. Behavioural
and physical therapies have good evidence for their use
alone or in combination with pharmacotherapy. There
are significant problems with access to some of the
owing to cost, availability of providers and time to par-
ticipate. Telemedicine consultation for non-acute head-
ache is useful and non-inferior to traditional in-person
clinic evaluation263. Using mobile health platforms and
telehealth may increase access to these therapies by low-
ering cost and increasing convenience. Research needs
to be conducted to determine the efficacy and feasibility
of alternative modes of delivery.
Published online xx xx xxxx

1. GBD 2016 Headache Collaborators. Global, regional,
and national burden of migraine and tension-type
headache, 1990-2016: a systematic analysis for the
Global Burden of Disease Study 2016. Lancet Neurol.
17, 954–976 (2018).
An important study that used data from the
GBD 2016 study to provide global, regional,
and national estimates for prevalence and years
of life lived with disability for migraine and TTH.
2. Deuschl, G. et al. The burden of neurological diseases
in Europe: an analysis for the Global Burden of
Disease Study 2017. Lancet Public. Health 5,
e551–e567 (2020).
Updated data from the GBD 2017 providing
global and European estimates for incidence,
prevalence and years of life lived with disability
for migraine and TTH.
3. GBD 2017 US Neurological Disorders Collaborators.
Burden of neurological disorders across the US from
1990-2017: a Global Burden Of Disease Study.
JAMA Neurol. 78, 165–176 (2020).
Updated data from the GBD 2017 providing
estimates for incidence, prevalence and years
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NATURE REVIEWS | DISEASE PRIMERS | Article citation ID:
Acknowledgements
The authors thank T. P. Do, for skilful assistance and provid-
ing the initial sketches for Figs. 1 and 2. They also thank
R. Burstein for helping with editing and advising on structural
and functional neuroanatomy in Fig. 2. They also thank
K. MacDonald from Alliance for Headache Disorders Advocacy
for providing her perspective on tension-type headache.
Author contributions
Introduction (H.A., R.B.L. and S.A.); Epidemiology (S.J.W.,
S.A. and R.B.L.); Mechanisms/pathophysiology (R.M.,
M.J.L., S.A. and R.H.J.); Diagnosis, screening and prevention
(H.A., H.C.D. and S.A.); Management (D.D.M, D.C.B. and
R.B.L.); Quality of life (N.Y., P.P.R. and R.B.L.); Outlook
(S.A., H.-C.D., R.H.J. and R.B.L.); Overview of Primer (S.A.)
Competing interests
S.A. received honoraria for consulting from Allergan/AbbVie,
Amgen, Biohaven, Eli Lilly, Impel NeuroPharma, Novartis,
Satsuma, Supernus, Theranica and Percept. S.A. is an associ-
ate editor for Neurology Reviews and BMC Neurology, serves
on an Advisory Board for the Journal of Headache and Pain,
and is a member of the Education Committee of the
International Headache Society. D.D.M. has received hono-
raria as a consultant and/or speaker from Allergan/AbbVie,
Amgen, Biogen, Cefaly, Eli Lilly, Genesis Pharma, Medscape,
Merz, Mylan, Novartis, Roche, Sanofi, Specifar and Teva
Pharmaceuticals; has received funding for clinical trials from
Alder, Cefaly, Electrocore, Biogen, Eli Lilly, Genesis Pharma,
Merz, Novartis and Teva. D.D.M. is also past president of
the European Headache Federation, current co-chair of the
Headache Panel in the European Academy of Neurology and
president of the Hellenic Headache Society, and is an associ-
ate editor for Journal of Headache and Pain. D.D.M. does not
own stocks from any pharmaceutical company. M.J.L. has
received honoraria as a consultant and/or speaker for Eli Lilly,
Sanofi-Aventis and YuYu Pharma; has been the PI or
co-investigator in trials sponsored by Eli Lilly, Novartis, Teva
(Otsuka), Allergan/AbbVie, Yuhan Company, Samjin Pharm
and DongA ST; received research support from the National
Research Foundation of Korea; is a trustee member of the
board of the International Headache Society and junior editor
of Cephalalgia. S-J.W. has served on the advisory boards of
Daiichi-Sankyo, Eli Lilly and Taiwan Novartis; has received
honoraria as a moderator from Allergan/AbbVie, Pfizer, Eli
Lilly and Eisai and has been the PI in trials sponsored by
Eli Lilly, Novartis, and Allergan/AbbVie. S-J.W. has received
research grants from the Taiwan Minister of Technology and
Science (MOST), Brain Research Center, National Yang-Ming
University from The Featured Areas Research Center Program
within the framework of the Higher Education Sprout Project
by the Ministry of Education (MOE) in Taiwan, Taipei Veterans
General Hospital and Taiwan Headache Society. R.M. has
received honoraria as speaker for Eli Lilly, Novartis and Teva
Pharmaceuticals. D.B. received honoraria for consulting for
Allergan, Amgen, Biohaven, Eli Lilly, Novartis and Teva, and
has received grant support from Amgen, the National
Headache Foundation and the FDA. D.B. is an editor for
Current Pain and Headache Reports. P.P.-R. has received
(2021) 7:24
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Primer
honoraria as a consultant and/or speaker for Allergan/AbbVie,
Almirall, Biohaven, Chiesi, Eli Lilly, Lundbeck, Medscape,
Neurodiem, Novartis and Teva Pharmaceuticals. Her research
group has received research grants from AGAUR, ERANet
Neuron, la Caixa foundation, International Headache Society,
Migraine Research Foundation, FEDER RISC3CAT, Instituto
Investigación Carlos III, PERIS, Novartis and Teva; and has
received funding for clinical trials from AbbVie, Alder,
Electrocore, Eli Lilly, Lundbeck, Novartis and Teva. P.P.-R. is a
trustee member of the board of the International Headache
Society and a member of the Council of the European
Headache Federation, and is on the editorial board of Revista
de Neurologia; is an associate editor for Cephalalgia,
Headache, Frontiers in Neurology, Neurologia and is on the
Scientific Advisory Board of the Journal of Headache and
Pain. P.P.-R. does not own stocks from any pharmaceutical
company. R.H.J. has received honoraria for lectures and
patient leaflets from MSD, Berlin-Chemie Menarini, ATI,
Novartis, Teva, Allergan and Pfizer and is conducting clinical
trials for Eli-Lilly and Lundbeck. H.-C.D. received honoraria for
participation in clinical trials, contribution to advisory boards
or oral presentations from Allergan/AbbVie, Amgen,
Electrocore, Lilly, Medtronic, Novartis, Pfizer, Teva and Weber
& Weber. Electrocore provided financial support for research
projects. The German Research Council (DFG), the German
Ministry of Education and Research (BMBF) and the
European Union support his headache research. H.-C.D.
serves on the editorial boards of Cephalalgia and Lancet
Neurology, chairs the Clinical Guidelines Committee of the
German Society of Neurology and is a member of the Clinical
Trials Committee of the IHS. R.B.L. is the Edwin S. Lowe
Professor of Neurology at the Albert Einstein College of
Medicine in New York. He receives research support from the
NIH. R.B.L. also receives support from the Migraine Research
Foundation and the National Headache Foundation. R.B.L.
serves on the editorial board of Neurology, is senior adviser
to Headache, associate editor for Cephalalgia and has
reviewed for the NIA and NINDS, holds stock options in
Biohaven Holdings and CntrlM; serves as consultant, advisory
board member, or has received honoraria or conducted
research funded by Allergan/Abbvie, American Academy of
Neurology, American Headache Society, Amgen, Biohaven,
Biovision, Dr. Reddy’s (Promius), Electrocore, Eli Lilly, eNeura
Therapeutics, GlaxoSmithKline, Grifols, Lundbeck (Alder),
Merck, Pernix, Pfizer, Teva, Trigemina, Vector, Vedanta. R.L.
receives royalties from Wolff’s Headache seventh and eighth
editions, Oxford University Press, 2009, Wiley and Informa.
All other authors declare no competing interests.
Peer review information
Nature Reviews Disease Primers thanks V. Gómez-Mayordomo,
who co-reviewed with M. Cuadrado, H. Göbel, P. Martin and
L. Stovner for their contribution to the peer review of this work.
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