Cephalalgia. 2011 (Apr); 31 (5): 550–561 ~ FULL TEXT
Dimos D Mitsikostas, Leonidas I Mantonakis and Nikolaos G Chalarakis
Athens Naval Hospital,
77A Vas. Sofias Avenue,
The aim was to determine the magnitude of the nocebo (adverse effects following placebo administration) in clinical trials for primary headache disorders. We reviewed randomized, placebo-controlled studies for migraine, tension-type headache (TTH), and cluster headache treatments published between 1998 and 2009. The frequency of nocebo was estimated by the percentage of placebo-treated patients reporting at least one adverse side effect. The dropout frequency was estimated by the percentage of placebo-treated patients who discontinued the treatment due to intolerance.
In studies of symptomatic treatment for migraine, the nocebo and dropout frequencies were 18.45% and 0.33%, but rose to 42.78% and 4.75% in preventative treatment studies. In trials for prevention of TTH, nocebo and dropout frequencies were 23.99% and 5.44%. For symptomatic treatment of cluster headache, the nocebo frequency was 18.67%. Nocebo is prevalent in clinical trials for primary headaches, particularly in preventive treatment studies. Dropouts due to nocebo effect may confound the interpretation of many clinical trials.
Keywords Migraine, tension-type headache, cluster headache, nocebo, placebo
From the FULL TEXT Article:
The term nocebo (‘I shall harm’) was introduced in
contraposition to the term placebo (‘I shall please’) by
Kennedy in the early 1960s in order to distinguish the
noxious from the pleasing effects of placebo. 
Nocebo is, therefore, the antipode of placebo, and
may result from the patient’s apprehension that medical
treatment will harm instead of heal.  Nocebo effects
encompass both non-specific side effects that cannot be
explained by the pharmacological action of a drug and
symptoms that resemble those expected of the active
drug. [2, 3]
More recently, these terms have been redefined to
denote only those symptoms powered by psychological
factors. If the positive psychological context that mediates
the placebo effect is controlled or reversed, then the
nocebo effect can be studied. Additional factors also
contribute to symptom changes in patients treated
with placebo such as the natural time course of the
condition under investigation, co-interventions or
bias. The nocebo effect results from the negative
psychological context surrounding the treatment, and
includes both pretrial suggestion and previous negative
experiences during treatment.
investigations have begun to explore how this negative
context influences both qualitative experience (the
drug response) and neurological information processing.  By recording fMRI signals during the evaluation of painful stimuli, Benedetti and his colleagues
have begun to investigate the patterns of activity characteristic
of nocebo-related hyperalgesia and placebo-related
analgesia. These studies implicate an interaction
between the stress response mediated by the hypothalamic–
pituitary–adrenal axis (HPA) and limbic regions
like the hippocampus, amygdale, nucleus accumbens, prefrontal cortex, and cingulate cortex involved in associative
learning. [4–10] Blockers of cholecystokinin
(CCK) attenuated hypo-algesia in this nocebo model. [5, 7] Significantly, nocebo and placebo effects were associated with opposing changes in the activity of several
neurotransmission systems, including dopamine,
opioids, and b-endorphins. 
Alternatively, little is known about how these
nocebo effects influence therapeutic responses in the
clinic. Reports from clinicians  indicate that the
nocebo effects are very prevalent, but the exact magnitude
remains elusive. It appears that nocebo side effects
vary by disease, and that conditions characterized by
chronic pain may potentiate the nocebo effect. [7, 10, 12, 13]
In an extensive review of the literature, psychological characteristics like anxiety, depression,
and tendency to somatize, together with prior adverse
reactions to medication, were recognized as key predictors
of nocebo.  Since nocebo may increase treatment
discontinuation, non-adherence, and treatment
failure, it is essential to estimate nocebo’s exact size
and strength in each disorder. Greater insight into
nocebo could lead to the development of treatment
strategies that ameliorate its effects in clinical practice
and improved clinical trial design. [14, 15]
In the field of headaches, Reuter and colleagues
found that up to one-third of migraineurs treated
with placebo experience adverse side effects. In trials
that tested the therapeutic efficacy of triptans for
migraine, 21±9% of control patients reported at
least one side effect from the placebo. Symptoms were
grouped into three categories:
migraine-related (symptoms like nausea, photophobia, and phonophobia),
drug-related (symptoms typical of the experimental compound like chest pressure in response to triptans), and
non-specific or coincidental (symptoms like sleep disturbance).
Thus, symptoms in the placebo group
were related to the drug under study and to the symptomatology
of migraine, whereas some others had no
obvious relation to the condition or treatment. 
In another review aimed at estimating the placebo
response in migraineurs treated with oral triptans, it
was found that 23.40±14.05% of participants treated
with placebo reported side effects. Interestingly, studies
performed in North America showed a higher nocebo
frequency than those conducted in Europe. 
Recently, the Benedetti group published an extensive
systematic review of nocebo in clinical trials for
migraine.  They investigated the adverse events
after placebo in migraine trials testing non-steroidal
anti-inflammatory drugs (NSAIDs), triptans, or anticonvulsants
and found that nocebo mirrored the
adverse effects expected of the active medication studied.
In other words, nocebo in migraine trials arose
from patients’ distrust. 
The aim of the present study was to determine the
magnitude of nocebo in trials for all primary headache
types, including all available drugs for both preventive
and symptomatic treatment, in order to alert practitioners
and trial designers to additional explanations
for treatment discontinuation and treatment failures.
We estimated both the nocebo frequency and its
strength (dropout frequency) in clinical trials for all
primary headache disorders published during the past
Subjects and methods
We performed a systematic literature review of randomized,
controlled, clinical trials for headache treatments
that documented noxious side effects and
dropouts in the control group. The MEDLINE database
was searched for English–language articles from
September of 1998 to 26 September 2009 using the
Medical Subject Headings (MeSH) shown in Figure 1.
We performed six consecutive searches for clinical studies
focused on either acute or prophylactic (preventative)
treatment of migraine, tension-type headache, and
cluster headache. The search followed the PRISMA
recommendations.  Two independent reviewers
(LIM and NGC) screened all references retrieved.
In the last phase of filtering, all articles meeting previous
criteria (placebo-controlled, randomized clinical
trials investigating headache drugs) were fully reviewed
and further processed for statistical analysis based on
two specific inclusion criteria: headache classification
according to IHS criteria (ICHD-I or ICHD-II), and
report of CONSORT flow diagrams. Reviewers also
included studies under the non-IHS classification in
the case of chronic daily headache and transformed
The former was classified as TTH and the
latter as migraine. When patients with both headache
subtypes participated in a study, the study was included
in the analysis for both migraine and TTH. Studies with
either cross-over or parallel design were included.
On the other hand, studies were excluded when:
(i) they did not report safety data in sufficient detail (no CONSORT flow diagram or no documentation of side effects);
(ii) the data were from previously published sources;
(iii) they were not written in English; and
(iv) the Jadad score for quality of the article was <3. The reviewers agreed on inclusion assignment for all articles.
The quality of reports was classified using the Jadad
scale because it is considered the most reliable. 
This scale includes only three dimensions – randomization,
blindness (of participants, care-givers, and investigators), and adequate documentation of withdrawals
and dropouts. 
Data were extracted from each study in a structured
coding scheme that included citation information and
country or countries where the study was performed,
headache subtype, sample size, median age and sex
ratio of participants, drug dosage, treatment duration
(in the case of preventive treatments), study design
(parallel or cross-over), number of patients treated
with placebo, number of patients treated with placebo
who experienced side effects, and placebo-treated
patients who withdrew due to side effects (information
gathered directly from CONSORT flow charts).
To estimate the frequency of nocebo in these trials,
we calculated the percentage of patients treated with
placebo who reported at least one side-effect. In this
evaluation, any side-effect reported by patients treated
with placebo was considered as nocebo. The frequency
of nocebo dropouts was estimated by the percentage of
patients treated with placebo who discontinued the
treatment because of intolerance. These estimates
were calculated separately for both symptomatic and
preventative studies, and for each drug studied, headache
type, root of drug administration, and year of
publication. Each reviewer made a separate Excel
data file and both files were compared and reviewed
by a third reviewer (DDM) to produce the final data
StatsDirect statistical software was employed to perform
the meta-analysis to calculate pooled estimates
across selected trials. Pooling was conducted using the
DerSimonian Laird method (random effects model).  The heterogeneity within trials was tested by
Cochran’s Q-test based on inverse variance weights.  The I2 statistic was also used to quantify the extent of inconsistency in outcomes across studies.
In the current analysis, only random effects models
which assume that the variability between effect sizes
is due to sampling error plus variability in the population
were considered. The effect of publication and
selection bias on the summary estimates was tested by
the Harbord–Egger bias indicator  and by the
Egger indicator.  Student’s unpaired t-test was
used for comparing the nocebo frequency between
North American and European studies, and for oral
versus parenteral administration. The strength of the
association between dropout rate in placebo groups
and active drug groups in topiramate studies was measured
by the Pearson product moment correlation coefficient
(weighted by the population size). Finally, to
compare placebo and active treatment dropouts,
mixed effects models using treatment as fixed and
study as the random factor were used.
Literature search and nocebos
The results of our MEDLINE search are summarized
in Figure 1 and the results of our analysis are summarized
in Table 1. After repetitive filtering, only 56 articles
studying acute symptomatic treatment for migraine
were analyzed. Statistical analysis revealed that the
nocebo effects and nocebo dropouts frequencies for
all trials were 18.45% (95% CI 14.90–22.23%) and
0.33% (95% CI 0.19–0.53%), respectively. In trials
studying triptans, nocebo effects and nocebo dropout
frequencies were 20.93% (95% CI 16.46–25.78%) and
0.36% (95% CI 0.18–0.61%). In trials with oral drugs,
nocebo and dropout frequencies were 19.82% (95% CI
15.84–24.12%) and 0.33% (95% CI 0.17–0.55%).
In the migraine prevention era, 45 trials were analyzed
(Figure 1). Nocebo effects and nocebo dropout frequencies
were 42.78% (95% CI 34.73–51.36%) and
4.75% (95% CI 3.28–6.45%). Nocebo frequencies
between trials for botulin toxin type A (BTX) and
topiramate did not differ significantly except that
nocebo dropouts in trials for BTX were significant
lower than the average for all other prophylactic antimigraine
treatments (0.22% vs 4.755%; Table 1).
four trials were retrieved that tested drugs for TTH
prevention; in these trials, nocebo effects and nocebo
dropout frequencies were 23.99% (95% CI 4.61–
52.20%) and 5.44% (95% CI 1.32–12.12%). We did
not find sufficient data to analyze trials for symptomatic
treatment of TTH. In the case of cluster headache,
only a few studies fulfilled the search and review criteria
(Figure 1). For symptomatic cluster headache treatment,
four trials were analyzed and the nocebo
frequency was estimated at 18.67% (95% CI
10.65–28.33%); insufficient data were gathered to
calculate the nocebo dropouts. All relevant proportion
meta-analysis plots (random effects) for prophylactic
treatments are presented in Figures 2–4, together with
bias assessment plots, Cochran Q values, inconsistencies
(I2), pooled proportions, Egger biases, and
Harbord biases. Plots for symptomatic treatments are
In migraine studies, nocebo effects and nocebo dropout
frequencies were higher in preventive trials than in
symptomatic trials (P<0.001). Additionally, nocebo
frequency varied by year of publication in trials for
symptomatic treatment of migraine, decreasing from
22.05% (95% CI 16.46–28.21%) for trials published
within 1998–2004 to 14.39% (95% CI 10.81–18.39%)
for trials published within 2005–2009 (P<0.001).
Nocebo did not change with route of drug administration
and no differences were found between studies performed
in North America compared to Europe.
In studies for migraine prevention with topiramate,
we compared dropouts in the placebo group versus
dropouts in the active treatment group; nocebo dropouts
were lower in the placebo group (mean difference
7.09%; 95% CI 4.1–10.1%; P<0.0001). In addition,
dropout rates were strongly associated in both treatment
groups (placebo and topiramate (r = 0.824;
Synopsis of results
Our meta-analysis revealed that approximately 20% of
migraineurs assigned to the placebo group in symptomatic
drug trials experienced adverse side effects
(nocebo), but that only a small fraction (less than
1%) discontinued treatment. Patients suffering from
cluster headache showed similar patterns. On the contrary,
in chronic treatment studies, the nocebo effect
was much more prevalent and powerful; almost half
of headache sufferers, whether from migraine or
TTH, reported nocebo side effects and about 5% withdrew
from the study. Nocebo rates did not vary with
the drug tested, with headache type, or by continent.
Only in the symptomatic migraine treatments did
nocebo change over time.
Meta-analyses of the nocebo effect
Our findings confirm and extend the finds of several
recent meta-analyses of nocebo. In the meta-analysis
of Amanzion et al. , nocebo dropout in triptans
studies was only 0.39%, which is comparable to the
0.36% derived by our analysis. Furthermore, the
nocebo dropout frequency for preventive anticonvulsants
(topimate, valproate, and gabapentine) was
7.71% compared to 6.75% in the topiramate studies
that we analyzed. In trials with oral triptans, nocebo
frequency was estimated at 23.40% (95% CI 9.35–
37.45%) by Lober and colleagues , similar to the
20.93% (95% CI 16.46–25.78%) reported by our analysis.
Interestingly, in Lober’s review for trials published
between January 1991 and March 2002, studies conducted
in Europe reported lower side-effect rates than
studies conducted in North America.  These findings
emphasize the need for more accurate evaluation
of number needed to treat (NNT) and number needed
to harm (NNH) for efficacy and safety comparisons
across different trials. Due to cultural differences,
study location may influence placebo effects, particularly
in anxiety-mediated disorders like blood hypertension
and ulcer disease.  Our meta-regression
analysis, however, did not confirm this finding.
Implications for clinical trial design
Clinical trial data and basic human research utilizing
nocebo models like hyperalgesia clearly indicate that
both baseline psychological profile (level of anxiety or
depression due to past treatment failures)  and pretrial
suggestion can increase negative side-effects. 
We found that nocebo effect with concomitant trial
dropout was common in preventative drug trials while
dropout was relatively rare in symptomatic trials. This
difference may relate to the psychological profile of
chronic headache sufferers as discussed below. The
length of treatment per se may also be significant, as
preventative studies obviously require longer treatment
periods. There is also considerable instability of nocebo
effect over time, but whether this reflects changes in
trial design or the participants’ behaviour over time
remains unclear. Stratified analysis demonstrated that
nocebo did not vary with trial phase (although the
majority of studies examined were phase-IV).
Participants may become more familiar with the drug
family (e.g. triptans) even in cases where they were
na?¨ve to the particular drug investigated. Old drugs in
new combinations may also explain this familiarity.
The new anti-migraine calcitonin gene-related peptide
receptor (CGRP) antagonists did not differ significantly
in nocebo, although the ratio was smaller arithmetically
(the nocebo frequency was 36.2% and 30.9% in two
studies included in analysis vs 42.78% for all prophylactic
treatments). Thus, these recent trials may contribute
to understanding the effects of trial duration in
It is believed that CGRP-antagonists exhibit an
improved safety profile compared to triptans. 
The efficacy of the active drug often correlates with
the placebo effect (positive outcome in the control
group) , suggesting that better safety of the active
drug may result in a lower nocebo effect. To investigate
this issue, we performed a post-hoc analysis in all studies
of the anticonvulsant topiramate. We found that
dropouts in the placebo arm were indeed associated
with dropouts in the active drug arm. This is in line
with recent findings from experimental human studies
indicating that nocebo may arise from verbal suggestions
of negative outcome. [4, 29] In clinical trials, investigators
deliver safety information to all participants in
the some way; thus, all subjects are equally aware of the
possible side-effects. Cued and contextual conditioning
may also increase nocebo frequency, although the
effects of these forms of pretrial conditioning appear
to augment the placebo effect (analgesia) more than
the nocebo effect (hyperalgesia). 
We also investigated the role of drug delivery.
In trials with BTX, some investigators reported that
symptoms could be a consequence of the injection itself
(e.g. swelling and redness at the site of the injection).
These side-effects have no known connection to administration
of placebo. For this reason, we compared
injection and oral placebo, and found that placebo
injections caused fewer side-effects and fewer dropouts
than oral placebo. However, this difference may be
related with the treatment frequency (once every three
months for the placebo injection compared to every day
administration for the oral placebo).
Since the nocebo effect may play an important role
in clinical trial outcomes, new recruiting policies are
essential to avoid biased selection, particularly in studies
of behaviour-modifying drugs or when comparing
behaviour and drug-based treatments.  Nocebo
should be taken into account in sample size calculations
and data safety reports , but more importantly,
investigators should scan trial participants for characteristics
predisposing to nocebo even before randomization
to prevent high dropout rates. Thus, while
patient numbers in the placebo group should be minimized,
this ethical concern must be balanced against the
scientific rationale underpinning study design.
Is the nocebo effect common in clinical practice?
Our data clearly demonstrate that the nocebo effect is
a confounding factor in clinical drug trials, but the
prevalence of an analogous nocebo effect may even
greater in the clinic. Indeed, patients participating in
clinical trials may not accurately reflect the patient
population treated in daily clinical practice. Patients
who are reluctant to receive novel medical treatments
due to anxiety or general mistrust might avoid participating
in clinical trials completely. For this reason, a
nocebo effect, whereby patients experience adverse
side effects seemingly unrelated to the pharmacological
activity of the medication, may be common. Indeed,
nocebo may be more frequent among headache sufferers
in the general population. Co-morbidity with
anxiety disorders, neuroticism, somatization, hypochondria,
and depression increases the negative expectation
for possible drug side-effects [6, 27, 33] and these
traits are characteristic of chronic headache sufferers. [34–36] This may also explain why the nocebo effect was more prevalent and stronger in studies of preventive
headache treatments than in trials of symptomatic
treatments; preventative or prophylactic trials focus
on chronic sufferers.
It was recently demonstrated that the adverse
events in placebo arm are qualitatively similar to the
adverse effects of the active medications.  For
example, nocebo in the control groups of anticonvulsant
trials was characterized by anorexia and memory
loss, a side-effect profile similar to the treatment
group. This is a key finding and contrasts with the
previously held belief that nocebo effects were simply
non-specific and unexpected side-effects following
Since nocebo is associated with the safety profile of
the active drug, one should expect more nocebo sideeffects
when administrating drugs with poor safety profiles.
Based on our clinical experience, nocebo patients
are those that have experienced failure with pharmacotherapy,
and so may have lower expectations that they
will respond to a new drug. Reading the drug brochures
or Internet information on drug safety without proper
re-assurance from their physician may increase nocebo.
It is important, therefore, for practitioners to search for
characteristics predisposing to nocebo and tailor strategies
for delivering safety information.  Discussing
the likely risk for nocebo and explaining the phenomenon
to the patient may help. In addition, face-to-face
follow-up could help to minimize patients’ fears and
maximize their understanding of the pharmacotherapy
Limitations of the meta-analysis
The heterogeneity observed in the frequency of adverse
side-effects and dropouts due to intolerance among the
selected trials limits the accuracy of pooled estimates
for nocebo. As in all meta-analyses, our study was
also prone to selection bias. Although meta-regression
and stratified analyses uncovered some potential
sources of bias, it should be stressed that the type of
data used for the nocebo analysis necessitated significant
culling of the literature. More standardized reporting
of clinical trials may reduce the number of trials
that must be excluded, and so reduce these sources of
bias. In addition, new methodologies to assess nocebo
within trials are warranted. To apply a proper comparator
for determining nocebo, side-effects could be compared
with those observed in a ‘no intervention’ group
(no drug or placebo). Additionally, some placebos like
saline injection are not truly inert and should be
To pool homogeneous data, this study was limited
to the past 10 years. Older preventive medications that
are still currently prescribed (like propranolol) were
under-represented while newer drugs with limited clinical
use may be over-represented. Finally, this study
provides evidence-based information regarding nocebo
in clinical trials, not in clinical practice. Documented
knowledge to prevent nocebo in trial designing
and clinical practicing is missing, although we
believe that the observed side effects in the placebo
arm of clinical trials underestimates the occurrence
of nocebo when active pharmacological treatments
Nocebo may be a serious confounding factor in clinical
trials for primary headaches, particularly in studies of
preventive treatments. Clinicians should be aware that
drug intolerance and treatment failure may be caused
by nocebo. Nocebo does not change with the type of
headache, but co-morbidity with affective disorders
typically increases nocebo. Nocebo includes both unexpected
(non-specific) side-effects and symptoms that are
specific to the tested drug. Thus, the proper delivery of
drug safety information is crucial and clinicians should
use tailored strategies to prevent nocebo. In the field of
clinical science, the potential risk for nocebo supports
the use of non-treatment arms in trials for headaches.
This study also underscores the need for precise and
homogeneous safety reports, allowing improved metaanalyses
that will further clarify factors contributing to
this phenomenon. Single trials that control contextual
variables and assess prior patient history are required in
order to identify the specific factors contributing to
nocebo. Nocebo limits the therapeutic effects of medical
treatment in headaches, while placebo increases
them. To improve headache therapeutics, nocebo warrants
greater attention, both in clinical practice and in
clinical trial design.
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