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Efficacy of fixed combinations of acetylsalicyclic acid,
acetaminophen and caffeine in the treatment of
idiopathic headache: a review
K. Annekena,b, S. Eversb and I. W. Husstedtb
aDepartment of Neurology, Community Hospital of Dortmund, Dortmund; and bDepartment of Neurology, University Hospital of Muenster,
Muenster, Germany
acetylsalicyclic acid,
combination analgesics,
headache, headache
therapy, migraine,
tension-type headache
Received 7 July 2009
Accepted 11 November 2009
Headache is one of the most common reasons for patients to visit their general
practitioner. Most of these patients su\ufb00er from migraine, tension-type headache, or a
combination of the two; they tend to self-medicate using over the counter combination
headache preparations, particularly acetylsalicyclic acid (ASA) and acetaminophen
coformulated with ca\ufb00eine, which is one of the most commonly used combination
analgesics in these patients worldwide. We reviewed studies on the e\ufb03cacy and safety
of this combination. In the treatment of migraine and tension-type headache, the
combination of ASA, acetaminophen, and ca\ufb00eine has been shown to be more e\ufb03-
cacious and superior to monotherapy with the single substances of the combination.
According to literature, there is no evidence for higher prevalence of undesirable side-
e\ufb00ects of combination analgesics in comparison to monotherapy.
Headache is one of the most prevalent disorders
worldwide and is associated with severe socioeconomic
consequences. Approximately 90% of headache
patients su\ufb00er from migraine, tension-type headache, or
a combination of the two [1]. Headache is generally
managed via over the counter analgesics (OTC),
combination analgesics playing a key role. The \ufb01xed
combination consisting of acetylsalicyclic acid (ASA),
acetaminophen and ca\ufb00eine is one of the most widely
used combination analgesics worldwide for headache
The global burden of migraine in adults is 11%, for
tension type headache 42% and for chronic daily
headache 3% [2]. In an epidemiologic danish study the
ratio of men to women was 1:6 for migraine and 1:3 for
tension type headache. [3]. The daily activities of more
than half of headache su\ufb00erers are severely disrupted. A
US study found that 31% of migraine patients missed
at least 1 day of school or work owing to headache
during the 3-month investigation period [4].
Most headache su\ufb00erers take medication for their
condition, but approximately two-third of these indi-
viduals [5] and more than 80% of tension-type head-
ache patients [6] do not consult a physician for their
condition. Instead, the preferred form of treatment
for idiopathic headache is self-medication via OTC
analgesics [1,6,7], and particularly OTC combination
analgesics. More than 90% of patients who take
these combination preparations use them for headache
therapy [8].
The most widely used combination analgesic world-
wide is the \ufb01xed combination comprising ASA, acet-
aminophen, and ca\ufb00eine [9], which was \ufb01rst approved
in Germany in 1971. The key pharmacokinetic prop-
erties of the constituents of this combination are vir-
tually indistinguishable [9]. The anti-in\ufb02ammatory,
analgesic, and anti-pyretic e\ufb00ect of ASA is attributable
to inhibition of the isoenzyme cyclooxygenase-2 (COX-
2), whereas its undesirable e\ufb00ects are attributable to
inhibition of the isoenzyme cyclooxygenase-1 (COX-1)
As likewise a key e\ufb03cacious non-opioid analgesic,
acetaminophen has an antipyretic and analgesic e\ufb00ect
but no signi\ufb01cant antiphlogistic e\ufb00ect. There is evidence
that acetaminophen inhibits nociceptive thalamic
activity, and that it has an e\ufb00ect on the serotoninergic
system, substance P, the prostaglandin system, and the
arginine NO synthetase system [9]. The toxic potential
is dose-dependent [9,11].
Acetaminophen-induced inhibition of COX-2 activity
has been observed in the cerebral glial cells of animal
Correspondence: I. W. Husstedt, Klinik und Poliklinik fu¨r Neurologie,
Universitaetsklinikum Muenster, Albert Schweitzer-Str. 33, 48149
Muenster, Germany (tel.: +49 251 8348 188; fax: +49 251 8345 065;
\ufffd 2010 The Author(s)
Journal compilation \ufffd 2010 EFNS
European Journal of Neurology 2010, 17: 534\u2013540 doi:10.1111/j.1468-1331.2009.02922.x
models [10]. It has also been shown that the COX-
inhibiting e\ufb00ect is dose-dependent [9,10,12]. The
intrinsic analgesic e\ufb00ect of ca\ufb00eine is a matter of debate
[13,14]. In combination with analgesics, ca\ufb00eine has
been shown to have an adjuvant, potentiating e\ufb00ect (up
to 50% greater e\ufb03cacy) [9,15,16]. The same analgesic
e\ufb03cacy can be achieved with half the normal combi-
nation analgesic dose [11,17].
It has been shown that ca\ufb00eine is an adenosine
antagonist, induces interaction with adrenergic recep-
tors in the CNS, and stimulates cholinergic neurons
[9,18]. More recent investigations point to ca\ufb00eine-
induced inhibition of COX-2 protein synthesis [10]. It
has also been shown that the adjuvant analgesic e\ufb00ect
of ca\ufb00eine is una\ufb00ected by normal ca\ufb00eine consump-
tion in food [19]. The combination of ASA, acetami-
nophen, and ca\ufb00eine in animal models exhibits a
synergistic e\ufb00ect with respect to COX inhibition that is
more than just additive and that is attributable to the
di\ufb00ering molecular mechanisms of action of the com-
bination\ufffds individual constituents [10,13].
In the following, we review studies that have inves-
tigated the e\ufb03cacy of the \ufb01xed combination comprising
ASA, acetaminophen, and ca\ufb00eine for migraine and
tension headache. This review is based on a PubMed
database search of German and English articles from
1966 to 2008 containing the terms \u2018\u2018combination-anal-
gesics, ASA, acetaminophen, paracetamol and caf-
feine\u2019\u2019.We took account of all studies that investigated
the aforementioned combination and that met the
criteria de\ufb01ned by Balk et al. [20] for good randomized
controlled studies.
Efficacy of the fixed combination comprising
ASA, acetaminophen, and caffeine (COM)
A number of controlled clinical trials have investigated
the analgesic e\ufb03cacy of a \ufb01xed combination comprising
ASA, acetaminophen, and ca\ufb00eine for idiopathic
headache, relative to placebo, the constituents of the
combination, or other established mono-analgesics (see
Appendix 1). A multicenter, double-blind, randomized
three-cohort study by Goldstein et al. [6] compared the
combination comprising ASA 500 mg, acetaminophen
500 mg, and ca\ufb00eine 130 mg with ibuprofen 400 mg
and placebo for migraine therapy with respect to
analgesic e\ufb03cacy, rapidity of action, and e\ufb00ect on
migraine-associated symptoms.
Comparison of COM with ibuprofen
The combination of ASA, acetaminophen, and ca\ufb00eine
was signi\ufb01cantly superior with respect to the primary
end-point of e\ufb03cacy, which was the weighted pain score
2 h following administration. Under the combination
analgesic, patients experienced signi\ufb01cant pain relief
20 min sooner than with ibuprofen [6]. Combination
analgesic was also signi\ufb01cantly superior to ibuprofen in
terms of pain intensity reduction relative to baseline, as
well as the proportion of patients whose pain resolved
or signi\ufb01cantly lessened after taking the medication
Comparison of COM with placebo
Results were better for both the ibuprofen and combi-
nation analgesic groups than for placebo for all of the
aforementioned parameters. In terms of the e\ufb00ect on
migraine-associated symptoms such as nausea and
photophobia, no signi\ufb01cant di\ufb00erence was observed
between the combination analgesic and ibuprofen
groups; however, such a di\ufb00erence was observed
between both of the aforementioned groups and the
placebo group. Increasing the ibuprofen dose in
accordance with guidelines such as the European Fed-
eration of Neurological Societies (EFNS) presumably
would have narrowed the discrepancy between the
cohorts [21]. Another placebo-controlled study com-
pared the