NARRATIVE REVIEW

Muscles and their role in episodic tension-type headache:

implications for treatment
L. Bendtsen1, S. Ashina2, A. Moore3, T. J. Steiner4,5
1 Danish Headache Centre, Department of Neurology, Rigshospitalet Glostrup, University of Copenhagen, Glostrup, Copenhagen, Denmark
2 Department of Neurology, Headache Program, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3 Pain Research and Nuffield Division of Anaesthetics, University of Oxford, The Churchill, Oxford, UK
4 Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway
5 Division of Brain Sciences, Imperial College London, UK

Correspondence
Lars Bendtsen
E-mail: lars.bendtsen@regionh.dk
Funding sources
None.
Conflicts of interest
Lars Bendtsen has received honoraria for
lectures from MSD, Allergan and Pfizer,
serves on the scientific advisory board for
Berlin-Chemie, has been a consultant to Rec-
kitt Benckiser and been on Reckitt Benckiser
speaker panels and has been principal inves-
tigator for Convergence Pharmaceuticals.
Sait Ashina received honoraria for lecturing
from Allergan, Nautilus Neurosciences and
Neurogesx and served as a consultant for
Depomed. Andrew Moore has been a con-
sultant to Eli Lilly, Futura Medical, Grunen-
thal, Menarini, Novartis, and Reckitt
Benckiser, received honoraria for lectures
from Astellas, Grunenthal, Eli Lilly, MSD, Pfiz-
er, Reckitt Benckiser, and been in receipt of
grants for research from Grunenthal, Pfizer,
and Reckitt Benckiser.
Timothy J. Steiner has been a consultant to
Bayer HealthCare and Reckitt Benckiser, and
is Director and Trustee of Lifting The
Burden, a UK-based charity conducting
the Global Campaign against Headache in
official relations with the World Health
Organization.
Abstract
Background and Objective: Tension-type headache (TTH) imposes a
heavy burden on the global population but remains incompletely
understood and poorly managed.
Databases and Data Treatment: Here, we review current knowledge
of peripheral factors involved in the mechanism of TTH and make
recommendations for the treatment of episodic TTH based on these.
Results: Peripheral activation or sensitization of myofascial nociceptors
is most probably involved in the development of muscle pain and the
acute episode of TTH. Repetitive episodes of muscle pain may sensitize
the central nervous system resulting in progression of TTH to the
chronic form. Thus, muscular factors may be responsible not only for
the acute headache episode but also for chronification of the disorder.
Simple analgesics and non-steroidal anti-inflammatory drugs are the
mainstays of management of individual headache episodes. Ibuprofen
400 mg and aspirin 1000 mg are recommended as drugs of first choice
based on treatment effect, safety profile and costs. Non-pharmacological
therapies include electromyographic biofeedback, physiotherapy and
muscle relaxation therapy. Future studies should aim to identify the
triggers of peripheral nociception and how to avoid peripheral and
central sensitization. There is a need for more effective, faster acting
drugs for acute TTH.
Conclusion: Muscular factors play an important role in episodic TTH.
Ibuprofen 400 mg and aspirin 1000 mg are recommended as drugs of
first choice.

Accepted for publication

8 June 2015

doi:10.1002/ejp.748

166 Eur J Pain 20 (2016) 166--175 © 2015 European Pain Federation - EFICâ
L. Bendtsen et al.
What’s already known about this topic?
• Muscles play a role in tension-type headache
• Analgesics have an effect in episodic tension-
type headache
Databases
• PubMed and Cochrane Central were searched
What does this study add?
• Up-to-date review of role of muscles in head-
ache with emphasis on role of peripheral sensi-
tization
• Critical review of efficacy and safety of analge-
sics for episodic headache
• Changed recommendation of drugs of first
choice for episodic tension-type headache
1. Introduction
Tension-type headache (TTH) is the second most
prevalent disorder in the world (Vos et al., 2012),
but still remains poorly understood and inadequately
managed (Schwartz et al., 1997). TTH is classified
into three subtypes according to headache fre-
quency: infrequent episodic TTH, frequent episodic
TTH and chronic TTH. The subtypes are further sub-
divided according to absence or presence of
increased pericranial tenderness on manual palpation
(Table 1) (Headache Classification Subcommittee of
the International Headache Society, 2013).
In contrast to migraine headache, no significant
improvements in treatment or new treatment
options for TTH have emerged in the last decades.
While this may be because our understanding of
TTH pathophysiology is less complete than that of
migraine, it has to be asked why this itself is so.
Nonetheless new knowledge of the pathophysiology
of TTH is emerging, and we are beginning to under-
stand some of its complex mechanisms (Jensen,
1999; Bendtsen, 2000; Vandenheede and Schoenen,
2002; Ashina, 2004; Ashina et al., 2005; Bendtsen
and Jensen, 2006, 2009; Mathew, 2006; Fernandez-
de-Las-Penas et al., 2007b; Fumal and Schoenen,
2008). Although past research has focused mainly
on peripheral factors, i.e. muscular factors and
peripheral nociceptors, more recently the crucial role
of the central nervous system, especially in the
chronic form of the disorder, has become clear.
Understanding the pathophysiology of TTH is a
first and necessary step towards developing more
effective treatments. Without this there will be no
specific drugs for its management. Paracetamol (acet-
© 2015 European Pain Federation - EFICâ
Role of muscles in tension-type headache
Table 1 Diagnostic criteria of tension-type headache of the IHS classi-
fication (Headache Classification Subcommittee of the International
Headache Society, 2013).
2.1 Infrequent episodic tension-type headache
A. At least 10 episodes occurring on <1 day/month on average
(<12 days/year) and fulfilling criteria B–D
B. Headache lasting from 30 min to 7 days
C. Headache has at least two of the following characteristics:
1. bilateral location
2. pressing/tightening (non-pulsating) quality
3. mild or moderate pain intensity
4. not aggravated by routine physical activity such as walking or
climbing stairs
D. Both of the following:
1. no nausea or vomiting (anorexia may occur)
2. no more than one of photophobia or phonophobia
E. Not attributed to another disorder
2.2 Frequent episodic tension-type headache
As 2.1 except for:
A. At least 10 episodes occurring on ≥1 but <15 days/month for at
least 3 months (≥12 and <180 days/year) and fulfilling criteria B-D
2.3 Chronic tension-type headache
As 2.1 except for:
A. Headache occurring on ≥15 days/month on average for >3 months
(≥180 days/year) and fulfilling criteria B–D
B. Headache lasts hours or may be continuous
D. Both of the following:
1. no more than one of photophobia, phonophobia or mild nausea
2. neither moderate or severe nausea or vomiting
The three subtypes are further sub-divided according to the absence
or presence of increased pericranial tenderness on manual palpation.
aminophen) and non-steroidal anti-inflammatory
drugs (NSAIDs) including aspirin are recommended
as drugs of first choice (Bendtsen et al., 2010). Here,
we review current knowledge of peripheral factors
involved in the mechanism of TTH, with suggestions
as to how these might influence the choice and use
of analgesics and non-pharmacological treatments
for treating episodic TTH. We searched PubMed and
Cochrane Central (last search January, 2015) using
the keyword TTH and examined bibliographies of
original papers and reviews for additional studies.
2. Muscular factors
2.1 Muscle nociceptors
Muscular factors have long been of interest and sev-
eral may play roles in the pathophysiology of TTH.
Nociceptors are present in skeletal muscle (Mense
and Meyer, 1985) and are located along the walls of
arterioles and in connective tissue in muscle (Mense,
1993). Muscle nociceptors can be stimulated chemi-
cally by endogenous substances such as bradykinin,
Eur J Pain 20 (2016) 166--175 167
Role of muscles in tension-type headache
5-hydroxytryptamin and high concentration of
potassium ions, and mechanically by noxious stim-
uli. Ischaemic contractions can also stimulate noci-
ceptors in skeletal muscle (Mense and Stahnke,
1983). Prostaglandins are involved in muscular pain
by mediating inflammation and sensitizing periph-
eral nociceptors (Korotkova and Lundberg, 2014).
NSAIDs most probably exert their analgesic proper-
ties partly by inhibition of prostaglandin synthesis.
2.2 Myofascial tenderness and hardness in TTH
Studies have consistently shown that the pericranial
myofascial tissues are considerably more tender in
patients with TTH than in healthy subjects, and that
the tenderness is positively associated with both the
intensity and the frequency of TTH episodes (Jensen,
1999; Lipchik et al., 2000; Buchgreitz et al., 2006;
Fernandez-de-Las-Penas et al., 2007a). Tenderness is
uniformly increased throughout the pericranial
region in both episodic and chronic subtypes of TTH
(Langemark and Olesen, 1987; Jensen et al., 1998;
Buchgreitz et al., 2006). It has also been demon-
strated that the pericranial muscles are harder on
palpation (Ashina et al., 1999). Tenderness and
hardness have been found to be increased both on
days with and on days without headache (Ashina
et al., 1999; Jensen, 1999; Lipchik et al., 2000) sug-
gesting that these factors are of importance for the
development of headache and not only a conse-
quence of the headache. Moreover, neck pain is sig-
nificantly more prevalent in subjects with TTH
compared with the control population (Ashina et al.,
2015). Frequency of neck pain was shown to corre-
late with frequency of TTH (Ashina et al., 2015).
What could be the pathophysiological basis for the
pain originating in the myofascial tissues? Under
normal conditions, myofascial pain is mediated by
thin myelinated [Ad] fibres and unmyelinated [C]
fibres, while the thick myelinated [Aa and Ab] fibres
normally mediate innocuous sensations (Newham
et al., 1994). Various noxious and innocuous events
such as mechanical stimuli, ischaemia and chemical
mediators could excite and sensitize Ad-fibres and
C-fibres (Mense, 1993) and thereby play a role in
producing increased tenderness in TTH.
2.3 Muscle contraction
The origin of pain in TTH has traditionally been
attributed to increased contraction and consequent
ischaemia of head and neck muscles. Sustained
experimental tooth clenching was reported to induce
more headache in patients with TTH than in healthy
168 Eur J Pain 20 (2016) 166--175
L. Bendtsen et al.
controls (Jensen and Olesen, 1996), although a
study in young female TTH sufferers found no differ-
ence in headache development between jaw clench-
ing and a placebo procedure (Neufeld et al., 2000).
Another study demonstrated that TTH patients were
more liable than healthy controls to develop shoul-
der and neck pain in response to static exercise
(Christensen et al., 2005). Numerous laboratory-
based electromyographic (EMG) studies have
reported normal or only slightly increased muscle
activity in TTH (Jensen, 1999). However, EMG activ-
ity was reportedly increased in myofascial trigger
points (Hubbard and Berkoff, 1993), and it is possi-
ble that continuous activity in a few motor units
over long time could be sufficient for excitation or
sensitization of peripheral nociceptors (Bendtsen,
2000). It has also been suggested that long-lasting,
low-level muscle activity might damage muscle
fibres (Zennaro et al., 2003). However, a blinded
study from another group could not detect increased
spontaneous EMG activity in trigger points in
patients with chronic TTH (Couppe et al., 2007).
Thus it is possible, but far from proven, that muscles
in TTH exhibit normal global EMG activity, but some
specific points, i.e. trigger points, reveal small areas
of increased EMG activity.
The existence and importance of trigger points in
myofascial pain disorders have long been debated
(Fernandez-de-Las-Penas et al., 2007b; Quintner
et al., 2015). A series of studies performed in a
blinded fashion reported an increased number of
active trigger points in patients with frequent epi-
sodic TTH and in patients with chronic TTH (Fernan-
dez-de-Las-Penas et al., 2006a,b, 2007c; Couppe
et al., 2007). These studies showed that the referred
pain elicited by active trigger points in neck and
shoulder muscles reproduced the headache pattern
in patients with frequent episodic and chronic TTH.
In addition, in chronic, but not episodic, TTH, the
presence of active trigger points was associated with
greater headache severity. Another study revealed
that the presence of bilateral trigger points in the
upper trapezius muscle was associated with lower
pressure pain thresholds in chronic TTH (Fernandez-
de-Las-Penas et al., 2007d).
It has been suggested that active trigger points
cause higher levels of chemical mediators such as
bradykinin, calcitonin gene-related peptide (CGRP),
substance P, serotonin and norepinephrine, not only
in the vicinity of the trigger points but also in distant
regions that are free of pain (Shah et al., 2008). If
this is true, then in theory, active trigger points
could cause sensitization of peripheral nociceptors,
© 2015 European Pain Federation - EFICâ
L. Bendtsen et al.
which could in turn through persistent nociceptive
input contribute to central sensitization and chronifi-
cation of TTH (Fernandez-de-Las-Penas and Schoe-
nen, 2009). Chronification of TTH would then lead
to increased pericranial tenderness (Buchgreitz et al.,
2008). Indeed, active trigger points were found in
muscles, innervated by the trigeminal nerve, such as
temporalis, masseter and extraocular muscles, and in
muscles innervated by C1–C3 segments, such as
sternocleidomastoid, suboccipital and upper trapezius
(Fernandez-de-Las-Penas et al., 2007b).
Muscle tenderness and hardness at tender muscle
sites could also result from a local contracture (i.e.
shortening of the contractile apparatus without
action potentials in the muscle fibres) rather than
normal contraction of motor units (Simons and
Mense, 1998). This mechanism would explain the
lack of EMG abnormalities in TTH, but the mecha-
nisms of peripheral nociceptor activation by a con-
tracture have not yet been studied in enough detail
(Mense et al., 2003).
By use of microdialysis technique, Ashina et al.
(2002) demonstrated that lactate levels in a tender
site in the trapezius muscle did not differ between
patients and healthy subjects during rest and static
exercise, ruling out muscle ischaemia in these
patients. However, the increase in muscle blood flow
during exercise was lower in patients than in con-
trols. The investigators suggested the altered blood
flow was caused by altered sympathetic outflow to
blood vessels in striated muscle secondary to plastic
changes in the central nervous system (central sensi-
tization) (Ashina et al., 2002).
It can be concluded that the muscle pain in TTH is
not caused by generalized excessive muscle contrac-
tion and muscle ischaemia. However, it cannot be
excluded that a locally increased muscle tone with-
out EMG activity (contracture) may result in micro-
trauma of muscle fibres and tendon insertions or
that excessive activity in a few motor units may
excite or sensitize peripheral nociceptors. In fact, the
theory of active trigger points playing a role in TTH
supports the hypothesis, as muscles with trigger
points can exhibit normal EMG activity at rest (Fer-
nandez-Carnero et al., 2010). The trigger point
would then be the only small area of the muscle
exhibiting increased EMG activity. Future research is
needed to elucidate these questions.
2.4 Peripheral sensitization
The increased myofascial pain sensitivity in TTH
could be due to release of inflammatory mediators
© 2015 European Pain Federation - EFICâ
Role of muscles in tension-type headache
resulting in excitation and sensitization of peripheral
sensory afferents in muscles (Bendtsen, 2000). How-
ever, Ashina et al. (2003) demonstrated that the
in vivo interstitial concentrations of adenosine 5-tri-
phosphate, glutamate, glucose, pyruvate, urea and
prostaglandin E2 in tender muscles during rest and
static exercise did not differ between patients with
chronic TTH and healthy controls. The investigators
concluded that tender muscle sites in these patients
are not sites of ongoing inflammation. On the con-
trary, Shah et al. (2008) reported ongoing inflamma-
tion in active trigger points. It is possible, but so far
not clarified, that tender points represent a different
entity from trigger points (Mense, 2011). This is clin-
ically important and should be examined in future
studies.
Schmidt-Hansen et al. (2006) demonstrated that
infusion of hypertonic saline into various pericranial
muscles elicited referred pain that was perceived as
head pain in healthy subjects. Mork et al. (2004)
infused a combination of endogenous substances
such as bradykinin, serotonin, histamine and prosta-
glandin E2 into the trapezius muscle and reported
that patients with frequent episodic TTH developed
more pain than healthy controls. Concomitant psy-
chophysical measures indicated that peripheral sensi-
tization of myofascial sensory afferents was
responsible for the muscular hypersensitivity in
these patients.
2.5 Chronification of TTH
Progression from episodic to chronic TTH, i.e. having
headache at least every other day, is of major impor-
tance for both the individual and for society. This is
so because the development of chronic TTH increases
the risk of refractoriness to treatment and of overuse
of headache abortive medications, and increases dis-
ability resulting in high personal and socioeconomic
costs (Chen, 2009). In a 12-year longitudinal epide-
miological study of TTH, approximately one half of
subjects experienced remission while 16% had
unchanged chronic or newly developed chronic TTH
at follow-up (Lyngberg et al., 2005).
Muscular factors play a role not only in the acute
episode of TTH. On the basis of numerous pain per-
ception, imaging, pharmacological and longitudinal
studies, it has been demonstrated that prolonged
nociceptive input from peripheral myofascial tissues
in subjects with episodic TTH can lead to sensitiza-
tion of the central nervous system and in this way to
transformation from episodic to chronic TTH (Bendt-
sen, 2000; Bendtsen and Jensen, 2006; Fernandez-
Eur J Pain 20 (2016) 166--175 169
Role of muscles in tension-type headache
Figure 1 The proposed pathophysiological model of chronic tension-
type headache delineates two major aims for future research: (1) to
identify the triggers of peripheral nociception to prevent the develop-
ment of central sensitization in patients with episodic tension-type
headache, and (2) to reduce established central sensitization in
patients with chronic tension-type headache. TTH: Tension-type head-
ache.
de-Las-Penas et al., 2007b; Ailani, 2009; Chen, 2009;
Cathcart et al., 2010; Bendtsen and Fernandez-de-la-
Penas, 2011; Bezov et al., 2011) (Fig. 1). It is most
likely that this risk is minor for subjects with infre-
quent TTH, but that it becomes increasingly impor-
tant with increasing headache frequency and
severity. Theoretically, therefore, optimal treatment
of episodic TTH will prevent chronification of the
headache.
3. Muscles and their relevance for non-
pharmacological management
Non-pharmacological management aimed at muscu-
lar components is widely used. Scientific evidence
for efficacy of most treatment modalities is sparse.
This is partly because few studies have been per-
formed, and partly because high quality studies are
difficult to design, with proper blinding being a
major obstacle. So how can we use our present
knowledge of muscular factors to optimize manage-
ment of TTH?
It can be explained to the patient that muscle pain
can be referred to the head and perceived as head-
ache. Furthermore, it can be explained that if the
muscle pain and headache become very frequent,
they may lead to a disturbance of the brain’s pain-
modulating mechanisms; what would otherwise be
innocuous stimuli are then consequently perceived
as painful, with secondary perpetuation of muscle
pain and headache. The location and degree of peri-
cranial myofascial tenderness and trigger points
170 Eur J Pain 20 (2016) 166--175
L. Bendtsen et al.
should be examined by manual palpation to demon-
strate the possible sources of pain.
Education incorporating this physical demonstra-
tion of the importance of muscular factors may help
the patient to understand the mechanisms of TTH
and motivate him or her to perform the suggested
non-pharmacological treatments. Moreover, this
examination helps the health care professional
choose the most relevant of the non-pharmacological
managements.
Physical therapy is the most used non-pharmaco-
logical treatment of TTH and includes improvement
of posture, instruction in optimal working positions,
relaxation and exercise programmes. Active treat-
ment strategies, such as home-based relaxation exer-
cises for the shoulders rather than passive treatments
such as massage, are generally recommended (Jen-
sen and Roth, 2005). Adding craniocervical training,
i.e. low-load endurance exercises to train and/or
regain muscle control over the cervicoscapular and
craniocervical regions, to classical physiotherapy may
be better than physiotherapy alone (van and Lucas,
2006). One study indicated a beneficial effect of
manual therapy combining mobilization of the cervi-
cal and thoracic spine with exercises and postural
correction (Castien et al., 2011).
Psychological treatment strategies have been
thought to have reasonable scientific support for
their effectiveness, though more recent examination
of the evidence has questioned this (Verhagen et al.,
2009). Relaxation training is a self-regulation strat-
egy that provides patients with the ability con-
sciously to reduce muscle tension and autonomic
arousal that can precipitate or result from headaches.
EMG biofeedback has a documented effect (Nest-
oriuc et al., 2008). During EMG biofeedback,
patients are presented with an auditory or visual dis-
play of electrical activity of the muscles in the face,
neck or shoulders. This feedback helps the patients
to learn how to relax.
4. Muscles and their relevance for
pharmacological management
4.1 Acute pharmacotherapy
The effect of drugs for treating acute TTH has been
examined in a number of studies, which have used a
range of efficacy measures and different outcomes.
This makes comparing results difficult. In 2010, a
task force of the European Federation of Neurologi-
cal Societies (EFNS) published a guideline for treat-
ment of TTH based on the available controlled trials,
© 2015 European Pain Federation - EFICâ
L. Bendtsen et al. Role of muscles in tension-type headache

reviews, meta-analyses, and, because trial-based evi- 4.2 Recent studies on acute pharmacotherapy
dence was often lacking, also on expert opinion
Two meta-analyses provide new data since the
(Bendtsen et al., 2010). For acute treatment, the
publication of the international guidelines. This
guideline recommended paracetamol and NSAIDs,
could potentially change recommendations for
including ibuprofen, aspirin, ketoprofen, naproxen
acute drug treatment of TTH. A meta-analysis of
and diclofenac. Combination analgesics containing
randomized placebo-controlled trials from 2012
caffeine were recommended as drugs of second
investigated efficacy and safety of paracetamol ver-
choice, because of a possible higher risk of inducing
sus NSAIDs including aspirin (Yoon et al., 2012).
medication-overuse headache. In practice, analgesics
Unfortunately, it used a method designed specifi-
are often used in combination with codeine, other
cally for acute postoperative pain to convert mean
opioids, sedatives or tranquilizers, but these combi-
to dichotomous data; the conclusion that there was
nations should be avoided because of the risk of
no difference between low-dose NSAIDs and parac-
dependency, abuse and chronification of headache
etamol in treating TTH might therefore be
(Bendtsen et al., 2010). Triptans, muscle relaxants
doubted.
and opioids were not recommended for the treat-
However, a broad-ranging systematic review
ment of TTH (Bendtsen et al., 2010).
examined any intervention for treating acute TTH
There are few studies investigating the ideal dose
where trials were randomized and double blind; it
of drugs for the acute treatment of TTH (Steiner and
included 55 such trials with 12,143 patients (Moore
Lange, 1998; Steiner et al., 2003). The EFNS guide-
et al., 2014c). Numbers needed to treat (NNT) values
line recommended ibuprofen 200–800 mg, ketopro-
in comparisons with placebo for being pain-free at
fen 25 mg, aspirin 500–1000 mg, naproxen 375–
2 h were 8.7 (95% CI: 6.2–15) for paracetamol
550 mg, diclofenac 12.5–100 mg and paracetamol
1000 mg, 8.9 (5.9–18) for ibuprofen 400 mg and 9.8
1000 mg. The task force concluded that the evidence
(5.1–146) for ketoprofen 25 mg, with no data avail-
for optimal doses was sparse, and that the most
able for aspirin. While pain-free at 2 h may be a
effective dose of a drug well tolerated by a patient
desired outcome, NNTs in the range 8–10 do not
should be chosen.
suggest that it provides a clinically helpful measure,
Likewise, there are few studies comparing the var-
at least for the drugs currently available. Lower
ious drugs for efficacy and side effects in patients
(better) NNTs (3.5–8.4) for these four drugs were
with TTH (Steiner and Lange, 1998; Steiner et al.,
calculated for the outcomes of mild or no pain at
2003). The EFNS guideline concluded that paraceta-
2 h, and patient global assessment. It was likely that
mol 1000 mg is probably less effective than the NSA-
naproxen and diclofenac were also more effective
IDs, but had a better gastric side effect profile.
than placebo, but there were insufficient data to be
Ibuprofen 400 mg was recommended as drug of
certain. Much more data would be needed to dem-
choice among the NSAIDs because of a favourable
onstrate superiority of one drug over another, and
gastrointestinal side effect profile compared with
we do not know whether fast-acting formulations of
other NSAIDs. However, it was also concluded that
NSAIDs might provide better pain relief, as they do
efficacy of the acute drugs was modest and that
in other acute pain (Moore et al., 2014b).
there was room for better acute treatment of epi-
The best evidence for acute relief of episodic TTH
sodic TTH.
therefore exists for ibuprofen 400 mg, aspirin
An earlier systematic review also concluded that
1000 mg, ketoprofen 25 mg and paracetamol
NSAIDs are more effective than paracetamol for the
1000 mg. It is likely, but not proven, that paraceta-
treatment of episodic TTH and that ibuprofen should
mol 1000 mg is somewhat less effective than the
be recommended among the NSAIDs on the basis of
other three.
fewer side effects (Verhagen et al., 2006). The guide-
lines of the German, Swiss and Austrian Headache
4.3 Side effects of acute drugs for TTH
Societies recommend a fixed combination of aspirin,
paracetamol and caffeine as drug treatment of first Tension-type headache typically requires only occa-
choice (Haag et al., 2011), the British Association for sional use of OTC doses with a consequent very
the Study of Headache recommend ibuprofen and low risk of significant adverse events. Most of the
aspirin (MacGregor et al., 2010), while the Danish available evidence on adverse events of paracetamol
Headache Society recommend ibuprofen, ketoprofen, and NSAIDs comes from RCTs or observational
aspirin, naproxen, diclofenac and paracetamol studies examining high doses used over long peri-
(Bendtsen et al., 2012). ods.

© 2015 European Pain Federation - EFICâ Eur J Pain 20 (2016) 166--175 171
Role of muscles in tension-type headache
A review article concluded that over-the-counter
use of ibuprofen and diclofenac is associated with
symptomatic gastrointestinal side effects comparable
to those from placebo (Bjarnason, 2013). Another
systematic review reported that adverse event rates
from ibuprofen, ketoprofen, naproxen and paraceta-
mol in single doses used postoperatively were no dif-
ferent from those from placebo, but those from
aspirin were slightly elevated (13% of patients trea-
ted with aspirin had at least one adverse event com-
pared with 11% of patients given placebo) (Moore
et al., 2011a). Another review concluded that
adverse event rates for treatment of short-lasting
acute pain were 14.9% for aspirin and 11.1% for
placebo and that the small differences in adverse
events should not support decision choices for short-
lasting acute pain which should better be based on
efficacy (Steiner and Voelker, 2009). There is no evi-
dence of any cardiovascular risk with ibuprofen used
at non-prescription doses (Moore et al., 2014a).
Analysis of the large Nurses’ Health Study demon-
strated no increased risk of major cardiovascular
events over 12 years of follow-up in occasional users
(1–14 days/month) of aspirin, NSAIDs or paraceta-
mol (Chan et al., 2006). The rate of acute liver fail-
ure leading to transplantation was 3.3 for non-
overdose paracetamol exposure and 1.59 for NSAID
exposure per million treatment years (Gulmez et al.,
2013). There is no obvious evidence of a safety
advantage for paracetamol over ibuprofen for non-
prescription doses taken for 7 days or less (Rainsford
et al., 1997), or for 3 months (Doherty et al., 2011).
4.4 Conclusion on efficacy and safety
It is most likely, but not proven, that ibuprofen
400 mg, aspirin 1000 mg and ketoprofen 25 mg are
more effective than paracetamol 1000 mg. Among
these drugs, we recommend ibuprofen and aspirin as
drugs of first choice. In excluding ketoprofen from
our final recommendation, we have regard not only
for the evidence of efficacy and safety set out above
but also for the important factor of universal avail-
ability at minimal cost (International Drug Price
Indicator Guide, 2015), which ketoprofen lacks. In
many parts of the world this factor is crucial; it also
means that experience of usage is worldwide, and
safety data have not been gathered only from cosset-
ed populations. For people taking occasional doses of
analgesics for TTH there is no evidence of increased
risks of serious adverse events. In particular, there is
no evidence that paracetamol has a better side effect
profile than NSAIDs.
172 Eur J Pain 20 (2016) 166--175
L. Bendtsen et al.
On the basis of data on efficacy together with
safety data and cost considerations, we recommend
that ibuprofen 400 mg and aspirin 1000 mg should
be the drugs of first choice for acute treatment of
TTH.
4.5 What is needed to be able to improve the
acute treatment of TTH?
While paracetamol and NSAIDs do have a significant
effect in episodic TTH, the effect size is not impres-
sive. Rates for being pain-free 2 h after treatment
are approximately 30% (Bendtsen et al., 2010); a
recent review reported that NNTs for this outcome
compared to placebo were 8–10 for paracetamol
1000 mg, ibuprofen 400 mg and ketoprofen 25 mg
(Moore et al., 2014c). On this basis, there is clearly a
need for more effective treatments.
Which drugs would be most likely to be effective
in episodic TTH? Since it is most likely that periph-
eral sensitization plays a role in episodic TTH, and
that central sensitization is responsible for the con-
version from episodic to chronic TTH as we described
previously, drugs with both peripheral and central
actions might be candidates. This includes NSAIDs
which inhibit prostaglandin synthesis in both the
periphery and in the central nervous system (Burian
and Geisslinger, 2005). Paracetamol has a less promi-
nent effect on prostaglandin synthesis and, consis-
tent with this, most probably also less analgesic
effect in TTH. This is also in agreement with a recent
important study that found no effect of paracetamol
for acute low-back pain (Williams et al., 2014). The
authors of this study questioned the universal
endorsement of paracetamol as first-line analgesic
for acute low-back pain (Williams et al., 2014).
Apart from a high degree of pain relief, rapid onset
of pain relief is considered particularly important by
patients, as has been shown in patients with
migraine (Lipton et al., 2002). This might be
achieved by using soluble formulations of NSAIDs
(Moore et al., 2014b). A recent review of studies of
fast-acting forms of ibuprofen for acute pain, includ-
ing over 10,000 patients mainly with dental pain,
concluded that fast-acting formulations produced sig-
nificantly better and faster onset of analgesia than
standard formulations of ibuprofen. Rapid reduction
in pain was linked with reduced need for remedica-
tion (Moore et al., 2014b). It would be highly rele-
vant to investigate whether the same were true for
TTH. Likewise drugs with rapid penetration of the
CNS like etoricoxib might be useful in TTH (Renner
et al., 2010).
© 2015 European Pain Federation - EFICâ
L. Bendtsen et al.
Combining different analgesics together also offers
the potential to improve therapy. In acute pain and
migraine, drug-specific benefits are known to be
additive, so that possible combinations can be
explored before embarking on clinical trials (Moore
et al., 2012). Combinations that include caffeine
probably should and those that include opioids defi-
nitely should be avoided, but combining paracetamol
with ibuprofen in acute pain produces high efficacy
at relatively low dose (Moore et al., 2011b). The rel-
ative efficacy of analgesics in acute pain is probably
relevant to TTH, and should inform progress for TTH
(Moore et al., 2011a).
It can be concluded that more effective and faster
acting drugs are needed for treatment of episodic
TTH. This might be achieved by developing drugs
that better counteract peripheral and central sensiti-
zation in TTH. Moreover, it should be tested
whether faster acting formulations of analgesics also
have a clinically important faster acting effect in
TTH.
5. Conclusions
Peripheral activation or sensitization of myofascial
nociceptors is most probably involved in the devel-
opment of muscle pain and the acute episode of
TTH. Repetitive episodes of muscle pain may sensi-
tize the central nervous system resulting in progres-
sion of TTH to the chronic form. Muscular factors
may therefore be responsible not only for the acute
headache episode but also for chronification of the
disorder. Non-pharmacological therapies should
include EMG biofeedback, physiotherapy and muscle
relaxation. Ibuprofen 400 mg and aspirin 1000 mg
are recommended as drugs of first choice for the
treatment of episodic TTH based on treatment effect,
safety profile and costs. More effective and faster act-
ing drugs are needed for treatment of episodic TTH.
This might be achieved if we gain better understand-
ing of how to counteract peripheral and central sen-
sitization in TTH.
Author contributions
All authors have been involved in all aspects of the review
including discussion of results and comments to the manu-
script.
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