Blackwell Science, LtdOxford, UKCHACephalalgia0800-1952Blackwell Publishing, 200323Supplement 1Original ArticleClinical randomized trials of analgesics in migraineL Bendtsen et al.

Placebo response in clinical randomized trials of analgesics in

migraine
L Bendtsen, P Mattsson1, J-A Zwart2 & RB Lipton3
Copenhagen Headache Research Centre, Department of Neurology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark,
1
Department of Neuroscience, Neurology, University Hospital, Uppsala, Sweden, 2Department of Clinical Neuroscience, Section of Neurology,
Norwegian University of Science and Technology, Trondheim, Norway, and 3Departments of Neurology, Epidemiology, and Social Medicine, Albert
Einstein College of Medicine and the Montefiore Headache Unit, New York, NY, USA

Bendtsen L, Mattsson P, Zwart J-A & Lipton RB. Placebo response in clinical
randomized trials of analgesics in migraine. Cephalalgia 2003; 23:487–490. Lon-
don. ISSN 0800-1952
The objective was to assess the placebo response in randomized clinical trials of
analgesics in the treatment of migraine attacks. We included placebo-controlled
studies that used the criteria of the International Headache Society for the diag-
nosis of migraine and headache response as the primary efficacy parameter. In the
11 studies that qualified for inclusion, headache response occurred after placebo
treatment in 7–50% of the migraineurs with an average placebo response rate of
30% (95% confidence interval (CI) 23–36). Two hours after treatment with placebo
an average of 9% (95% CI 7–12, range 7–17%) of the patients were found to be
pain free. In conclusion, the average headache response rate to placebo was 30%
in randomized clinical trials of analgesics in migraine with a tremendous variation
among studies. Placebo response rates vary with the choice of primary efficacy
measure as well as patient characteristics and study design.
Migraine, analgesics,
placebo response, clinical trials
Lars Bendtsen MD, PhD, Heimdalsvej 8, DK-4200 Slagelse, Denmark. Tel.
+ 45 58525044, fax + 45 43233926, e-mail bendtsen@dadlnet.dk

group (number of patients/(response)*(1–

Introduction and methods
response)). If there were data from more than one
The aim of this review was to summarize the rates analgesic, different doses or more than one attack in
of placebo response in randomized clinical trials of a study, the arithmetic mean was calculated. Corre-
analgesics in the acute treatment of migraine. The lations were analysed by the test of Spearman. Dif-
search for trials was done in Medline (1988–2001, ferences in responses between groups were analysed
restricted to the English language), using Keywords by the unpaired t-test after weighting for differences
‘analgesics’ and ‘migraine’. To be eligible for inclu- in group size and by the test according to Mann–
sion studies used the criteria of the International Whitney. Since the P-values derived from these tests
Headache Society for the diagnosis of migraine, differed marginally, only the P-values from the latter
were placebo controlled and used headache test are presented.
response as an outcome measure. We evaluated the
two most widely used efficacy parameters: headache
Results and discussion
response, i.e. the proportion of attacks that go from
moderate or severe pain to pain that is mild or Dahlöf and Björkman (2) found that treatment with
absent within 2 h; and pain free, i.e. the proportion diclofenac 50 mg and 100 mg resulted in headache
of patients free of pain at 2 h after treatment (1). The response rates of 39% and 44% compared with 22%
results are summarized in Table 1. following treatment with placebo.
We calculated the arithmetic means of responses Boureu et al. (3) reported that acetaminophen
of all the studies. The arithmetic means were 400 mg in combination with codeine 25 mg, aspirin
weighted by the inverse of the variance of each study 1000 mg and placebo resulted in positive headache

© Blackwell Publishing Ltd. Cephalalgia, 2003, 23, 487–490 487

488 L Bendtsen et al.

Table 1 Headache response and pain-free rates following acute treatment of migraine with active drugs and placebo

Headache response Pain-free

Study (ref.) Active drug(s) n R active/placebo active/placebo

Dahlöf and Diclofenac 50/100 mg 64c 1.0 39%/44%/22% –/–

Björkman (2)
Boureu et al. (3) Acetaminophen 400 mg–Codeine 198c 1.0 44%/43%/18% 22%/26%/11%
25 mg/Aspirin 1000 mg
Chabriat et al. (4) Aspirin 900 mg–Metoclopramide 250P 1.0 56%/28% 18%/7%
10 mg
Tfelt-Hansen et al. (5) Aspirin 900 mg–Metoclopramide 385P 2.0 57–43%/24–25% 22–24%/8–11%
10 mg First–second attack
Lipton et al. (6) Acetaminophen 500 mg–Aspirin 1220P 1.0 59%/33% 21%/7%
500 mg–Caffeine 130 mg
Lipton et al. (7) Acetaminophen 1000 mg 289P 1.0 58%/39% 22%/11%
Myllylä et al. (8) Tolfenamic acid 200 mg 126P 2.0 77%/29% 31%/15%
Sandrini et al. (9) Ibuprofen 400 mg 29c 1.0 52%/7% –/–
Lange et al. (10) Aspirin, effervescent 1000 mg 343P 1.0 55%/29% 37%/17%
Kellstein et al. (11) Ibuprofen, liquigel 200/400/600 mg 729P 3.0 64%/72%/72%/50% 25%/28%/29%/13%
Diener et al. (12) Aspirin 1000 mg i.v. 278P 6.0 74%/24% 44%/14%

Headache response, The proportion of attacks that go from moderate or severe pain to pain that is mild or absent within 2 h;
pain-free, the proportion of patients free of pain at 2 h after treatment; n, number of patients treated; nc, cross-over study; np,
parallel study; R, randomization ratio: active to placebo; –, data not provided. Placebo results are shown in bold. Three studies
included a triptan (5, 8, 12).

responses in, respectively, 44%, 43% and 18% of the
patients. The corresponding pain-free rates were
22%, 26% and 11%. Another French study evaluated
the combination of lysine acetylsalicylate 1620 mg
(equivalent to 900 mg of aspirin) and metoclopra-
mide 10 mg (4). Positive headache response rates
were 56% for active and 28% for placebo treatments.
The corresponding pain-free rates were 18% and 7%.
In a European multicentre study, the combination
of lysine acetylsalicylate 1620 mg (equivalent to
900 mg of aspirin) and metoclopramide 10 mg
resulted in a positive headache response to the drug
in 57% and 43% in the first and second attacks,
respectively, compared with 22% and 24% to placebo
in the first and second attacks, respectively (5). Pain-
free rates for active drug were 22% and 24% in the
first and second attacks, respectively, and for placebo
8% and 11% in the first and second attacks, respec-
tively. This study included a comparison with
triptan.
Lipton et al. (6) compared the combination of ace-
taminophen 500 mg, aspirin 500 mg and caffeine
130 mg with placebo, pooling the results of three
separate clinical trials involving about 1200 patients
in total. Patients with severe pain or vomiting were
excluded. Fifty-nine percent of patients had a posi-
tive headache response following active treatment
compared with 33% after placebo, while the pain-
free rates were 21% and 7%. In a later study, Lipton
et al. (7) compared oral acetaminophen 1000 mg
with placebo. Patients with severe pain or vomiting
were again excluded. Fifty-eight percent of patients
had a positive headache response following active
treatment compared with 39% after placebo, while
the pain-free rates were 21% and 12%, respectively.
In a Finnish multicentre study, Myllylä and col-
leagues (8) found that 77% of migraineurs receiving
tolfenamic acid rapid release 200 mg and 29% of
patients receiving placebo had a positive headache
response at 2 h. The pain-free rates were 31% and
15%. This study included a comparison with a
triptan.
Sandrini et al. (9) compared a fast absorbed for-
mulation of ibuprofen 400 mg with placebo. The
headache response was 52% following treatment
with ibuprofen and 7% after placebo.
Lange et al. (10) evaluated effervescent aspirin
1000 mg in 343 German migraineurs and found a
headache response with aspirin and placebo of 55%
and 29%, respectively, while pain-free rates were
37% and 17%.
An American multicentre study (11) evaluated a
liquigel formulation of ibuprofen 200 mg, 400 mg
and 600 mg and found headache response rates of

© Blackwell Publishing Ltd. Cephalalgia, 2003, 23, 487–490


64%, 72% and 72% for active treatment and 50% for
placebo. The pain-free rates were 25%, 28% and 29%
for active treatment and 13% for placebo.
Diener and colleagues (12) compared lysine
acetylsalicylate 1800 mg (equivalent to 1000 mg of
aspirin) i.v. and placebo i.v. Treatment was given in
out-patient clinics. Headache response rates were
74% and 24%, respectively, while pain-free rates
were 44% and 14%. This study included a compari-
son with a triptan given subcutaneously.
Table 1 shows that a positive headache response
within 2 h after placebo treatment was found in 7–
50% of the patients, with an average response rate of
30% (95% confidence interval (CI) 23–36). A positive
headache response to simple or combination analge-
sics was found in 39–77% of the patients, with an
average response rate of 60% (95% CI 54–66). The
mean proportion of pain-free patients 2 h after treat-
ment with placebo and plain analgesics were 9%
(95% CI 7–12) and 24% (95% CI 19–28), respectively.
The placebo headache response and pain-free rates
observed in these trials of analgesics are of the same
magnitude as the placebo rates observed in triptan
trials (13). The results show that the analgesic and
placebo rates were lower for pain-free than headache
response, which is expected since the outcome of
pain free is hardest to attain. There was a marginally
significant correlation between headache response to
analgesics and placebo (Spearman, r = 0.43, P = 0.08)
and a highly statistically significant and positive cor-
relation between the proportion of patients pain free
after 2 h following treatment with analgesics and
placebo (Spearman, r = 0.91, P = 0.0006). These find-
ings indicate that within individual studies the mag-
nitude of the placebo response and the response to
active drug are explained by shared factors, perhaps
the characteristics of the study population or the
study design. The findings should be interpreted
cautiously, as three of the studies were cross-over
studies and, hence, the response to drug and placebo
were not collected in independent samples. It has to
be emphasized that the above-mentioned placebo
rates do not reflect only the placebo effect. The mag-
nitude of the placebo effect can be evaluated only by
including a natural history group because both
active and placebo treatments may be followed by a
spontaneous resolution of the attacks (14).
The study design considerably influenced the
magnitude of the headache response rate. Thus,
the placebo response was significantly lower for the
three cross-over studies (mean response rate 16%,
95% CI 6–26) than for the eight studies that used the
parallel group design (mean response rate 33%, 95%
CI 28–39) (Mann–Whitney U-test, p = 0.02). The
© Blackwell Publishing Ltd. Cephalalgia, 2003, 23, 487–490
Clinical randomized trials of analgesics in migraine 489
headache response rate to active treatment was also
significantly lower for the three cross-over studies
(mean response rate 44%, 95% CI 31–57) than for the
eight studies that used the parallel group design
(mean response rate 62%, 95% CI 57–67) (Mann–
Whitney U-test, P = 0.02). The analgesic effectiveness
is influenced by past experience with effective anal-
gesic agents (e.g. conditioning) and expectations of
the efficacy of the treatment (15). It is possible that
when the patient knows that he or she will receive
placebo at some time during the trial then expecta-
tions of the efficacy of the treatment will be lower.
The highest headache response rates to placebo
were seen in the three American studies (6, 7, 11),
which had a mean response rate of 36% (95% CI 28–
45) compared with a mean response rate of 24% (95%
CI 17–31) in the eight European studies (P = 0.03 in
both t-test and Mann–Whitney U-test despite over-
lapping 95% CI). This may be explained in part by
factors related to patient selection. All three Ameri-
can studies evaluated approved over-the-counter
medications and not prescription drugs, a factor
which may lead to enrolment of less severely
affected patients. In addition, two of the American
studies (6, 7) excluded the most disabled
migraineurs, increasing the possibility that less
severely affected more placebo-responsive patients
were enrolled. Moreover, the American studies used
population-based recruiting to a higher degree than
the European studies. In addition, all the American
studies used the parallel group design, which
favours higher response to active drug and placebo.
There was no significant correlation between the
randomization ratio (ratio of the number of patients
randomized to active or placebo treatment) and the
headache response to placebo (Spearman, r= 0.19,
P = 0.57). There was no statistically significant differ-
ence in the headache response between the three
studies that included triptans (5, 8, 12) and the other
studies (response rates of 25% (95% CI 5–47) vs. 30%
(95% CI 23–38)). The only study in which placebo
was given parenterally (12) had a placebo response
rate similar to the other studies.
There was much less variation in magnitude of the
placebo response between studies when pain free
was used as the end point (mean 9%, range 7–17%)
instead of headache response (mean 30%, range 7–
50%). In contrast with the finding for headache
response rates, there was no significant difference
between the American and the European studies in
the proportion of patients pain free 2 h after placebo
(8%, 95% CI 5–12 vs. 10%, 95% CI 5–15) (Mann–
Whitney U-test, P = 0.44). Two of the European stud-
ies did not measure the proportion of pain-free
490 L Bendtsen et al.
patients. These data indicate that pain free is a more
robust outcome measure and should be preferred as
primary end point in headache trials. In addition, the
variability in analgesic effectiveness may also be due
to differences in non-specific activation of endoge-
nous opioid systems (16), and factors such as expec-
tations of the outcome, suggestibility and
conditioning may contribute to the magnitude of
placebo analgesia (17).
In conclusion, a positive headache response was
seen in between 7% and 50% of the migraineurs
within 2 h after treatment with placebo, with an
average headache response rate of 30%. Two hours
after treatment with placebo an average of 9% (range
7–17%) of the patients were found to be pain free.
The headache response rates were lower in studies
that used the cross-over design than in parallel
group studies and higher in studies that excluded
patients difficult to treat. The variability between
studies was lower when pain free rather than head-
ache response was used as efficacy parameter. A
high response to placebo was correlated to a high
response to active drug.
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