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combination of ASA 500 mg, acetaminophen
500 mg, and ca\ufb00eine 130 mg with sumatriptan 50 mg in
early stage migraine treatment with respect to analgesic
e\ufb03cacy, responder rate, e\ufb00ect on migraine-associated
symptoms, relapse rate, overall patient satisfaction with
the therapy, recovery of normal everyday functions,
and undesirable e\ufb00ects [22].
Comparison of COM with sumatriptan
The combination analgesic was superior to both su-
matriptan and placebo with respect to the primary end-
point of e\ufb03cacy (reduction of pain intensity relative to
baseline 4 h following administration) as well as the
secondary end-points of e\ufb03cacy. The responder rate
(de\ufb01ned as the proportion of patients whose headache
subsided from moderate or severe at baseline to mild or
pain-free) for the combination analgesic was signi\ufb01-
cantly higher than for sumatriptan, beginning 2 h fol-
lowing administration until the end of the observation
period (4 h following intake); the reverse e\ufb00ect was
observed during the \ufb01rst 30 min following administra-
tion. The relapse rate (de\ufb01ned as the percentage of
patients whose headache had subsided completely or
almost completely 2 h following administration, but
whose headache returned to a moderate or severe level
thereafter) did not di\ufb00er signi\ufb01cantly in the three pa-
tient groups. With respect to the e\ufb00ect on photophobia
and phonophobia, overall patient satisfaction with the
migraine therapy, and restoration of normal everyday
Ef\ufb01cacy of \ufb01xed combinations of analgetics 535
\ufffd 2010 The Author(s)
Journal compilation \ufffd 2010 EFNS European Journal of Neurology 17, 534\u2013540
functions, the results obtained with the combination
analgesic were signi\ufb01cantly better than with sumatrip-
tan; but there was no signi\ufb01cant di\ufb00erence with respect
to nausea and vomiting [23].
A direct dose\u2013e\ufb00ect relationship was observed for the
triptan sumatriptan, with some patients \ufb01nding a 50-mg
dose to be unduly low. As was shown by a meta-anal-
ysis, slightly greater pain reduction is obtained with
100 mg sumatriptan than with 50 mg [24]. It can
therefore be assumed that use of 100 mg in the study
described here would have narrowed the discrepancy
that was observed.
Comparison of COM with other combinations,
monotherapy and placebo
The combination analgesic was superior to placebo
with respect to the primary end-point of e\ufb03cacy
(reduction of intensity relative to baseline 4 h following
administration) as well as the secondary end-points of
A large, multicenter, double-blind, randomized study
by Diener et al. [13] compared the combination of ASA
500 mg, acetaminophen 400 mg, and ca\ufb00eine 100 mg
with a ca\ufb00eine-free formulation of this combination, its
constituent substances (ASA 1000 mg, acetaminophen
1000 mg, and ca\ufb00eine 100 mg) and placebo, with
respect to e\ufb03cacy gradient, time until onset of action,
and tolerability. The study cohort consisted of patients
with tension-type headache and migraine (84%
migraine, 13% tension-type headache, 3% of unclear
origin) that generally treat their headaches using over
the counter drugs. The study showed that the combi-
nation of ASA, acetaminophen, and ca\ufb00eine is signi\ufb01-
cantly more e\ufb03cacious than the other therapies
administered. The study investigated not only the
analgesic e\ufb03cacy of the triple combination but also its
analgesic potency. The primary end-point of e\ufb03cacy
was de\ufb01ned as the time that elapsed until the patient\ufffds
pain subsided by 50%. The onset of action for the triple
combination was signi\ufb01cantly faster than for any of the
other therapies. The median was 1:05 h:min following
administration of the triple combination, compared to
1:13, 1:19, 1:21, 1:47 and 2:13 h:min following admin-
istration, respectively, of ASA and acetaminophen,
ASA, acetaminophen, and placebo. All non-placebo
therapies, except for ca\ufb00eine alone, showed signi\ufb01cantly
better results than placebo. The triple combination
yielded better results than the comparison groups with
respect to the secondary end-points as well. The time
needed to reduce pain intensity to £10 mm on the visual
analog scale was signi\ufb01cantly shorter for the triple
combination, which also reduced pain relative to
baseline at all measuring points. The triple combination
group di\ufb00ered signi\ufb01cantly from all other patient
groups (except for ASA/acetaminophen and acetami-
nophen monotherapy) with respect to disruption of
normal everyday functions. Concomitant with this,
patients that received the triple combination rated
overall drug e\ufb03cacy as being signi\ufb01cantly better than
did all other patient groups. The overall tolerability of
the triple combination was characterized as \u2018\u2018very
good\u2019\u2019 to \u2018\u2018good\u2019\u2019 by more than 90% of study probands
and physicians. Fifty percent of the probands antici-
pated that their pain would be palliated within 30 min
following administration [25].
Another multicenter, double-blind, parallel-group
study [26] on the management of two separate episodes
of idiopathic or symptomatic headache revealed a sig-
ni\ufb01cant e\ufb03cacy sequence, whereby the combination of
ASA, acetaminophen, and ca\ufb00eine was more e\ufb03cacious
than the non-ca\ufb00eine combination, which was in turn
superior to ASA monotherapy. The patients took one
of the following analgesics per headache event and then
took the same medication again after 30 min if the \ufb01rst
tablet had no e\ufb00ect by then: (a) ASA 250 mg, acet-
aminophen 200 mg, and ca\ufb00eine 150 mg; (b) ASA
250 mg and acetaminophen 250 mg; (c) ASA 500 mg.
For the initial headache event, 83% of group (a), 75%
of group (b) and 71% of group (c) reported \u2018\u2018no
symptoms\u2019\u2019 or \u2018\u2018substantial relief.\u2019\u2019 In addition, group
(a) patients used the smallest number of tablets and
expressed the greatest willingness to take the same
tablet again in the event of a recurrence. There was no
indication of any patient preference for combination (a)
owing to the psychotropic e\ufb00ect of ca\ufb00eine.
Four randomized, double-blind, placebo-controlled,
crossover studies by Migliardi et al. [15] with identical
study designs investigated the analgesic e\ufb03cacy of the
combination comprising ASA 500 mg, acetaminophen
500 mg, and ca\ufb00eine 130 mg relative to acetaminophen
1000 mg in approximately 1900 patients with episodic
tension-type headache. All four studies revealed the
same signi\ufb01cantly superior e\ufb03cacy: ASA, acetamino-
phen and ca\ufb00eine > acetaminophen > placebo, irre-
spective of ca\ufb00eine consumption.
An analysis of three placebo-controlled studies by
Lipton et al. [27] investigated the e\ufb03cacy and safety of
the combination comprising ASA 500 mg, acetamino-
phen 500 mg, and ca\ufb00eine 130 mg for migraine man-
agement with and without aura. A signi\ufb01cant di\ufb00erence
between the combination analgesic and placebo was
observed with respect to the two primary end-points of
e\ufb03cacy, i.e. lessening of pain intensity relative to base-
line 2 h following administration, and percentage of
patients with mild or no pain 2 h following administra-
tion. In all three studies, 1\u20136 h following administration
of the combination analgesic (and at all measuring
536 K. Anneken et al.
\ufffd 2010 The Author(s)
Journal compilation \ufffd 2010 EFNS European Journal of Neurology 17, 534\u2013540
points during the analysis, i.e. 0.5\u20136 h following
administration), signi\ufb01cantly greater reduction in pain
intensity was observed when compared to placebo.
The individual analyses revealed that 1\u20136 h following
administration, a signi\ufb01cantly larger proportion of the
patients treated with the combination analgesic had
little or no pain relative to placebo. This also held true
in the analysis for all measuring points (0.5\u20136 h fol-
lowing administration). Two hours following adminis-
tration, the analysis revealed that 59.3% of the non-
placebo patients had mild or no headache, compared
with 32.8% in the placebo group. The combination
analgesic was also signi\ufb01cantly superior to placebo with
respect to the secondary end-points of e\ufb03cacy, whose
parameters were