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Placebos and nocebos in headache

Headache
Series Editor: Paolo Martelletti
Dimos D. Mitsikostas
Fabrizio Benedetti Editors
Placebos and
Nocebos in
Headaches
Headache
Series Editor
Paolo Martelletti
Roma, Italy
The purpose of this Series, endorsed by the European Headache Federation (EHF),
is to describe in detail all aspects of headache disorders that are of importance in
primary care and the hospital setting, including pathophysiology, diagnosis,
management, comorbidities, and issues in particular patient groups. A key feature of
the Series is its multidisciplinary approach, and it will have wide appeal to internists,
rheumatologists, neurologists, pain doctors, general practitioners, primary care
givers, and pediatricians. Readers will find that the Series assists not only in
understanding, recognizing, and treating the primary headache disorders, but also in
identifying the potentially dangerous underlying causes of secondary headache
disorders and avoiding mismanagement and overuse of medications for acute
headache, which are major risk factors for disease aggravation. Each volume is
designed to meet the needs of both more experienced professionals and medical
students, residents, and trainees.
More information about this series at http://www.springer.com/series/11801
Dimos D. Mitsikostas · Fabrizio Benedetti
Editors
Placebos and Nocebos
in Headaches
Editors
Dimos D. Mitsikostas
Neurology Department, Aeginition Hospital
National and Kapodistrian University
of Athens
Athens
Greece
Fabrizio Benedetti
Neuroscience Department
University of Turin Medical School
Torino
Italy
ISSN 2197-652X ISSN 2197-6538 (electronic)
Headache
ISBN 978-3-030-02975-3 ISBN 978-3-030-02976-0 (eBook)
https://doi.org/10.1007/978-3-030-02976-0
Library of Congress Control Number: 2019930284
© Springer Nature Switzerland AG 2019
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Foreword
This volume of the EHF Headache Series is dedicated to placebo and nocebo in
headaches, with Dimos-Dimitrios Mitsikostas and Fabrizio Benedetti as editors.
Their acknowledged expertise in this area of clinical medicine is a guarantee of
completeness and deepening of a topic that, in headaches, is rightly considered
fundamental.
The randomized control trials present today small margins of difference between
active substance and the response of healthy controls, and such a small difference,
although statistically significant, makes the fundamental role of placebo evident.
The thaumaturgical role of the doctor, the protected context of a health environment, and the patient’s expectations have produced brilliant results far beyond the
real effectiveness of the prescribed drug. On the other hand, the nocebo effect can
balance or limit drug outcomes and also decrease the patient’s therapeutic
adherence.
Nocebo and placebo effects exert their function by activating a complex interweaving of neural circuits in the central nervous system that modulate the perception of pain.
The headache expert needs a reading of this volume to be able to act wisely
through the right use of the placebo effect, saving and limiting pharmacological
prescriptions where possible, providing for and accompanying the nocebo effect
where expected.
Paolo
Rome,
Italy
Martelletti
v
Preface
Headaches, migraine, and cluster headache, in particular, are major health problems
almost completely underestimated and underappreciated by health-care providers,
decision-makers, people, and patients themselves eventually. Recent international
epidemiological studies using disability metrics appointed migraine as the second
leading cause of disability among all medical conditions after low back pain, but
first for people younger than 50. The economic burden of migraine exceeds €18 billion annually in Europe, yet there is no global strategic plan to border the consequences, nor the causes of the conditions. As many other chronic pain disorders,
headache affects life quality dramatically, requiring efficient therapeutic procedures. For decades, migraine and cluster headache have being sharing the privilege
to be treated with disease-specific acute medications targeting the serotonin 1B and
1D receptor subtypes, but only recently a mechanism-based preventative treatment
appeared in the horizon. The anti-CGRP class drugs, both as small molecules and as
large monoclonal antibodies, limit migraines and migraine progression into chronic
form, as phase 2 and 3 studies have shown. It is a wonderful moment for scientists,
for headache specialists, and for patients in particular to live this explosive year that
only rarely happens in neurology.
However, therapeutics does not end by the right diagnosis and the choice of
appropriate medicines. It goes further into the adherence to the treatment, into the
parallel management of potential comorbid conditions and finally into a better
understanding of the patients’ needs and expectations.
Within this context, placebos and nocebos play a fundamental role. Whereas
placebos potentially enhance medications’ efficacy, nocebos limit outcomes and
decrease adherence. Both are controlled by expectations and conditioning mainly.
Because individual perception of pain is also controlled by similar factors, placebos
and nocebos have important implications for chronic pain conditions. Headaches
and migraine above all carry an essential symbolism, since pain and mind are tightly
interconnected. This book is aimed at focusing on both placebos and nocebos and at
covering the entire spectrum of headaches, although most data are related to
migraine. Top specialists have been invited to present their work in this field, and we
are deeply thankful they accepted our invitation and devoted their precious time to
vii
viii
Preface
this project. We also thank Madona Samuel and Donatella Rizza from Springer for
their professional administrative skills.
We hope that the following data will contribute to a better understanding of the
mechanisms of placebo and nocebo effects in headaches and that all physicians,
medical students, neurologists, general practitioners, and headache specialists will
improve the clinical management of headaches in everyday clinical practice.
Likewise, we hope that patients will get some benefit from this project.
Athens, Greece
Torino, Italy Dimos D. Mitsikostas
Fabrizio Benedetti
Contents
1Patient-Centred Care in Headaches �� 1
Christian Lampl and Elisabeth Bräutigam
2Unmet Needs in Headache Management �� 13
Andrea Negro and Paolo Martelletti
3Mechanisms of Pain and Headache �� 27
Alexandre F. M. DaSilva and Marcos Fabio DosSantos
4Mechanisms of Placebo and Nocebo �� 43
Elisa Carlino, Lene Vase, and Alessandro Piedimonte
5The Special Case of High-Altitude Headache �� 57
Diletta Barbiani, Eleonora Camerone, and Fabrizio Benedetti
6Placebo Response in Human Models of Headache �� 65
Jakob Møller Hansen and Messoud Ashina
7Nocebo in Headache Treatment �� 75
Christina Deligianni and Dimos D. Mitsikostas
8Placebos and Nocebos in Migraine: Children and Adolescents �� 85
Vanda Faria and David Borsook
9Placebos and Nocebos in Other Brain Disorders �� 103
Panagiotis Zis
10Implications of Placebos and Nocebos in Clinical Research �� 113
Luana Colloca and Nathaniel Haycock
11Implications of Placebos and Nocebos in Clinical Practice �� 125
Dimos D. Mitsikostas
12Informed Consent and the Ethics of Placebo-Based Interventions
in Clinical Practice �� 135
Marco Annoni and Franklin G. Miller
ix
Chapter 1
Patient-Centred Care in Headaches
Christian Lampl and Elisabeth Bräutigam
1.1
Introduction
The World Health Organization (WHO) has acknowledged headache disorders as of
global public health importance [38, 39]. However, headache disorders are still
under-diagnosed and mostly undertreated [34, 35], not because diagnosis is particularly difficult or because effective treatments do not exist but because of widespread
failure of health services to recognize the need for individualized health care for
headache sufferers and to take steps to deliver it [35]. These disorders give rise
directly, but intermittently, to symptom burden: pain, often accompanied in the case
of migraine by nausea, vomiting, and photo- and/or phonophobia. All of these tend
to cause debility, prostration and reduced functional ability, a secondary disability
burden which is the principal cause of world of years of healthy life lost to disability
(YLD) and consequential lost productivity [37]. Those in whom they occur frequently are very likely to worry about when the next headache may happen, and in
some this can reach a level of anxiety. More commonly it may provoke avoidance
behaviour, particularly among those with migraine who identify triggers and
endeavour to eliminate them by lifestyle compromise. Sensible this may be, but too
much lifestyle compromise may take the pleasure out of life.
The recent Global Burden of Disease Survey 2015 (GBD 2015) [12] found
tension-type headache (TTH) and migraine to be the second and third most prevalent disorders in the world and migraine the seventh highest specific cause of disability [36]. Estimates of disability due to disease are a principal objective of the
Global Burden of Disease (GBD) studies, performed since 1990 and described now
as “the most comprehensive worldwide observational epidemiological study to
date”. Headache disorders account for more disability-adjusted life years (DALYs)
C. Lampl (*) · E. Bräutigam
Headache Medical Center, Ordensklinikum Linz, Barmherzige Schwestern, Linz, Austria
e-mail: [email protected]
© Springer Nature Switzerland AG 2019
D. D. Mitsikostas, F. Benedetti (eds.), Placebos and Nocebos in Headaches,
Headache, https://doi.org/10.1007/978-3-030-02976-0_1
1
2
C. Lampl and E. Bräutigam
than all other neurological disorders combined (including dementias), despite having no association with mortality [36].
While a wide range of effective pharmacological and non-pharmacological therapies are available for treatment and prevention of headaches, current treatment
especially of chronic headache is frequently suboptimal [15–17]. Many patients
with debilitating headaches fail to consult a doctor, and those who do may not have
their headaches properly identified or treated.
1.2
he Attempt of a Definition of Patient-Centred
T
Care (PCC)
PCC has no globally accepted definition. PCC considers the patient’s standpoint
and circumstances during the decision-making process and extends beyond simply
setting goals with the patient [27]. This care could also be referred to as a style of
doctor-patient encounter characterized by responsiveness to patient needs and preferences using the patient’s informed wishes to guide activity, interaction, and
information-giving and share decision-making [29]. PCC is an approach of viewing
health and illness that affects a person’s general well-being and an attempt to
empower the patient by expanding his or her role in the patient’s health care.
Enhancing the patient’s awareness and providing reassurance, support, comfort,
acceptance, legitimacy, and confidence are the basic functions of PCC. A relatively
unanimous definition on PCC is “health care that establishes a partnership among
practitioners, patients, and their families (when appropriate) to ensure that decisions
respect patients’ wants, needs, and preferences”. This definition emphasizes the
involvement of patients in the medical decision-making process. However, some
definitions seem ambiguous on patient’s preferences, that is, whether patient’s preferences are just one consideration or the ultimate decisive factor in care provision.
1.3
he Importance of Recognizing Patients’ Health
T
Problems as They See Them as Headache Patients
In the past, modern health care has been evolving from the traditional disease-centred
model of care to a more PCC model, which provides a better approach to individualized patient treatment and education. PCC requires adequate recognition of health
problems experienced by people suffering from headache. Care is better when it recognizes what headache patients’ problems are, rather than what the diagnosis is [33].
The challenge is to do better at recognizing and documenting their problems. Assessing
quality of problem recognition requires documenting the problems and how they
change in response to what clinicians do. Headache diagnoses are professional interpretations of observations, of patient descriptions, and—increasingly—of technical
investigations and laboratory values. A few primary care researchers in various
1
Patient-Centred Care in Headaches
3
countries have been trying at least since the late 1980s to understand the relationship
between presenting headache symptoms and eventual diagnoses. There is still poor
understanding of this relationship, and the more it is neglected, the less attention can
be focused on problem reduction over time as a legitimate goal of treatment.
Most studies of PCC are carried out in settings involving visits [20]. Prompted
by a perceived poor understanding of the term, it has to be asserted that PCC is
“determined by the quality of interactions between patients and clinicians” and indicated that they equate patient-centeredness with communication skills, which “are a
fundamental component of the approach to care that is characterized by continuous
healing relationships, shared understanding, emotional support, trust, patient
enablement and activation, and informed choices” [18]. So the concept of PCC may
be one fundamental way of improving the quality of care in headache patients.
1.4
General Aspects of PCC
There are many different aspects of PCC, including:
––
––
––
––
––
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Respecting people’s values and putting people at the centre of care
Taking into account people’s preferences and expressed needs
Coordinating and integrating care
Working together to make sure there is good communication, information, and
education
Making sure people are physically comfortable and safe
Emotional support
Involving family and friends
Making sure there is continuity between and within services
Making sure people have access to appropriate care when they need it
PCC is a way of thinking and doing things that sees the people using health and
social services as equal partners in planning, developing, and monitoring care to
make sure it meets their needs. This means putting people and their families at the
centre of decisions and seeing them as experts, working alongside professionals to
get the best outcome. PCC is not just about giving people whatever they want or providing information. It is about considering people’s desires, values, family situations,
social circumstances, and lifestyles; seeing the person as an individual, with a high
burden of the disease(s); and working together to develop appropriate solutions.
1.5
PCC in Headaches
There can be no doubt that migraine and medication overuse headache are a major
contributor to public ill health in all countries, climes, and cultures. There is evidence
that in a considerable proportion of people with migraine and in a small proportion of
4
C. Lampl and E. Bräutigam
people with TTH, ictal and interictal burden are real and measurable [36]. The significance of interictal burden is that, although it may be at relatively low level, it is present
for longer periods of time than ictal burden [17]. Whereas the ictal burden of episodic
headache is typically present during only 1 or 2 days in every month, interictal burden
can impose itself on all of the other days. This means two things. First, interictal burden ought not to be ignored: the burden of headache is very poorly described if it does
not take interictal burden into account. Second, if interictal burden is overestimated
and then multiplied by time, quantification of overall burden is likely to be greatly
distorted. This should also be taken into account when performing PCC.
PCC seems to be a promising avenue for headache management. In order to
improve understanding of how caregivers could use PCC more effectively in headache patients, headache researchers need rigorous methods to capture the different
components of this approach.
1.6
Nocebo in PCC
For drug-nonspecific effects causing unwanted side effects, the corresponding term of
nocebo has been established [1]. The nocebo effect has impact on therapeutic response,
adherence, and quality of life. The nocebo response is influenced by the content and
the way information is presented to patients in clinical practice. Specifically, research
on the nocebo effect indicates that information disclosure about potential side effects
can itself contribute to producing adverse effects [7]. On the other hand, informing a
patient that a prescribed drug may cause side effects may itself produce the same side
effects independent of the pharmacological properties of the drug. But it is not only
the drug; it is also the doctor: just as the interpersonal and environmental dimensions
of the clinician have a potentially powerful therapeutic benefit [5, 19], negative aspects
of the clinician can have negative, nocebo effects. In daily clinical practice, nocebo
effects can be a result of the interactions between clinicians and patients.
Clinicians have an obligation to bring adequate, truthful information to their patients
so that they can make individualized decisions about their medical care. One of the key
purposes of informed consent is to communicate to patients the benefits and risks of
recommended treatment interventions, so that they can decide for themselves whether
undergoing these treatments is a reasonable option for them [7]. This information can
be conveyed “negatively” (by focusing on the minority of patients who experience a
particular side effect) or “positively” (by focusing on the majority of patients who do
not experience the side effect). These different ways of framing side effect information
may have differential effects on patients with respect to forming nocebo responses [22].
1.7
Placebo in PCC
It is evident that placebo effects play a crucial role in the treatment process, and its
effects remain a key contributor to patient well-being and treatment outcome [6, 9,
11]. Placebo effects can be defined as the component of a medical treatment effect
1
Patient-Centred Care in Headaches
5
that is directly attributable to patients’ expectations of and prior learning experience
with a therapeutic intervention [10]. Experimental studies and randomized placebo-
controlled clinical trials (RCTs) are the two sources our knowledge of placebo
effects primarily comes from. Although the goals and approaches are distinct, a
shared characteristic is that treatment randomization and distribution occur without
any participant/patient involvement (so they have a passive role). However, as part
of a larger movement towards PCC, the absence of participant/patient involvement
in treatment decisions in placebo studies and RCTs stands in contrast to many practices and trends in modern health care. And this leads us to the right way: research
now indicates that the magnitude of placebo effects differs depending upon the
amount of participant involvement via decisional control. In PCC the relationship
between the physician and the patient should be seen (and make used) as a social
mechanism for beneficial impact on the patient. Therefore it is more than important
to realize why this social interplay is necessary to stimulate the endogenous mechanisms that handle expectation and placebo outcomes. According to Humphrey [14],
the ability to stimulate expectation in addition to placebo mechanisms following the
doctor-patient encounter is an emergent issue and essential feature of the “natural
health-care service”. The conceptualization of an endogenous health-care system is
extremely useful to know why the doctor-patient encounter is necessary in order to
trigger expectation in addition to placebo mechanism in the patient’s brain. From
the PCC perspective, it is obvious that the physician belongs to the system and has
a pivotal role in triggering all mechanisms that take place in the patient’s brain [21].
Therefore it is of great importance to involve the patient via choice making. Patient’s
participation in treatment decisions or planning may strengthen placebo effects and
should enhance treatment effectiveness. This provides a clear avenue for harnessing
placebo effects in clinical practice. As patients’ role in health care has increased,
understanding the connections between patient involvement and placebo effects
will be vital for PCC [13].
1.8
Successful Headache Management
It is essential for an appropriate headache management to start with a patient and
provider collaborative partnership, with a thoughtful understanding of the individual’s needs, preferences, and values. In addition, it takes open communication that
encourages information sharing, choices, and mutual respect that leads to patient
empowerment, self-responsibility, and at least self-management of their
headache(s). This patient-centred approach must to be integrated into an evidencebased system that delivers sound scientific basis for headache treatment. Combining
PCC and evidence-based practice provides the pinnacle of quality and value in
headache care [28].
First step of PCC in headache is patient elucidation and education; here within
individualized patient education is the method of first choice. This includes accurate
headache diagnosis—nearly half of migraineurs who seek medical care in a given
year are unaware of their migraine diagnosis [2]; thus, it is essential to provide and
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C. Lampl and E. Bräutigam
discuss headache diagnosis at each appointment—discussion about appropriate treatment options, and information about trigger (environmental, medication, emotional,
physical, or dietary influences that can potentially cause a migraine attack) and lifestyle factors (the broad subject of lifestyle management included diet, exercise, sleep
hygiene, and stress) which can directly affect migraine frequency. Knowing person’s
trigger and lifestyle factors is crucial to prevent migraine attacks. The main goals are
to increase patient’s knowledge and understanding about the disease and show skills
to independently manage their headache. To achieve these it is of importance to
establish headache diary information and initial assessment. For example, tracking
the migraine trigger factors through a diary is important in the evaluation of migraine
headaches in order to get a better understanding of the relationship of the triggers to
migraine occurrences. A first study comparing the assessment of lifestyle and trigger
factors in retrospective questionnaires to daily diaries showed diverging results [40].
Questionnaires and diaries correlated for lifestyle factors in 91% but for trigger factors in only 33%. The poor correlation between questionnaire and diary regarding
triggers remained unchanged with a more sophisticated approach, i.e. the calculation
of odd ratios for each factor. Accordingly, assessing lifestyle factors in migraine
patients by means of a questionnaire is highly reliable, but there is an inconsistency
between questionnaires and diaries regarding trigger factors.
The headache diary is also used to keep track of medication changes, keeping
count of abortive medications used (if needed), as well as the frequency and intensity of headache(s) which helps to provide accurate information to bring to clinic
appointments. However, the first European study to evaluate headache care quality
indicators across a culturally diverse multinational range of settings showed lack of
systematic use of diagnostic diaries and disability and quality-of-life assessment
instruments and restricted opportunities for follow-up visits [31]. The same may
apply to quality-of-life assessment, a problem in almost all centres, although this is
more relevant to outcome assessment during follow-up than to the formulation of
treatment plans at time of presentation. The mind-set of most of the centres appeared
to focus on treatment of patients’ symptoms.
Most patients suffering from headache who receive timely and good-quality
health care can expect this care to be effective, but good quality in health care has
not been the automatic result of the marked changes in scope, character, and content
of headache practice and care that have occurred during the last years. Quality of
care has not been much subject to social awareness or interest: a collaborative EHF/
LTB project of which the study [31] was part of it is a step towards bringing headache service quality centre-stage. This takes importance from the fact that there has
been no similar initiative preceding it—individualized PPC could be one.
Besides individualized PCC education sessions may also be a possible way of
headache patient education (particularly in case of lack of resources to provide
patient education). Rothrock et al. [30] employed a group intervention at a headache
specialty clinic using lay (non-professional) instructors as educators citing a very
large migraine patient population and patient education. They also provided information regarding when to treat migraine abortively with the emphasis on treating
early in the course of migraine as leaving migraine progress in severity without
1
Patient-Centred Care in Headaches
7
proper treatment will lead to poor outcomes. Cady et al. [4] research took place at a
headache specialty clinic using a 12-min video of migraine pathophysiology (with
and without a nurse present), identifying which phases of migraine are best to initiate migraine abortive treatment. The study showed that having the presence of a
nurse during the education video was more effective than no support.
Several of the studies placed a major focus on stress management by providing a
behavioural skills component to the patient education intervention (e.g. relaxation
techniques, behavioural therapies, coping techniques, biofeedback audio tapes).
With interest one study [5] took the stress management emphasis, offering a 4-h-long
session on Acceptance and Commitment Training (ACT) which is a behavioural
therapy that incorporates acceptance and mindfulness strategies for behavioural
changes used in depression and anxiety which is a known comorbidity with migraine.
Many of the studies incorporated headache medication and non-pharmacological
treatments into the intervention in various ways, but none of the information was
well defined [3, 4, 8, 19, 30, 32]. Interestingly only one study provided information
regarding medication overuse headaches (MOH) and how to prevent them by using
proper medication management [8]. But, this is again a very important issue to discuss with the patient. It is well known that chronic migraine represents migraine
natural evolution from its episodic form. It is realized through a chronification phase
that may require months or years and varies from patient to patient. The transition
to more frequent attacks pattern is influenced by lifestyle, life events, comorbid
conditions, and personal genetic terrain, and it often leads to acute drugs overuse.
MOH may complicate every type of headache, and all the drugs employed for headache treatment can cause MOH [23]. MOH is more a complication of chronic
migraine than a single entity. MOH can be minimized by patient education at the
very first on and by treating them with prophylactics in a proper way.
PCC is not only a pretreatment necessity; moreover it is an “in-between companionship and monitoring”. Since headaches, especially migraine, chronic migraine,
MOH, and trigeminal-autonomic cephalalgias (TACs), are influenced with a high personal and interpersonal disability, disability monitoring and outcome assessments are
essential to measure patient education outcomes. The Migraine Disability Assessment
(MIDAS) measurement questionnaire, which is well known for its reliability and
validity in evaluating migraine disability, evaluates migraine disability within a
3-month period of time. Others are the Headache Impact Test (HIT-6) or the Headache
Disability Inventory (without known reliability or validity). Measuring disability
using a valid and reliable migraine disability tool is needed to evaluate patient education outcome measures to determine whether the patient education activities are successful and migraine management is suitable for all individuals. For the MIDAS all
studies using this method showed statistically significant positive findings [19, 24, 30].
There are numerous headache treatment guidelines (nearly in each country in
Europe) providing comprehensive migraine management recommendations.
However, only a small number endorse initiation of patient education before or
shortly after the diagnosis is made. There is a strong recommendation for keeping
headache diaries to clarify frequency and severity, headache triggers, and treatment
responses. Other patient education recommendations should include understanding
8
C. Lampl and E. Bräutigam
headache(s), genetic predisposition, food and environmental triggers, and lifestyle
changes related to diet, sleep, stress reduction, and regular aerobic exercise. The
importance of limiting abortive migraine medication and to favour prophylactic
treatment must be stressed to avoid MOH.
There is limited research in the area of PCC in headache and the intention to
provide evidence of positive trials related to headache management that could be
used in clinical practice. This article was written from a clinician (and headache
sufferer) perspective and recommended a multidisciplinary approach to patients
suffering from headache(s), obtaining input from the patient, the family, and the
provider. All primary headaches are incurable diseases with complex management
issues necessitating a patient-centred plan of care that can be used as a comprehensive reference tool to assist in controlling headache(s) and improving quality of life.
It is also important to stress the importance of addressing headache comorbidities
like depression and anxiety, if needed, by prescribing antidepressant medication and
relaxation techniques such as biofeedback.
Reviewing the current literature on headache and the knowledge gap pertaining
to those who may not be receiving the knowledge and skills necessary to self-
manage their headache, particularly individuals with low reading levels, language
barriers, or cultural differences could heighten health-care disparities and patient
dissatisfaction. The Matchar et al. study [19] had the strongest research evidence for
a PCC model, which included patient stakeholder involvement with a patient education program offering individualized and (if not otherwise possible) group patient
education programs with personalized plans of care.
These should include the following:
1. Patient education should take place at regularly scheduled office visits by the
headache patient’s neurology provider.
2. Individualized headache plan of care that would outline the patient’s treatment
should be provided for the patient to take home.
3. Patient education materials that would be easy to understand for all individuals
should be provided.
4. Patient education information that includes recognizing different headache
symptoms, how to prevent headache by avoiding triggers, use of a headache
diary, how to manage headache at home, and understanding medication and non-
medication treatments should be provided.
5. The principles of health equity should be embedded in all headache patient education methods to ensure proper education to all diverse populations.
1.9
Conclusion
Reviews of research about this topic found that offering PCC in headache sufferers
usually improves outcomes [25]. Good-quality headache care achieves accurate
diagnosis and individualized management, has appropriate referral pathways,
1
Patient-Centred Care in Headaches
9
educates patients about their headache(s) and their management, is convenient and
comfortable, satisfies patients, is efficient and equitable, assesses outcomes, and is
safe [26].
Research has found that PCC in headache patients can have a big impact on the
quality of care. It can improve the experience people have of care and help them feel
more satisfied. It can encourage people with headache to lead a more healthy lifestyle, such as exercising or eating healthily; it should encourage people to be more
involved in decisions about their care, so they get services and support that are
appropriate for their needs. This may in turn reduce the overall cost of care. But
there is not as much evidence about this improves how confident and satisfied professionals themselves feel about the care provided.
While the evidence is mounting that PCC can make a difference, there are not
that many studies about outcomes yet and some research has mixed. This makes it
even more important to think about how to measure and put PCC into headache
practice, so that health services can better understand the benefits of this.
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placebo effects. Lancet. 2010;375(9715):686–95.
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15. Hu HX, Solomon GD, Conboy K, Deml L, Markson LE. Impact of a migraine disease management program. Dis Manag Health Out. 2004;12:273–80.
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migraine in Europe—evidence from the Eurolight study. J Headache Pain. 2018;19(1):10.
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Rastenyte D, Ruiz de la Torre E, Andrée C, Steiner TJ. Interictal burden attributable to episodic
headache: findings from the Eurolight project. J Headache Pain. 2016;17:9.
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A. The headache management trial: a randomized study of coordinated care. Headache.
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22. Miller FG, Colloca L. The placebo phenomenon and medical ethics: rethinking the relationship
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service quality: evaluation of quality indicators in 14 specialist-care centres. J Headache Pain.
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the first 7 years. J Headache Pain. 2010;15:451–5.
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36. Steiner TJ, Stovner LJ, Vos T. GBD 2015: migraine is the third cause of disability in under 50
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Chapter 2
Unmet Needs in Headache Management
Andrea Negro and Paolo Martelletti
2.1
Acute Treatment in Migraine
Acute treatments are aimed to abolish ongoing attacks, reduce migraine-related
symptoms, and improve functional disability. Those treatments include migrainespecific medications (i.e., triptans, ergotamine, and dihydroergotamine) and nonspecific agents (i.e., nonsteroidal anti-inflammatory drugs [NSAIDs], simple and
combination analgesics, opioids, barbiturates, antihistamines, antinauseants, and
muscle relaxants).
The choice of an acute therapy has important limitations in patients at risk or
after transient coronary heart disease, ischemic attack (TIA), ischemic stroke, or
cerebral bleeds. Triptans and ergots are contraindicated to treat migraine attacks in
patients with a history of stroke, coronary heart disease, or not-controlled hypertension, while aspirin and NSAIDs should not be used in patients with a history of
cerebral hemorrhage.
2.2
Preventive Treatment in Migraine
A preventive therapy is required when the frequency of the attacks is ≥4 per month.
Prophylactic migraine treatments are given on a daily basis to prevent the occurrence of migraine attacks, to reduce headache frequency and severity, and to
decrease associated disability and the need for acute medications which may be
contributing to concurrent medication overuse headache (MOH).
A. Negro (*) · P. Martelletti
Department of Clinical and Molecular Medicine, Regional Referral Headache Centre,
Sapienza University of Rome, Sant’Andrea Hospital, Rome, Italy
e-mail: [email protected]
© Springer Nature Switzerland AG 2019
D. D. Mitsikostas, F. Benedetti (eds.), Placebos and Nocebos in Headaches,
Headache, https://doi.org/10.1007/978-3-030-02976-0_2
13
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A. Negro and P. Martelletti
Several pharmacological classes can be used for migraine prevention: antihypertensive agents (e.g., β-blockers, calcium channel blockers, angiotensin-converting
enzyme [ACE] inhibitors, aldosterone receptor blockers), antiepileptic drugs (e.g.,
topiramate, divalproex sodium), tricyclic antidepressants (e.g., amitriptyline, nortriptyline), selective serotonin reuptake inhibitors (SSRIs), and norepinephrine
reuptake inhibitors (SNRIs) [65]. OnabotulinumtoxinA (Botox®) is indicated for the
prevention of chronic migraine (CM) and is the only FDA-approved treatment for
this indication. As for acute treatment, the choice of the best preventive therapy
requires clinical considerations.
Migraine is frequently associated with several comorbidities that it is important to consider in treatment decision-making. A therapy, particularly those used
for prevention, could be contraindicated in presence of a comorbid disease where
another therapy could be effective to treat both migraine and the other condition.
Moreover, patients with migraine, in particular migraine with aura, have a higher
risk of ischemic [69] and hemorrhagic stroke [6] as well as cerebral hemorrhage
[45]. Migraineurs needing prevention and having cardiovascular comorbidities
should be treated with beta-blockers, candesartan, or lisinopril, while NSAIDs
and SSRIs are contraindicated as prevention in patients with a history of cerebral
bleeds.
2.3
Physician-Patient Communication: Treatment
Decision-Making
The quality of physician-patient interaction can improve patient outcomes. Several
studies proved that attempts to positively influence patients about the effects of
therapy had a significant impact on health outcomes [26, 32, 36, 76, 77].
There are three models for medical treatment decision-making. The “paternalistic model,” in which decisions are taken by the physician without considering
patient’s preferences, has been replaced by more patient-centered approaches [15].
In the “informed model,” the patient makes a treatment decision after being informed
about treatment options, risks, and benefits. In the “shared model,” after discussing
treatment, both physician and patient actively participate in making a shared medical decision.
In case of triptan prescription, nearly the totality of patients (92%) prefers the
decision to be joint with the provider [56]. Physician-patient communication
and patients’ involvement and agreement on care and treatment plan are associated with improved patient adherence and compliance with prescribed medication, improved satisfaction, resolution of emotional and physical symptoms, and
fewer repeated consultations, referrals, and investigations [35, 44, 57, 74].
However, in actual practice, involvement in decision-making is poor, with
patients reporting that for triptan prescription, the physician was the sole decision-maker 55.1% of the time [56].
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Unmet Needs in Headache Management
2.4
15
Patients’ Expectations: What Migraineurs Want
Patients’ satisfaction is determined by both therapeutic reality and expectations.
The most frequent expectations about the attributes of migraine medications
reported by patients include effective and long-lasting pain relief, low rate of
migraine recurrence, few side effects, easy route of administration, low number of
doses needed to achieve pain relief, effective relief of associated symptoms, and fast
return to normal activities [24].
Understanding patients’ preferences regarding education and their role in decision-making when treatments are prescribed can enhance satisfaction and adherence with treatment plans. The majority of patients want to participate in
decision-making when a triptan is prescribed and prefer to receive education
about the triptan from the prescribing provider [56]. The most desired topics for
education included if/when a triptan should be taken and how many times for each
migraine, how many doses can be taken each week/month, what to do in case of
inefficacy, co-administration with other acute medications, and possible side
effects [56].
Patients’ expectations are not limited to the prescribed treatment but also to the
quality of the headache services. Quality indicators for headache centers include the
availability of referral pathway from primary to specialist care and urgent referral
pathway when necessary, a service environment that is clean and comfortable, short
waiting times in the clinic, and sufficient time allocated to each visit [68].
2.5
Barriers in Episodic Migraine Management
An adequate migraine management requires three crucial steps: (1) medical consultation, (2) correct diagnosis, and (3) acute pharmacologic therapy. Failure at any
level makes good clinical outcomes unlikely.
The American Migraine Prevalence and Prevention (AMPP) study sample was
used to identify barriers to care in any of the three steps in a population of individuals with episodic migraine (EM) with unmet treatment needs, defined by a Migraine
Disability Assessment Scale (MIDAS) score of mild-to-severe grade [52]. Only one
quarter of individuals successfully completed all three steps. The strongest predictors of medical consultation were having health insurance (OR 1.73), elevated headache-related disability (OR 1.06 for a 10-point change in MIDAS score), and high
composite migraine symptom severity score (OR 1.19). Among consulters, 86.7%
reported receiving a medical diagnosis of migraine, which was more likely in
women than in men (OR 4.25) suggesting that gender bias in diagnosis may be an
important barrier for men. Diagnosis was more likely in those with higher annual
household incomes (OR 1.94) and became increasingly likely with increasing average headache pain severity (OR 1.44). Among the diagnosed patients, 66.7% used
acute migraine treatments. The strongest predictors of treatments were annual
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A. Negro and P. Martelletti
household income (OR 1.44) followed by a high headache-related disability (OR
1.16 for a 10-point change in MIDAS score).
2.6
Barriers in Chronic Migraine Management
Regarding CM patients with unmet needs, the issue of the barriers to medical care
was investigated by the Chronic Migraine Epidemiology and Outcomes (CaMEO)
study [27]. When comparing the results with those in EM patients from the AMPP
study, what emerges for CM patients is an even larger unmet need for improving
care. Less than 5% of persons with CM traversed three barriers to receiving care for
headache (vs. 26% in EM). Consultation rates were lower for people with CM than
EM (41% vs. 46%), and among consulters the diagnostic rates were also lower for
those with CM than EM (25% vs. 87%). Finally, among those who were diagnosed,
treatment rates were also lower for those with CM than EM (44% vs. 67%). The
strongest predictors of medical consultation among CM patients were age, having
health insurance, and greater levels of headache-related disability and symptom
severity. An appropriate diagnosis was more likely in those consulting a specialist,
in women, and with greater migraine severity.
2.7
reatment Optimization and Progression from EM
T
to CM
The migraine Treatment Optimization Questionnaire in 6 items (mTOQ-6) is a
helpful tool to assess response to acute treatment in persons with migraine exploring
six domains: (1) Quick Return to Function, (2) 2-h Pain-Free, (3) Sustained 24-h
Pain Relief, (4) Tolerability, (5) Comfortable to Make Plans, and (6) Perceived
Control. The mTOQ-6 was used to measure acute treatment optimization among
EM and CM patients that responded to the 2006 AMPP study survey [72]. Both the
EM and CM groups exhibited low rates of treatment optimization, though treatment
optimization was worse for CM across all domains. Poor treatment optimization
was associated with allodynia, depression, use of NSAIDs or ergotamines, and the
absence of a preventive therapy.
Patients with EM and poor acute treatment optimization of 1 year have an
increased risk of progression to CM the following year [54]. In the AMPP study, the
rate of evolution into CM was 1.9% for subjects with maximally optimized treatment, 2.7% for those moderately optimized, 4.4% for those poorly optimized, and
6.8% for those very poorly optimized. Other risk factors for chronicization include
the number of migraine attacks, sleep disorders (such as snoring and sleep apnea),
obesity, stress, depression, and caffeine use/misuse (dietary and drug-containing
caffeine) [64].
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Unmet Needs in Headache Management
17
CM is often complicated by MOH. Two principal factors lead to overuse: (1) the
recommendation of an early treatment, increasing the risk to take more of the drug
than is necessary; and (2) the acute treatment is partially or not effective. All the
acute treatments, when overused, can cause MOH, which in turn decrease responsiveness to acute or prophylactic drugs [66]. Due to an insufficient response to classic therapies, a significant percentage of patients shift in refractoriness, developing
what is defined as refractory CM [62].
2.8
Acute Migraine Treatment: Triptans
Triptans are considered the standard of acute therapy for migraine attacks.
Nevertheless, the minority of potentially eligible persons use them. The AMPP study
showed that in 2005 less than one in five persons with migraine in the United States
used triptans over the course of a year [17]. Groups less likely to use triptans included
males, African Americans, older adults, and the uninsured. Increased triptan use was
associated with several markers of severe headache, including high headache frequency, disability, and allodynia. New triptan use occurred in only 4.9% of the sample surveyed. Starting triptan was lower in patients aged 60 years or older vs. those
18–29 years of age. In adjusted model analysis, age, disability, preventive medication use, income, and insurance were associated with new triptan use [7].
AMPP survey showed that 92% of EM subjects used acute medications, and
among them the 52% used multiple classes [51]. Triptans were used by 18.3% of
respondents, but only 21.7% of them used triptans as monotherapy, while 38.7%
used one additional class of medication, and 39.6% used two or more additional
classes [10]. The 57% of triptan users continued their regimen over the course of
1 year, while 14.4% added additional types of medication, and 28.6% discontinued
at least one type of medication. Higher education was protective against medication
escalation, while depression was found to be a predictor of increasing medication
use. Together with older age and allodynia, depression was also a predictor of
decreasing medication use.
2.9
Triptan Discontinuation
Data from the 2008 and 2009 AMPP surveys were used to assess reasons for discontinuation of two commonly used classes of medication, triptans and opioids,
between EM patients [40]. Opioid use was associated with an increased risk of
medication discontinuation compared to triptans (59.0% vs. 34.6%). Opioid discontinuers were 52% more likely to discontinue because of pain recurrence than those
discontinuing triptans, 53% more likely to discontinue because of concern about
interactions with other medications, and 58% more likely due to concern about
effects to the stomach.
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A. Negro and P. Martelletti
Factors associated with triptan discontinuation among migraine patients were
further investigated by a multicenter cross-sectional survey performed at US tertiary
care headache clinics that enrolled EM and CM patients who were current or past
triptan users [79]. Discontinuation was most correlated with lack of efficacy (OR
17), greater migraine-related disability (OR 2.6), depression (OR 2.5), and the use of
opioids for migraine attacks (OR 2.2). Compared with patients who had discontinued triptans, current users were more likely having a triptan prescribed by a specialist and using other abortive medication with the triptan. Moreover, triptan users felt
they had more control over their migraine attack and confidence in their prescribing
provider and were educated about their triptan. A recent systematic review showed
that 25–60% of patients never refill their index triptan and an annual rate of discontinuation among a general population of triptan users between 30 and 60% [58].
2.10
2.10.1
How to Improve the Efficacy of Triptans
Response Predictors
Several studies have examined predictors and rates of successful treatment outcomes for single attacks in clinical trials. Data from 2006 AMPP survey was used to
identify predictors of acute treatment success or failure at 2 h and 24 h post dose
over multiple migraine attacks [55]. Fifty-six percent of respondents reported inadequate 2-h pain-free (2hPF) response, 53.7% reported inadequate pain relief at 24 h
(24hPR), and 25.7% reported inadequate 24-h sustained pain freedom (24hSPR) or
recurrence. Predictors for each of the three outcomes included higher migraine frequency and symptoms severity, allodynia, and depression. Other predictors of inadequate 2hPF response included male sex, higher body mass index (BMI), and not
using preventive migraine medications, while medication overuse was a predictor of
both inadequate 24hPR and 24hSPR. These data are supported by the results of
randomized controlled trials (RCTs) that showed 2hPF ranging from 12% (frovatriptan 2.5 mg) to 40% (rizatriptan 10 mg) and 24hSPR ranging from 16% (naratriptan 2.5 mg) to 26% (almotriptan 12.5 mg) [75].
2.10.2
Choice of the First-Line Therapy
Time to treatment and type of first-line therapy play an important role in improving
migraine outcomes [46]. On average, migraines treated with a prescription or an
over-the-counting (OTC) medication within 1 h of onset are of 3.2 h shorter in duration compared with those treated more than an hour after onset [46]. Migraines
treated with triptan as first-line therapy showed better outcomes over those treated
with an OTC medication first, as evidenced by a significantly lower proportion
requiring a rescue medication, a shorter migraine duration, and a higher proportion
of alleviated symptoms within 4 h [46].
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Unmet Needs in Headache Management
2.10.3
19
Time to Treatment
Evidence from clinical studies suggest that early treatment and treating while
migraine pain is still mild result in improved clinical outcomes [12, 13, 31, 41, 67],
but real-world studies have shown that migraineurs tend to delay treatment until pain
is severe [29, 31, 41]. Personal beliefs have a strong influence on how migraineurs
manage their migraines. The main reasons for waiting before using a triptan are
concerns to run out of triptans, concerns about taking medications, concerns about
side effects, and fear of developing tolerance to triptans [47]. An observational study
conducted in the United States showed that 58.8% of migraineurs delayed triptan
treatment, and for the 55% of them, the reason was to be certain that the headache
was a migraine [47]. The same study found that the decision to use a triptan immediately was influenced by some migraine-related factors as moderate or severe pain,
throbbing or stabbing type of pain, and certain symptoms such as nausea, vomiting,
and light and sound sensitivity [47]. However, only the 61% of patients took triptan
first, while the 49% took an OTC or non-triptan as first medication [47].
2.10.4
Switching Acute Treatment
Several studies reported that 5–9% of patients initiating a new triptan switch to a
different triptan before refilling their original medication [58]. The principal reasons
that push patients to switch from a triptan to another triptan include efficacy, consistency, migraine recurrence, curiosity, and formulation [73].
The effect of changes in treatment from one triptan to another or from a triptan
to another medication class was investigated using AMPP study data to assess
change in headache-related disability [71]. Switching between triptans or from a
triptan to another class of medication was not associated with improvements in
headache-related disability, but switching from a triptan to an NSAID was associated with significant increases in headache-related disability among patients with
high-frequency episodic migraine/chronic migraine (HFEM/CM).
2.10.5
dding Additional Acute Treatments to Current
A
Triptan Therapy
An alternative strategy to increase triptan efficacy could be adding additional acute
treatments to current triptan therapy. This option was investigated using data from
the AMPP study and assessing change in MIDAS score from the first to the second
year of a couplet [11]. Subjects were divided based on headache days per month:
low-frequency episodic migraine (LFEM, 0–4), moderate-frequency episodic
migraine (MFEM, 5–9), and HFEM/CM (≥10 headache days per month). Adding
acute therapies to a current triptan regimen was generally not associated with
20
A. Negro and P. Martelletti
reductions in headache-related disability and in some cases was associated with
worse outcomes. Adding opioids and barbiturates was not beneficial overall. Adding
a second triptan was not beneficial in general, and for patients with HFEM, it was
associated with worsening of headache-related disability. Also adding NSAIDs was
associated with greater headache-related disability among HFEM/CM patients but
was beneficial for the MFEM group. The last finding is supported by prior observations showing that NSAIDs may protect against the progression from EM to CM for
MFEM cases [53]. The finding that for HFEM/CM subjects adding a triptan or
NSAIDs is associated with an increase in headache-related disability fits with prior
reports that frequent triptan and NSAID use in HFEM is associated with the progression to CM [4].
2.11
Unmet Needs in EM Patients
The AMPP study also provided important insights about the relative frequency
among persons with EM of five types of unmet treatment needs: (1) dissatisfaction
with current acute treatment, (2) moderate or severe headache-related disability
(based on MIDAS score), (3) excessive use of or dependence from opioids or barbiturates, (4) recurrent use of the emergency department for headache, and (5) history
of cardiovascular events indicating a contraindication to triptan use [4]. Of 5591
subjects with EM, 40.7% had one or more unmet needs. The three most common
unmet needs were moderate or severe headache-related disability (47.0%), dissatisfaction with current acute treatment (37.4%), and excessive opioid and/or barbiturate use or probable dependence (32.0%). The odds of having unmet treatment
needs were higher in those with more headache days, anxiety, or depression.
2.12
Unmet Needs in CM Patients
Chronic migraine interferes with daily activities and causes reduction in their quality of life more than EM does and represents the most important challenge for tertiary-level headache centers [64]. Preventive treatment is the key for a correct CM
management. Any of the oral preventive therapies indicated for EM may be prescribed to CM patients, but only the use of onabotulinumtoxinA and topiramate is
supported by RCTs [48]. For other medications (e.g., beta-blockers, calcium channel blockers, SSRIs, SNRIs, sodium valproate, gabapentin, amitriptyline, tizanidine,
zonisamide) proofs of efficacy come from single randomized controlled trials or
open-label studies and are often used on an empirical basis for CM prevention [16].
Migraine, particularly when chronic, is often associated with comorbidities as
cardiovascular and psychiatric disorders, fibromyalgia, myofascial pain syndromes,
and various forms of visceral pain [64]. The presence of comorbidities should drive
the choice of a preventive treatment in order to increase the efficacy for both the
2
Unmet Needs in Headache Management
21
disorders and at the same time reduce the medication intake. In addition, safety
might be difficult to manage due to drug-drug interactions [49]. However, a significant proportion of CM patients needing prevention do not receive it [50], and even
when it is prescribed, there is a high rate of nonadherence (approximately 35–50%)
[39]. Low adherence to preventive drugs is mainly due to relatively low and inconstant efficacy and to bothersome side effects [5, 8, 38].
2.13
Placebo and Nocebo Effects in Headache Management
Placebo is defined as a physiologically inactive substance that elicits a therapeutic
response by inducing changes in symptoms or conditions [28]. The counterpart of
placebo is nocebo. The term refers to unpleasant or undesirable effects (e.g., adverse
events) that occur after the administration of placebo [28].
The therapeutic effect of any intervention, both pharmacological or not, is the
result of the efficacy of the intervention and the placebo effect. Similarly, the tolerability of medications depends on adverse events and nocebo. Nocebo adversely
influences quality of life and is a significant cofactor for treatment adherence and
failure [37].
While nocebo effect is a nuisance in both clinical research and clinical practice,
placebo effect has different meanings for doctors and scientists. In clinical research
the placebo effect is the enemy that needs to be neutralized in order to properly
demonstrate the benefits of active medications [61]. At the opposite, in clinical practice the placebo effect is the useful friend that provides additional efficacy or further
increasing tolerability [9, 14]. Accordingly, doctors should try to maximize the placebo effect while minimizing the nocebo effect.
The placebo responsiveness seems related to some psychological traits (e.g.,
somatic focus, hypnotic suggestibility, dispositional optimism, empathy) [25, 33,
34, 42, 43, 63] and personality traits (e.g., novelty seeking, behavioral drive, harm
avoidance, reward responsiveness) [70]. Previous experience influences future outcomes, and previous response to pain therapy influences future analgesia. For example, patients with chronic neuropathic pain have a different magnitude of placebo
analgesia depending on prior exposure to either successful or unsuccessful treatment [1]. Placebo analgesia can occur also without direct first-hand experience, for
example, in patients who have observed a benefit in another person [19].
Interpersonal interactions can play a fundamental role in placebo effects.
Empathy, the ability to empathize another’s feelings, may facilitate these effects
[19], and interacting with the physician can trigger the mechanisms underlying placebo analgesia with relevant clinical results [3, 22, 59]. Nice doctor’s manners, a
clear and empathic language, a clean and comfortable environment, and an easy
access to doctors and care are just some of the factors that contribute to a placebo
effect and that physicians should always take in great consideration.
In general, if placebo effects act as reinforcers of clinical outcomes, nocebo
effects may be responsible for drug intolerance and treatment failure [20]. Nocebo
22
A. Negro and P. Martelletti
effects encompass both symptoms that resemble those expected of the active drug
and nonspecific adverse events that cannot be explained by the pharmacologic
action of a drug [2]. This reaction originates from patient’s negative expectation that
a medical treatment will most likely produce harmful consequences instead of helping [60]. Some subjects could be more suitable to develop nocebo in presence of
comorbidity with anxiety and depressive disorders. Among other cofactors, patient’s
prior conditioning and suggestions, anxiety modulation, and previous repetitive
treatment failures or discontinuation due to adverse events generate negative beliefs
for the treatment outcome and safety, inducing nocebo.
As placebo is induced by pretrial positive suggestions [21, 30, 78], there is evidence that nocebo is verbally induced by investigators with pretrial negative suggestions [23]. Similarly, in clinical practice detailed and extensive information on
potential side effects by physicians can also trigger nocebo adverse events [18].
The proper delivery of drug safety information to patients is a crucial step that
can avoid nocebo generated by reading the drug brochures and nowadays the
Internet information on drug safety. Definitively, the content and the way information are presented to patients are fundamental to minimize in clinical trials both
placebo and nocebo effects and in clinical practice to increase placebo while neutralizing nocebo effects.
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Chapter 3
Mechanisms of Pain and Headache
Alexandre F. M. DaSilva and Marcos Fabio DosSantos
3.1
Introduction
Pain is a highly disabling and prevalent symptom present in many clinical conditions [37]. It can be classified into acute and chronic, an extremely simplistic terminology, but with distinctive importance for the patient’s daily life and therapeutic
decisions in the clinical practice [9, 35, 36, 87]. Although still a puzzle, understanding of the pain phenomenon and mechanisms has considerably evolved throughout
the last decades, leading to a broader concept of pain “an unpleasant sensory and
emotional experience associated with actual or potential tissue damage, or described
in terms of such damage” [66]. In fact, such designation has its bases intrinsically
linked to the seminal work published by Melzack and Casey [65]. Since then, it has
been largely accepted that pain cannot be restricted to nociception, simply confined
to the interpretation of nature, intensity, duration, and location of noxious stimuli.
Instead, pain goes beyond the discriminative evaluation of noxious stimuli and comprises emotional (motivational) and cognitive (evaluative) neural components.
Therefore, the contribution of not only sensory but also limbic and higher-order
A. F. M. DaSilva (*)
Headache and Orofacial Pain Effort (H.O.P.E.), Department of Biologic and Materials
Sciences, School of Dentistry, The Molecular and Behavioral Neuroscience Institute (MBNI),
University of Michigan, Ann Arbor, MI, USA
Center for Human Growth and Development, University of Michigan, Ann Arbor, MI, USA
e-mail: [email protected]
M. F. DosSantos
Headache and Orofacial Pain Effort (H.O.P.E.), Department of Biologic and Materials
Sciences, School of Dentistry, The Molecular and Behavioral Neuroscience Institute (MBNI),
University of Michigan, Ann Arbor, MI, USA
Laboratório de Morfogênese Celular (LMC), Instituto de Ciências Biomédicas (ICB),
Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
e-mail: [email protected]
© Springer Nature Switzerland AG 2019
D. D. Mitsikostas, F. Benedetti (eds.), Placebos and Nocebos in Headaches,
Headache, https://doi.org/10.1007/978-3-030-02976-0_3
27
28
A. F. M. DaSilva and M. F. DosSantos
brain structures as well as facilitatory and inhibitory pain pathways to this phenomenon has been explored and largely accepted [65]. Another important concept that
must be considered is that rather than differentiating acute and chronic pain only
based on chronological marks (e.g., 3 or 6 months), the differential participation of
etiological factors and the more important differences in their pathophysiologies
must be fully understood. In fact, the mechanisms related to chronic pain have been
partially unveiled in the recent years, and the uncreditable development of novel
neuroimaging techniques has allowed the translational of the results obtained in
experimental animal models of acute and chronic pain to translational clinical pain
research in humans. In this respect, several mechanisms ranging from peripheral
and central sensitization to maladaptive neuroplasticity (structural, functional, and
molecular) have been investigated [6]. Nevertheless, it is important to establish that
chronic pain is not considered a clinical diagnosis. Instead, it embraces several conditions that can be classified as neuropathic (trigeminal and postherpetic neuralgias,
burning mouth syndrome, or diabetic neuropathy) or nociceptive (e.g., osteoarthritis, non-neuropathic low back pain), each group with its characteristic symptom
profile [34, 47], which strongly suggest the presence of specific physiological
mechanism mediating each chronic pain condition [77]. Therefore, the term
“chronic pain syndromes” seems to be more appropriate to designate such conditions. Hence, the understanding of common as well as individual mechanisms might
contribute to the development of less empirical and more precise therapies for each
chronic pain syndrome, with significant lower side effects [45].
3.2
unctional and Molecular Neuroplasticity
F
in Chronic Pain
Advances in neuroimaging methods have allowed the identification of the main
brain structures related to pain processing and modulation. Those areas include the
primary (S1) and secondary somatosensory cortex (S2), rostral and dorsal anterior
cingulate cortex (rACC and dACC), posterior cingulate cortex (PCC), insula, medial
prefrontal cortex (mPFC), dorsolateral prefrontal cortex (DLPFC), thalamus, hypothalamus, amygdala, brainstem structures, and the main components of the reward
circuitry such as nucleus accumbens (NAc) and ventral tegmental area (VTA),
among others [60]. Several functional studies have demonstrated the presence of
structural and functional neuroplastic changes in chronic pain syndromes. One of
the classic studies in the field found decreased gray matter density in the bilateral
DLPFC and right thalamus in chronic back pain, with distinct characteristics in
neuropathic and non-neuropathic patients [3]. In addition, the amygdala volume as
well as the density of the white matter connections within the corticolimbic system
have been considered risk factors to the development of chronic pain [86].
Colocalization between structural changes and oscillations in the functional brain
activity related to pain have also been explored through functional magnetic
3
Mechanisms of Pain and Headache
29
resonance imaging (fMRI). One of the first studies revealed that functional activations induced by cutaneous allodynia in the maxillary territory of the trigeminal
nerve (V2) are colocalized with cortical thickening/thinning in sensorimotor areas
or cortical thinning in brain areas related to the emotional processing of pain in trigeminal neuropathic pain patients [23].
Using an original protocol, Baliki and collaborators used fMRI to demonstrate
that the activity of the NAc during the offset of painful thermal stimulus as well
as its connectivity with the PFC and insula permits to differentiate chronic back at
a very high accuracy chronic pain patients and healthy subjects [4]. Such pattern
of NAc activation has been considered a possible biomarker of chronic pain [94].
A further studied demonstrated that higher connectivity between the NAc and
PFC could also predict persistent pain. Based on such findings, it has been theorized that corticostriatal projections are very likely major elements in pain chronification [5].
It is important to consider that the input of the nociceptive information to the
central nervous system (CNS) is under direct control of complex endogenous modulatory systems. Those systems act through several different neurotransmitters,
including glutamate, gamma-aminobutyric acid (GABA), endogenous opioids,
dopamine, and serotonin, among others, and regulate the flow of information to
cortical regions of the CNS, acting mainly at the level of the dorsal horn of the spinal cord [64]. They also act through a descending pain inhibitory system, composed
by several brainstem structures mainly the locus coeruleus, periaqueductal grey
matter (PAG), raphe nuclei and rostroventromedial medulla (RVM). The involvement of the thalamus, hypothalamus, and cortical areas, including the insula, amygdala, and cingulate cortex, has also been shown [46]. However, PAG, RMV, and
spinal dorsal horn have been described as the principal structures in the descending
pain modulation [58]. PAG and RVM act mainly through serotonin (5-HT) receptors [2]. More recently the contribution of endocannabinoid receptors CB1 to this
inhibitory process has been suggested [32]. Moreover, those structures seem to be
important to the analgesia related to several classes of drugs including antidepressants, nonsteroidal anti-inflammatory, and opioids [70]. Nonetheless, scarce information is available regarding the specific anatomical structures and pathways
involved in the endogenous pain modulation. In this scenario, novel studies have
explored the in vivo activation of chief modulatory systems (e.g., opioidergic and
dopaminergic) through positron-emission tomography (PET) related to both acute
experimental condition [95] and chronic pain syndromes [24, 26, 33, 57, 68].
The first studies investigating the presence of changes in the opioid neurotransmission related to chronic pain measured the nondisplacable binding potential
(BPND) of the nonselective opioid receptor radiotracer [11C] diprenorphine and
found a decrease in [11C] diprenorphine BPND in such patients [48, 89]. Further
studies started to evaluate the same parameter of the selective mu-opioid receptor
(MOR) radioligand, [11C] carfentanil. One of those studies explored functional
changes in the mu-opioid system in patients with a fibromyalgia syndrome, a highly
prevalent chronic pain condition with still unknown pathophysiology wherein opioid analgesic has low effectiveness. In fact, the results of that study were considered
30
A. F. M. DaSilva and M. F. DosSantos
an initial evidence that a dysfunction of the mu-opioid system may play a role in
fibromyalgia. More specifically, that study indicated that fibromyalgia patients have
lower availability of MORs in several brain areas related to pain, including dorsal
dACC, NAc, and amygdala. Moreover, a negative correlation between the MOR
BPND within the NAc and the clinical pain scores was demonstrated, which corroborates the hypothesis of the involvement of a dysfunctional opioid and particularly
mu-opioid neurotransmission in that syndrome [43].
Another clinical neuroimaging study conducted in fibromyalgia patients found a
positive correlation between the pain-evoked brain activity, measured through fMRI
and MOR availability in the rACC and in the DLPFC as well as a negative correlation between both BOLD (blood oxygen level dependent) signals related to pain and
MOR BPND and the affective/sensory pain ratio in the medial frontal gyrus (MFG)
and in the CC [73]. A mechanism involving lower affinity or downregulation of
MORs on GABAergic interneurons located in the PFC and anterior cingulate cortex
caused by tonic higher levels of endogenous opioids has been suggested based on
such results [73]. Therefore, the inhibition of GABAergic interneurons produced by
phasic release of endogenous opioids associated with noxious stimulation would be
impaired in fibromyalgia syndrome, leading to a faulty descending pain modulation
that would explain the persistent pain present in those patients.
PET studies have also demonstrated altered dopaminergic functioning driven by
chronic pain, and results suggest that specific mechanisms can occur in each group
of chronic pain disorder. For example, while a decreased availability of dopamine
D2/D3 receptors in the ventral striatum has been found in fibromyalgia patients [90]
and chronic back pain [57], an increased availability of dopamine receptors has
been demonstrated in chronic orofacial neuropathic disorders such as burning
mouth syndrome (BMS) and atypical facial pain (AFP) [41, 42]. The reduced availability of dopamine D2/D3 receptors found chronic back pain patients was negatively correlated to the pain intensity [57]. Furthermore, a coupling between MOR
and D2/D3R in the amygdala was related to experimental pain. To which extension
this coupling could between the activity of the dopaminergic and opioidergic systems contribute to the mechanisms of chronic pain, analgesia, and opioid dependence remains to be investigated [57].
3.3
unctional and Structural Neuroplasticity in Headaches
F
and Migraine
While pain has been attributed as a major factor that conduces patients to seek medical advice [37], headache has been referred as the most prevalent symptom in
patients that seek medical care. In addition, primary headache disorders are the
most frequent brain disorders [83]. Among them, tension-type headache (TTH) and
migraine are the predominant subtypes of primary headaches [82]. Migraine lifetime prevalence has been estimated in 14% [84], while its 1-year prevalence is
around 35%, which is very close to the 38% estimated for TTH [82]. Trigeminal
3
Mechanisms of Pain and Headache
31
autonomic cephalalgias (TACs), including cluster headache, paroxysmal hemicranias, hemicrania continua, short-lasting unilateral neuralgiform headache attacks
with conjunctival injection and tearing (SUNCT), and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA), constitute
an additional class of primary headaches. Those headaches are characterized by the
occurrence of autonomic signal symptoms that take place ipsilateral to the pain.
They all share some pathophysiological features. Nonetheless, they differ in many
clinical aspects such as duration and frequency of the headache episodes and
response to therapy [17].
As previously mentioned, migraine is a very prevalent neurological disorder. It is
also markedly more common in women than in men [51]. Migraine is characterized
by episodes of unilateral pulsating headache, associated with nausea and/or phonophobia and photophobia. Sensitivity to touch and odor may also occur. Two migraine
subtypes have been described, migraine without aura (MwoA) and migraine with
aura (MwA). MwA is defined by the presence of related visual or sensory symptoms concurrent to or anticipating a migraine episode [28, 44]. Some individuals
evolve from episodic to chronic migraine, which is characterized by a headache that
happening on 15 or more days per month for a period greater than 3 months, and
that features the common aspects of a migraine headache on at least 8 days per
month [44]. Nonetheless, more important than the number of episodes is the occurrence of specific symptoms related to chronic migraine, including hyperalgesia and
allodynia, both highly prevalent in migraineurs [8, 11, 12, 52, 54] and directly
linked to neuroplastic phenomena, including central and peripheral sensitization
[10, 31]. In fact, it has also been reported that around two-thirds of migraineurs
experience allodynia during a migraine attack [12]. Its incidence seems to be more
frequent in chronic migraine patients. In addition, it has been shown that the duration of the disease might affect not only the occurrence but also the severity of those
symptoms [7]. Remarkably, a decreased connectivity between the PAG, ACC, and
PFC has also been found in migraine patients with allodynia when compared to
migraine patients without allodynia [55].
Several studies have shown the presence of changes in the structure and function
of patients with migraine headache [20, 25, 38, 39, 49, 55]. Those studies were
important to demonstrate that rather than affecting specific brain areas and neural
circuits, migraine is associated with changes in a broad set of brain structures and
connected networks, which helps to explain the variety of clinical symptoms that
constitute this disorder [16, 17]. One pioneer research in this area investigated the
mechanisms of MwA using fMRI [39]. The study showed a focal increase in the
BOLD signal within the extrastriate cortex (V3A), progressing slowly and contiguously over the occipital cortex following a retinotopic visual organization, during a
migraine headache attack with visual aura. Interestingly, this initial increase was
followed a reduction of the BOLD signal following the same retinotopic progression. Those events suggest the occurrence of vasodilatation (seen through an
increase in the BOLD signal) followed by a vasoconstriction (as observed by a
decreased in the BOLD signal) and the presence of cortical spreading depression in
the human visual cortex of migraineurs [39]. A following study also found structural
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A. F. M. DaSilva and M. F. DosSantos
changes, represented by increased cortical thickness in the V3A area and also MT+,
both involved in motion processing, in patients with MwA and MwoA [38].
Increased thickness was further demonstrated in the somatosensory cortex of
migraineurs, with most prominent changes discovered in the cortical area that contains a somatotopic representation of the head and face [21]. However, contradictory findings such as the lack of changes in the cortical thickness [27] and even
cortical thinning have also been reported in migraine patients [15], when compared
to healthy subjects. The results of one of those studies indicated that migraine
patients present age-related thinning of some cortical regions that do not thin in
healthy controls and that only exhibit more pronounce thinning with advancing age.
Such findings led the authors to suggest that migraine interacts with aging to produce structural cortical changes.
More recently, a growing number of studies have also explored the occurrence of
changes in the functional connectivity (fc) of the brain at rest (evaluated through
rs-fMRI) in headaches. However, such findings should be considered cautiously due
to the presence of methodological limitations [74]. Studies that investigated changes
related to the ictal phase of migraine headaches revealed decreased fc between the
executive and dorsoventral networks in migraine patients without aura, compared to
healthy controls [18], and increased fc between the insula (bilateral) and the mPFC
and between the mPFC and the PCC [19]. Moreover, the pain intensity during
migraine attacks negatively correlated to the strength of the mPFC-insula connectivity [19]. Another study performed in patients with migraine with aura found an
increased fc between the dorsolateral pons and the ipsilateral somatosensory cortex
(head and face somatotopic areas). Such results reinforce the concept of a migraine
“generator,” located in dorsolateral pons, a designation that comes from a classic
PET study that proposed a mechanism for migraine based on an imbalance in the
activity between the vascular control and the brainstem antinociceptive regulation
[88]. As a matter of fact, the brainstem seems to play a crucial role in the migraine
and headaches pathophysiology, especially the dorsal ponto-mesencephalic junction, the dorsal pons, and the trigeminal nuclei [13, 55, 67, 80, 81, 88]. For instance,
it has been demonstrated that the specificity of triptan to treat headaches and
migraine and not pain in general might be explained by a functional inhibition of
trigeminal-cortical projections [50]. Furthermore, a stronger connectivity between
the PAG and areas related to the somatosensory processing and nociception has
been reported in migraine patients when compared to healthy subjects [55]. These
results are in accordance with the findings of previous studies that had reported
lower functional anisotropy in the ventrolateral PAG in MwoA patients during interictal periods [22].
Nevertheless, although there is enough scientific evidence regarding the important role of the brainstem activity to migraine headache, the presence of a “migraine
generator” has been recently revisited. The results of one study that analyzed the
data of a migraine patient that underwent MRI exams every day for 30 days revealed
an increase in the hypothalamus activity 24 h prior to the pain onset (e.g., increased
hypothalamic activity toward a next migraine attack). In addition, the same study
showed changes in the coupling between the hypothalamus and the two areas of the
3
Mechanisms of Pain and Headache
33
brainstem: the spinal trigeminal nuclei and the “migraine generator” region [75].
Therefore, instead of a “migraine generator,” the connectivity between the hypothalamus and the brainstem seems to be determinant to the development of migraine
attacks. Furthermore, the role of spontaneous oscillations of complex networks
related to the brainstem, hypothalamus, and dopaminergic networks altering the
activity of brainstem and subcortical areas in the development of migraine headache
has also been discussed [61]. Interestingly, an anteroposterior segmentation of the
hypothalamic roles to different stages of migraine has been suggested. In this regard,
it has been postulated that the posterior hypothalamus would have a more relevant
participation in acute phases, while the anterior hypothalamus would be more
important to the chronification process [76].
Posterior hypothalamus activation seems also to be a key element not only for
migraine but also for TAC pathophysiology as demonstrated by several studies
involving hemicrania continua [59], SUNCT [63, 79], and cluster headache [62,
78]. In addition, altered hypothalamic fc has been demonstrated in cluster headache
patients [71, 92]. This abnormal hypothalamic activity and connectivity could
explain some unique aspects seen in this group of headaches, including the circadian and circannual rhythmus and restless sensation [17]. However, how exactly
these findings could explain the main signs and symptoms reported by TAC patients
must be examined in-depth.
When comparing the fc of MwA, MwoA, and healthy subjects, it is possible to
find shared and specific mechanisms. For instance, a previous study found that
migraine patients (with or without aura) had increased fc between the right temporal
region and the middle frontal gyrus. Nonetheless, MwA but not MwoA presented
reduced fc between the occipital cortex (V3A area) and the anterior insula, which
was in turn correlated to the headache severity in MwA but not in MwoA patients
[69]. Thus a contribution of the reduced fc observed in the occipital cortex of MwA
patients to the development of visual aura has been suggested [69]. Nonetheless, an
altered fc in extrastriate areas of the occipital cortex has also been raised as a potential biomarker of MwA, since, when evaluated in the interictal phase, MwA patients
exhibited increased fc in lingual gyrus of the extrastriate cortex, which is involved
in the initiation and propagation of the migraine aura, when compared to MwoA and
healthy subjects. Moreover, such abnormal resting-state connectivity was neither
correlated to the severity of migraine nor accompanied by structural changes which
indicates the specificity of the results of the study [85].
Differences between MwoA and MwA have been also investigated through
1
H-magnetic resonance spectroscopy (MRS), which permits a noninvasive estimative of central metabolite levels. One study that investigated oscillation in metabolite levels within the visual cortex related to photic stimulation assessed interictally
reported a more pronounced reduction in the signal of NAA (N-acetylaspartate) in
MwA patients when compared to MwoA and healthy individuals, which could be
interpreted as an impaired mitochondrial functioning in MwA, since no differences
were observed between MwoA and healthy individuals [72].
Some studies have also raised a possible mechanism involving different patterns
of amygdala fc as a mechanism to the development of episodic and chronic migraine.
34
A. F. M. DaSilva and M. F. DosSantos
In one of those studies, an increased fc occurred between the amygdala and the
secondary somatosensory cortex (S2) and anterior insula and thalamus in migraine
patients but not in other painful disorders that area not putatively related to cortical
spreading depression (CSD) such as trigeminal neuralgia and carpal tunnel syndrome. Such results have been interpreted as a dysfunction of a neurolimbic pain
network driven by repeated episodes of CSD which in turn would contribute to the
pathophysiology of migraine headaches [40]. A further study demonstrated differences in the amygdala fc (e.g., increased left amygdala in episodic migraine patients
and decreased right amygdala fc in chronic migraine patients) when compared to
healthy controls, supporting the involvement of the neurolimbic pain network to
migraine mechanisms and possibly to migraine chronification [14].
Finally, the participation of resting-state connectivity abnormalities to migraine
has also been evidenced by reduced regional homogeneity (ReHo) detected in the
PFC, orbitofrontal cortex (OFC), rACC, and supplementary motor area (SMA)
found in MwoA patients compared to healthy subjects and by the higher connectivity between the default mode network (DMN) and central executive network
(CEN) and the insula, which were correlated to the migraine duration in MwoA
patients compared to controls [91]. Increased ReHo in the PCC/precuneus, pons,
and trigeminal nerve entry zone and decreased fc between these areas with altered
ReHo and other brain regions have also been found in patients with MwoA compared to healthy subjects. Based on the crucial role of the precuneus/PCC to the
default mode network, which is important for several physiological functions
including self-monitoring and interoception, it has been suggested that MwoA
patients may have dysfunction involving information transfer and multimodal
integration [93].
3.4
olecular and Neuroplasticity and Metabolic Changes
M
in Headaches and Migraine
Changes in specific neurochemistry and endogenous modulatory systems in headaches have been recently explored through positron-emission tomography (PET).
Early scientific evidence of altered function of modulatory systems in headaches
comes from studies investigating changes in the availability of serotonin receptors,
5-HT(1A) receptors associated with episodes of migraine headaches. When compared to healthy controls and headache-free migraineurs, migraine patients that
developed a headache attack during the PET scan showed an increased BPND of the
a selective 5-HT(1A) antagonist [(18)F]MPP in the pontine raphe [29]. This study
brought insights the participation of the pontine raphe region and 5-HT(1A) receptors in the migraine pathophysiology. Increased MPP BPND has also been shown in
limbic regions as well as in the posterior parieto-occipital and temporal cortical
regions during interictal periods of MwoA patients, which could possibly reflect
decreased serotonin levels or increased expression of 5-HT(1A) in the brain of those
patients [53].
3
Mechanisms of Pain and Headache
35
In line with such studies, our group has recently demonstrated the occurrence
of functional changes of mu-opioid neurotransmission associated with ictal trigeminal allodynia, in migraineurs [68], corroborating the concept that maladaptive neuroplastic changes contribute to the mechanisms of migraine headache.
The first prelaminar PET study used an interactive 3D immersive approach to
investigate the mu-opioid neurotransmission in vivo during a migraine attack. The
results showed lower MORs BPND in the CC, PAG, NAc, and thalamus during the
ictal phase of a migraine patient (Fig. 3.1). Such findings could represent higher
occupancy of MORs by endogenous opioids released in response to the ongoing
headache [24].
Recent studies have also demonstrated changes in the mu-opioid neurotransmission associated with migraine headache attacks (ictal phase) in the medial prefrontal
cortex (mPFC), a brain region previously associated with migraine [1, 30]. Moreover,
another study found a positive correlation between migraine-related MOR activation in key brainstem structures for pain (e.g., red nucleus and PAG) and the concomitant occurrence of thermal allodynia in such patients [68].
Decrease in µ-Opioid Receptor Availability During a Migraine attack
ACC
Nac
Ictal
Interictal
Thal
Severe
Moderate
Mild
0
1
2
3
4
Fig. 3.1 Reduced MOR availability during a migraine headache attack in vivo. Lower panel represents a reduced nondisplacable binding potential (BPND) of the selective mu-opioid receptor
radiotracer [11C] carfentanil during the ictal phase of a migraine headache, possibly reflecting a
higher release of endogenous opioid in response to the ongoing pain, when compared to the interictal phase (upper panel). Thal (thalamus), Nac (nucleus accumbens), ACC (anterior cingulate
cortex). J Vis Exp. 2014 Jun 2;(88)
36
A. F. M. DaSilva and M. F. DosSantos
Interictal phase
(No headache)
Presynaptic
Migraine attack
(Headache at rest)
Postsynaptic
Dopamine (D2/D3 (endogenous)
(11C)raclopride
D2/D3 receptor
Cutaneous allodynia
(Headache + STPT challenge)
Decreased edogenous
dopamine release relative
to interictal phase
Sudden increase in endogenous
dopamine release
relative to
ongoing headache at rest
(11C)raclopride BP
Fig. 3.2 Imbalanced release of endogenous dopamine related to migraine headache and allodynia
in vivo. Left panel shows steady levels of endogenous dopamine during the interictal phase of
migraine. Center panel represents reduced striatal dopamine release during spontaneous migraine
attacks compared to the interictal phase. Right panel shows an increased release of dopamine during cutaneous allodynia when compared to ongoing headache at rest. STPT sustained thermal pain
threshold challenge; BP binding potential. Neurology. 2017 Apr 25;88(17):1634–41
Changes in the normal functioning of the dopaminergic system have only been
recently shown in the brain of migraineurs in vivo [26], wherein a significant
increased availability of dopamine D2/D3 receptors was found in the dorsal striatum (caudate and putamen nucleus) during the ictal migraine phase compared to the
interictal period. Interestingly, a decrease in the dopamine D2/D3 receptors availability was driven by thermal allodynia, indicting a possible contribution of a
dynamic fluctuation in dopamine levels to the migraine pathophysiology [26]
(Fig. 3.2). Although both structural and functional changes had been previously
observed in the striatum of migraineurs [56], the investigation of dynamic changes
comparing ictal and interictal phases and induced by cutaneous thermal allodynia
provides novel and significant information, since considering that migraine is a
cyclic pain disorder a simple comparison between migraineurs at the acute phase
and healthy subjects is no longer considered enough to explain the altered brain
function in migraine patients. As previously stated, the simple comparison between
migraine patients during the ictal phase and healthy subjects does not allow to separate the specific changes that are driven by a migraine headache attack from those
which are really related to the pathophysiology of the disease [17]. Hence, study
designs that include the evaluation of migraine patients at different phases of the
migraine cycle and longitudinal studies have been considered ideal [74] for migraine
research studies.
3.5
Concluding Remarks
There is mounting evidence in the current literature demonstrating the occurrence
of neuroplastic changes driven by chronic pain, including primary headaches and
especially migraine. Most of the studies focused on the presence of structural, functional, and more recently connectivity changes in the brain of chronic pain patients.
Some studies have also pointed toward the presence of potential biomarkers that
3
Mechanisms of Pain and Headache
37
could help to differentiate chronic pain patients from health controls or indicate an
ongoing chronification process. However, the translation of those findings to the
clinical practice is still very limited. Recent studies have also proved the presence of
an altered functioning of major endogenous modulatory systems (e.g., opioidergic
and dopaminergic) in different chronic pain disorders. Only with more detailed
information regarding the specific contribution of each of those systems, combined
with a precise evaluation of the altered structure and function of pain-related brain
structures in each chronic pain syndrome, will permit a complete understanding of
aberrant and/or deficient processing and modulation of nociceptive information in
chronic pain and headaches, which could then be applied in the tailoring of new
therapeutic strategies for those patients.
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Chapter 4
Mechanisms of Placebo and Nocebo
Elisa Carlino, Lene Vase, and Alessandro Piedimonte
4.1
Introduction
A placebo agent is usually defined as a substance, device, or procedure without
active properties, whereas the placebo effect is defined as the positive response following the administration of a placebo [10, 27, 39, 83]. Historically, placebos are
used in medical settings to please patients or in clinical trials to control the effectiveness of an active treatment [18, 47, 50, 97].
Today, however, it is evident that the conceptualization of placebo is more complex as placebo and nocebo effects are influenced by different external, internal, and
relational elements representing the “atmosphere around the treatment” [8, 24]. The
external elements refer to the physical context surrounding the medical treatment
and include the physical properties of the treatment itself, e.g., its color, shape, taste,
and smell, as well as the elements characterizing the place where the therapy is
administered, e.g., the presence of medical staff and of different medical instruments. The internal elements are represented by the patient’s characteristics, such as
personal beliefs, expectations, and emotions in relation to the therapeutic outcome,
memories about previous medical treatments, as well as different psychological
traits and genetic variables. The relational elements are represented by all the social
cues characterizing the patient-doctor relationship, such as the verbal information
that the doctor gives to the patient, the communication style, or the body language
[28, 86, 93, 100, 105].
When a treatment is delivered, the patient’s clinical improvement can be influenced by several factors such as spontaneous remission, regression to the mean,
E. Carlino (*) · A. Piedimonte
Department of Neuroscience, University of Turin Medical School, Turin, Italy
e-mail: [email protected]
L. Vase
Department of Psychology and Behavioural Sciences, School of Business and Social
Sciences, Aarhus University, Aarhus, Denmark
© Springer Nature Switzerland AG 2019
D. D. Mitsikostas, F. Benedetti (eds.), Placebos and Nocebos in Headaches,
Headache, https://doi.org/10.1007/978-3-030-02976-0_4
43
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patient and doctor biases, and unidentified effects of co-interventions [11]. Thus, to
isolate the genuine effect of the context, it is crucial to control for these confounding
factors, for example, by including no-treatment control conditions.
There is not one single placebo effect or nocebo effect but many. Placebo and
nocebo effects involve different mechanisms across various diseases and therapeutic interventions [10]. Still, the majority of our knowledge of the psychological and
neurobiological mechanisms involved in placebo and nocebo effects comes from
the field of pain. In this chapter, we will therefore focus on pain, a widespread phenomenon with a huge clinical impact.
First, we outline the psychological mechanisms underlying placebo and nocebo
effects, including expectations, learning, and their interaction. Second, we describe
the neurobiological, neuroanatomical, and neurochemical underpinnings of these
phenomena. Finally, we discuss ethical and conscious use of placebo and nocebo
factors in clinical practice.
4.2
Psychological Mechanisms
From a psychological point of view, two main mechanisms have been proposed to
explain both placebo and nocebo effects, namely, cognitive expectation and learning processes.
The first mechanism, expectation, can be defined as the experienced likelihood
of an outcome [83], and it represents an evolutionary advantage since it prepares the
organism to cope with the expected positive or negative effects related to a future
event [19]. This mechanism can lead to placebo analgesia or nocebo hyperalgesia
through the subjective belief of receiving an effective treatment that can, respectively, reduce [1, 17, 103] or increase [12, 35] pain perception. During a clinical
treatment, this belief is often induced by the clinician’s verbal suggestions [57, 83]
and/or by the experience of a warm and empathic relationship. For instance, different studies on healthy participants have shown that applying a placebo analgesic
cream on three contiguous skin areas produced different levels of analgesia, depending on which verbal suggestion was provided: strong effects were found when the
cream was defined as a strong analgesic, and weak effects were found if the cream
was defined as a weak analgesic [83]. The same phenomenon was observed in treatments for irritable bowel syndrome as well as in postoperative settings. Indeed,
patients with irritable bowel syndrome who received an “augmented” placebo acupuncture treatment, where practitioners created a warmer and more attentive relationship, resulted in a higher symptoms’ reduction and an overall stronger
improvement of the quality of life in comparison to patients who received a standard
placebo acupuncture [54]. Finally, in postoperative settings, patients receiving a
physiological (i.e., placebo) infusion showed a lower demand of additional painkillers when the infusion was defined as a powerful painkiller, while this demand
became higher when the infusion was correctly described as a placebo [79].
Interestingly, expectations about a treatment are not only generated by verbal
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Mechanisms of Placebo and Nocebo
45
s uggestions; rather, the participant/patient gathers information from all contextual
cues accompanying a treatment. For instance, branded analgesic tablets are more
effective in relieving headaches than their unbranded counterparts just as subcutaneous placebo administration is more powerful than oral administration in the treatment of migraine [7, 25, 43]. Furthermore, other cognitive factors influence
expectation [48, 83]: self-efficacy, i.e., the belief of being capable of managing
adverse events and inducing positive changes, and self-reinforcing or “somatic
focus,” i.e., the process of taking any improvement sign in a therapy as a crucial
evidence of successful treatment, disregarding all opposite evidence. All these cognitive factors modulate subjective expectations about a specific treatment and, in
turn, increase or decrease the outcome of a medical treatment. In particular, expectations may lead to these effects in combination with desire for pain relief and
reduction in negative emotions like anxiety, possibly by tapping into rewards systems. For instance, administering a placebo treatment to patients affected by irritable bowel syndrome has been shown to reduce their anxiety level, and this reduction
was significantly correlated to their pain relief [98]. Furthermore, within a clinical
model of visceral pain, it has been shown that participants who are more influenced
by negative expectations induced by verbal suggestions show an increased functional coupling between the insula and midcingulate cortex that leads to an exacerbation of pain induced by repetitive rectal stimulations [88].
Aside from cognitive expectations, learning mechanisms are crucial to placebo
and nocebo effects. Patients have a medical history, and during their lifetime they
gain experience with how different treatments produce specific clinical outcomes.
This knowledge is acquired through a process of classical conditioning where, for
instance, an analgesic substance, the so-called unconditioned stimulus, is associated
with a specific ritual of administration, “the conditioned stimulus,” leading to an
analgesic response, that is, the “unconditioned response.” After repeated associations, the simple rehearsal of the administration ritual can lead the patient to experience the analgesic response, now defined as a “conditioned response” [39, 84, 106].
Placebo analgesia induced via learning processes is typically stronger and tends to
last longer in comparison to analgesic effects generated by verbal suggestions alone.
This difference has been observed in several experiments including behavioral [29,
34], neuroimaging [69], and electrophysiological studies [72, 77] as well as in clinical settings [58]. Conditioned placebo analgesia is affected by efficacy of the treatment exposure as well as the number of learning sessions: in other words, the greater
the benefit from previous treatment and the higher the number of learning sessions,
the stronger and longer-lasting the conditioned analgesia [34, 40, 72, 77]. This
learning effect is less robust when conditioned nocebo hyperalgesia is induced [60].
Indeed nocebo effects seem less related to learning phenomena [41] and more resistant to extinction [33].
Whereas cognitive expectations are to a high extent mediated by conscious processes, classical conditioning seems to relate to unconscious physiological processes [59]. For instance, healthy participants who repeatedly received a flavored
drink as conditioned stimulus associated with the immunosuppressive drug cyclosporine A showed a conditioned immunosuppression, even after the administration
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E. Carlino et al.
of the drink alone, as assessed by lymphocyte, interleukin-2, and interferon-gamma
proliferation [49]. Even though learning via classical conditioning has been
described simply as the unconscious association between conditioned and unconditioned stimuli, more recent cognitive theories regarding this mechanism state that
the information contained in the conditioned stimulus, e.g., a colored pill, leads to a
specific conscious expectation that a given event, e.g., the analgesic effect, will follow the conditioned stimulus administration [71, 85, 99]. Thus, these mechanisms
do not work independently of one another; rather, their combination results in different placebo and nocebo effects, and their interaction may enhance or hamper
these effects [26, 58, 59]. Indeed, it has been shown in healthy participants that
verbally induced expectations of analgesia or hyperalgesia contrasted and eliminated opposite effects elicited by conditioning procedures [21]. Recently, significant placebo and nocebo effects on pain were also induced using subliminal stimuli,
indicating that, at least in some circumstances, placebo and nocebo effects can operate without conscious awareness [53, 60].
4.3
Neuroanatomical and Neurochemical Underpinnings
The cascade of neurobiological changes triggered by the psychosocial context has
been studied extensively [10, 19, 24, 27, 37, 44, 48, 101]. Studies using functional
magnetic resonance imaging (fMRI) and positron emission tomography (PET) have
identified different brain regions and brain pathways that contribute to placebo and
nocebo responses (see Fig. 4.1a). These regions include a complex cortical-brainstem system involving the dorsolateral prefrontal cortex (DLPFC), ventromedial
prefrontal cortex (vmPFC), lateral orbitofrontal cortex (LOFC), nucleus accumbens
(NAc), periaqueductal gray (PAG), anterior cingulate cortex (ACC), and rostroventral medulla (RVM) [51, 61, 68, 70, 75, 76, 82, 89, 90, 95, 101, 103, 104, 107, 108].
In particular, during the anticipation phase, when an analgesic effect is expected,
activation of ACC, precentral and lateral prefrontal cortex, and PAG has been documented. During pain inhibition, i.e., during the analgesic phase, a deactivation has
been found in different brain regions such as the mid- and posterior cingulate cortex, superior temporal and precentral gyri, the anterior and posterior insula, the
claustrum and putamen, and the thalamus and caudate body [73]. On the contrary,
when pain exacerbation is expected, a subjective increase in pain rating has been
reported along with an increased activity in different brain regions involved in pain
processing and emotion regulation, such as the prefrontal cortex (PFC), ACC, and
insula [32, 55, 60, 62, 63, 78, 80, 81, 87].
Recently, connectivity studies have shown that during placebo analgesia coupling between brain regions, including those involved in cognitive processes (e.g.,
attention, expectation, evaluation), was significantly enhanced (see Fig. 4.1b).
Specifically, a significantly consistent decrease in the coupling between DLPFC and
PAG was found [91, 92]. Furthermore, the extent of right midfrontal gyrus connectivity predicts placebo responses across chronic pain clinical trials [94]. Brain
4
Mechanisms of Placebo and Nocebo
a
47
c
Morphine
Placebo
Naloxone
Anticipation of pain Inhibition of pain Exacerbation of pain
relief
Prefrontal cortex MCC and PCC
Prefrontal cortex
ACC
Superior temporal and
precentral gyri
PAG
ACC
insula
µ-opioid
receptors
ANALGESIA
Thalamus
Insula and claustrum
Anticipatory anxiety
µ-opioid
receptors
µ-opioid
receptors
Placebo
ANALGESIA
Block of
Placebo ANALGESIA
Proglumide
Putamen and caudate body
CCK
receptors
b
Increase of Nocebo
HYPERALGESIA
Placebo
Analgesia
Nocebo
Hyperanalgesia
DLPFC
Operculum
PAG
Basal
Ganglia
Ketorolac
Pentagastrin
CCK
CCK-2
receptors
receptors
Increase of Placebo
Block of
ANALGESIA
Placebo ANALGESIA
Placebo
Rimonabant
Naloxone
CB1
receptors
CB1
receptors
CB1
receptors
ANALGESIA
Placebo
ANALGESIA
Block of
Placebo ANALGESIA
Fig. 4.1 Principal neurobiological mechanisms of placebo and nocebo effects. (a) Neuroanatomy
of placebo analgesia and nocebo hyperalgesia have been described through different brain imaging
studies. (b) Connectivity studies have shown that coupling between different brain regions occurs
during placebo analgesia and nocebo hyperalgesia. (c) The opioid and cannabinoid systems are
involved in placebo and nocebo effects. In some circumstances, placebo analgesia occurs through
the activation of the opioid system and can be reversed by naloxone. Anticipatory anxiety can
activate the pro-nociceptive cholecystokinin (CCK) system, leading to nocebo hyperalgesia. The
pro-nociceptive CCK effect can be reversed by proglumide and agonized by pentagastrin. Placebos
can also activate the CB1 cannabinoid receptors, producing an analgesic effect that can be reversed
by rimonabant
connectivity seems to be affected also by negative verbal suggestions; indeed,
nocebo hyperalgesia seems to be accompanied by the activation of the operculum
over an extended time period, and the operculum exhibited changes in coupling over
time during nociceptive input, as demonstrated by decreased connectivity with the
basal ganglia [46].
Pharmacological studies on placebo analgesia have so far documented the activation of two different neurochemical systems: the opioid and cannabinoid systems
(see Fig. 4.1c). The opioid system is the most studied and understood. The observation that μ-opioid antagonist naloxone blocks some types of placebo analgesia has
been documented using conditioning protocols, indicating that the opioid system
plays a pivotal role. In particular, it has been shown that when opioid drugs like
morphine are administered for several consecutive days and subsequently replaced
by a placebo, the ensuing placebo effect can be reversed by naloxone [1, 45, 65].
Further confirmation of the involvement of the opioid system comes from the study
of the anti-opioid action of cholecystokinin (CCK); indeed, the CCK antagonist
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E. Carlino et al.
proglumide enhances placebo analgesia [9, 13], whereas pentagastrin, a CCK-2
receptor agonist, disrupts it [15]. CCK also mediates nocebo hyperalgesic responses;
for example, nocebo hyperalgesia induced by expectations of pain and anxiety
increase can be reversed by the CCK antagonist proglumide [12, 16]. The involvement of the cannabinoid system has recently been documented using conditioning
protocols with non-opioid drugs such as ketorolac. After a pharmacological preconditioning with ketorolac, the placebo analgesic response cannot be reversed by naloxone but by the CB1 cannabinoid antagonist rimonabant [14]. The involvement of
this system has also been confirmed by the study of the functional missense variant
Pro129Thr of the gene coding for fatty acid amide hydrolase (FAAH), the major
degrading enzyme of endocannabinoids [74].
Also, electroencephalographic (EEG) studies have revealed insights into the
dynamical and temporal changes that occur before and after the administration of a
placebo treatment. Indeed, as suggested by Sevel et al. [91], small placebo effects
could be better described by changes in the temporal dynamics in pain modulatory
regions than by changes in the magnitude of blood oxygenation level-dependent
(BOLD) activation, and EEG is a good tool for investigating temporal changes in
neural activity. Different studies have demonstrated that placebo treatments produce
a reduction of pain along with a significant decrease in pain-evoked event-related
potentials (ERPs), suggesting that placebo analgesia affects early nociceptive processes [30, 42, 102] but also expectation of upcoming nociceptive stimuli [77].
Finally, studies on frequency analysis on ongoing (resting) EEG have proved that
alpha activity, known to be influenced by top-down processes, increased significantly after a placebo treatment [52]. Moreover, the subjectively reported decrease
of pain intensity correlates with the increase in the amplitude of alpha oscillations
during pain conditions in frontal-central regions [67].
4.4
Clinical Implications
The demonstration that the context surrounding a medical treatment can influence
its effectiveness has crucial clinical implications. First, the presence of the context
and the relationship with a healthcare provider are pivotal in order to maximize the
effectiveness of a medical treatment, as extensively demonstrated by the comparison of “open” versus “hidden” interventions. A classic example of an “open” intervention is the administration of medical treatment in full view of the patient (e.g.,
with a doctor at the bedside who explains and performs the procedure to the patient,
describing its therapeutic effects). On the contrary, the “hidden” intervention is the
administration of a treatment unbeknownst to the patient and without any previous
advice from a doctor or nurse (e.g., using a machine performing an automatic infusion). If a treatment is administered without any explicit information, the patient
cannot be aware of the treatment itself, and, in turn, this lack of awareness does not
elicit positive expectations and/or reductions in negative emotions, thus leading to
reduced treatment efficacy [20, 38]. For example, in seminal studies on placebo
4
Mechanisms of Placebo and Nocebo
49
analgesia, it has been observed that an open injection of saline solution, believed by
the patient to have analgesic properties, produced the same analgesic effects as a
hidden injection of 6–8 mg of morphine [64, 66]. The differential efficacy of open
and hidden interventions has been confirmed for different painkillers, such as
buprenorphine, tramadol, ketorolac, and metamizole [3, 21, 38]. Brain areas linked
to open or hidden administration of analgesic drugs have been identified by means
of neuroimaging techniques. An fMRI study showed that, compared to hidden
administration, open administration of the opioid agonist remifentanil significantly
increased analgesia and that this increase correlated with higher activity in DLPFC
and pregenual ACC. In addition, when participants were deceivingly informed that
the administration of remifentanil would be interrupted, the analgesic effect was
completely abolished even in the presence of the drug, and this analgesia loss was
associated with increased activity in the hippocampus [23]. Furthermore, using an
open-hidden design to manipulate the participants’ knowledge of drug administration, it has been observed that brain areas activated by positive expectation of
receiving an analgesic drug, e.g., remifentanil, differ from areas activated by its sole
pharmacodynamics action [6]. Indeed, while both remifentanil and expectancy
reduce pain, positive expectation modulates activity in the frontal cortex with a
separate time course from drug effects, thus showing that expectations and drugs
can operate without mutual interference.
A second clinical implication is that the assessment of a patient’s medical history
is essential to treatment optimization. For example, when healthy participants were
exposed to a negative treatment (negative history group), the placebo analgesic
response to a second treatment was lower compared to participants exposed to a
positive treatment (positive history group) [56]. Also, the decrease of analgesia in
participants who first experienced an unsuccessful treatment correlated with higher
brain activity in areas involved in pain processing, e.g., the insular cortex, as well as
with lower brain activity in areas involved in pain inhibition and placebo analgesia,
e.g., DLPFC [56]. Moreover, changing of the route of drug administration (e.g.,
from topical to oral) doesn’t counteract a negative treatment history, indicating that
learned carry-over effects generalize over time and across routes of drug administration [109]. Following a similar approach in patients with chronic pain treated with
repetitive transcranial magnetic stimulation (rTMS), it has been observed that successful active stimulation of the motor cortex followed by sessions of sham rTMS
produced 11% of pain reduction, while unsuccessful sessions of rTMS followed by
sham rTMS resulted in an opposite pain increase by 6% [4]. It is interesting to
notice that these patients were all resistant to pharmacological treatments, but placebo interventions still held positive results after effective sessions of rTMS, highlighting how conditioned analgesic responses can still be elicited and enhanced in
clinical treatments in these patients [37].
Third, in the clinical setting, it is crucial to avoid nocebo effects [22, 31, 36, 93].
Even though the study of the nocebo effect has received less attention, mainly due
to ethical constraints, it is well documented that a negative context can generate
negative therapeutic outcomes. For example, negative information provided during
the administration of an analgesic treatment can reverse the topical analgesic effect
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of the treatment itself [5] or exacerbate pain during invasive procedures [96].
Communication of a negative diagnosis or side effects is also a potentially harmful
situation in the clinical setting. For example, comparing the rates of adverse events
reported in the placebo arms of clinical trials for three classes of anti-migraine
drugs, the rate of adverse events in the placebo arms was high. Moreover, the
adverse events in the placebo arms corresponded to those of the anti-migraine medication with which the placebo was compared [2].
All the abovementioned studies emphasize that first, the information delivered
by healthcare professionals as well as the environment where the treatment is
administered is crucial for the outcome of a specific therapy, since less information
could translate into diminished efficacy. Second, the specific clinical history of each
patient is important to better understand how he/she will react to a new treatment
and to construct a clinical setting tailored to his/her expectations. Third, a negative
therapeutic context can compromise the effectiveness of a medical treatment so
preventing nocebo effects is of major importance in the clinical setting.
4.5
Conclusions
Current knowledge of placebo and nocebo effects provides evidence of the key role
of the psychosocial context accompanying the administration of medical treatments.
Different psychological mechanisms have been recognized as mediators of placebo
and nocebo effects, especially the relationship with the healthcare provider, expectation, emotions, and learning processes. Moreover, neuroimaging and psychopharmacological studies support the placebo and nocebo research, documenting the
involvement of specific neurochemical systems and the activation/deactivation of
different brain regions. More research is needed to increase our understanding of
these phenomena in order to apply these findings in the clinical setting with the aim
of improving personalized approaches and increase the effectiveness of medical
treatments.
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Chapter 5
The Special Case of High-Altitude
Headache
Diletta Barbiani, Eleonora Camerone, and Fabrizio Benedetti
5.1
High-Altitude Headache: Causes and Pathophysiology
High-altitude headache is one of the many neurophysiological symptoms associated
with the ascent to high altitudes and represents a core indicator of the clinical condition triggered by the drop in atmospheric oxygen pressure and by the decreased
oxygen concentration in the air, known as acute mountain sickness (AMS) [10, 21].
AMS is a complex syndrome, defined as the combination of the presence of headache in an unacclimatized person who has recently reached an altitude above
2500 m along with one or more of such symptoms as gastrointestinal disturbances
(anorexia, nausea, or vomiting), shortness of breath, dizziness, light headedness,
insomnia, or fatigue. Symptoms could present as early as 1 h after having reached
high altitude but usually develop within 6–10 h after ascent [14], and are generally
assessed by means of the Lake Louise Score Questionnaire [19]. About 80% of
people report headache as a main symptom when going to high altitudes, especially
with rapid ascent and very high altitude [16]. When little oxygen is available in the
air, a condition called hypoxia, several body functions counterbalance the oxygen
shortage by triggering at least three fundamental compensatory responses: increase
in ventilation (hyperventilation) through the activation of chemoreceptors; increase
in circulation through increased cardiac output, e.g., heart rate increase; and increase
in perfusion through vasodilation, e.g., cerebral vasodilation, whereby prostaglandins (PG) such as PGE2 have been found to be involved. Thus, the reduction of the
D. Barbiani · F. Benedetti (*)
Department of Neuroscience, University of Turin Medical School, Turin, Italy
Plateau Rosà Laboratories, Plateau Rosà, Breuil-Cervinia, Italy
Plateau Rosà Laboratories, Plateau Rosà, Zermatt, Switzerland
e-mail: [email protected]
E. Camerone
Department of Neuroscience, University of Genoa, Genoa, Italy
© Springer Nature Switzerland AG 2019
D. D. Mitsikostas, F. Benedetti (eds.), Placebos and Nocebos in Headaches,
Headache, https://doi.org/10.1007/978-3-030-02976-0_5
57
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partial pressure of oxygen in inspired air compromises the supply of oxygen to the
tissues resulting in high-altitude headache and mountain sickness [14].
Despite the complex nature of this hypoxia-related clinical syndrome, headache
is the cardinal symptom and indeed the most common symptom even at relatively
low altitudes [14].
As far as we know, there are at least two pathways triggering high-altitude headache. The first is represented by the acute effects of hypoxia on PG synthesis through
the cyclooxygenase (COX) enzyme, with the formation of PGD2, PGF2, PGE2,
PGI2 (prostacyclin), and thromboxane (TX) A2 [2, 18]. One of the most important
effects of these eicosanoids, particularly PGE2, is represented by vasodilation,
which is thought to be the principal factor inducing acute hypoxia headache [7–9,
15, 17], although the direct stimulation of nociceptive afferents cannot be ruled out
[12]. However, a second pathway involved in high-altitude headache is represented
by the hypoxia-related hyperventilation that, in turn, induces the excessive elimination of carbon dioxide (CO2) with the consequent increase in blood pH (alkalosis)
[20]. In keeping with the important role of alkalosis in AMS and high-altitude headache is the effect of blood pH reduction by means of acetazolamide [13].
Notwithstanding the therapeutic acidifying properties of acetazolamide, there are at
least two other effective treatments for high-altitude headache: oxygen inhalation
[1, 4] and oral cyclooxygenase inhibitors, such as aspirin [5, 6]. Whereas the former
restores blood oxygen saturation (SO2), thus decreasing hyperventilation and alkalosis, the latter inhibits the hypoxia-activated cyclooxygenase and PG synthesis,
thus reducing cerebral vasodilation [3].
In order to understand whether placebo effects have any role in these functions,
that is, whether placebo effects occur for any physiological function that is involved
in acute mountain sickness symptoms, what is needed is a model that is both ethical
and amenable to scientific investigation. Indeed, needless to mention are the ethical
constraints going hand in hand with the possible investigation of “anti-hypoxic”
placebo effects in the clinical setting, in that we would need to study patients in
hypoxic conditions, namely, with low blood oxygen saturation (SO2). For example,
replacing even a tiny amount of oxygen with a placebo in a patient with either respiratory failure or admitted to an intensive care unit would certainly be unethical, and
investigating the effects of placebo treatments on SO2 or impaired ventilation would
be impracticable at the bedside.
5.2
The High-Altitude Model
The majority of placebo and nocebo research has been conducted in experimental
rather than clinical settings [4], and there are at least three reasons for this. First,
there are less ethical issues when using experimental compared to clinical settings.
Second, there are a limited number of protocols and measurements that can be used
in patients compared to healthy volunteers. Third, the experimental setting allows to
control for confounding variables, such as spontaneous remission and various methodological biases, including subject biases, co-interventions, and regression to the
5
The Special Case of High-Altitude Headache
59
mean [2]. For example, spontaneous remission refers to the natural improvement of
the symptomatology mirroring the natural course of a disease or illness. In order to
control for such confounder, research must include a control group, often called the
“natural history” group, in which neither placebo nor true treatment is given to
patients so that it can be representative of the natural course of the condition under
investigation [2]. Ethical constraints restrain from including a natural history group
in clinical trials, thus an experimental setting becomes necessary [2]. Although
research relying on experimental setting has been proven to be extremely informative, this is limited, in that it prevents to extend our knowledge and understanding of
placebo and nocebo mechanisms to the clinical population and to clinical conditions
[2]. Within this context, the high-altitude, or hypobaric hypoxia, headache model
acts as an extremely valuable resource because it exemplifies a borderline condition
between the clinical and the experimental setting and allows to induce a clinical
condition by bringing subjects from a region of high oxygen pressure (sea level,
159 mmHg) to a region of lower oxygen pressure (high altitude, e.g., 3500 m,
102 mmHg). It is a clinical model because subjects actually experience headache.
However, this can be induced by simply bringing healthy volunteers to high altitude; that is to say, it is a model that allows us to study a clinical condition that is
induced experimentally.
As altitude increases, oxygen pressure drops, and in these extreme conditions,
where both physical and cognitive performances decline very quickly, hypoxia triggers several compensatory responses, such as hyperventilation through the chemoreceptors, increased cardiac output through augmented heart rate, and increased
brain perfusion through vasodilation. Basically, our body naturally reacts to oxygen
shortage by means of compensatory strategies, the success of which strongly
depends on the entity of the drop of oxygen pressure, in other words, on the altitude
to which subjects go up to. In this regard, it is possible to differentiate between four
high-altitude zones, depending on how the human body responds to oxygen shortage [11]. The zone from sea level to 1800–2000 m is called “indifferent,” as in most
people there are no detectable effects on the body. The zone from 2000 to 4000 m is
called “full compensation zone,” as many physiological responses compensate the
low oxygen pressure, e.g., hyperventilation, increased heart rate, and cerebral vasodilation. The zone from 4000 to 7000 m is called “partial compensation zone,”
where compensatory mechanisms do not fully cover the oxygen shortage and symptoms such as pulmonary edema and cerebral edema may occur. Finally, in the zone
above 7000 m, the so-called death zone, oxygen is insufficient, compensatory
mechanisms fail to compensate for the drop in atmospheric oxygen, and individuals
are at high risk of death.
Most of the studies at high altitude have been conducted in the “full compensation zone,” where oxygen availability is 64% compared to sea level. The reason for
that is simple: we need a degree of hypoxia in which several physiological compensatory responses develop, yet they are not threatening for life. This is made possible
by one of the locations where we work, namely, the Center for Hypoxia at the
Plateau Rosà Laboratories, located at an altitude of 3500 m in the Matterhorn area
at the border between Italy and Switzerland. In this zone, the abovementioned acute
mountain sickness symptoms are often detected in association with compensatory
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mechanisms which are capable of counterbalancing the low oxygen pressure.
Among these, hyperventilation and vasodilation are thought to be at the core of the
onset of altitude headache.
5.3
an Placebos and Nocebos Affect Headache at High
C
Altitude?
The hypobaric hypoxia headache model allows to investigate the effect that placebos and nocebos may have not only on the subjectively reported headache pain but
also on the neurobiological underpinnings [3–5]. Indeed, recent research has shown
that placebos and nocebos modulate high-altitude headache and its physiological
correlates [3–5]. For instance, in 2015, Benedetti et al. [4] investigated the effect of
placebo oxygen on headache pain along with the assessment of physiological
parameters [4]. Headache was assessed pre- and post-exercise by means of a numerical rating scale (NRS), and fatigue was also assessed, along with measures of SO2,
heart rate (HR), and PGE2. Exercise consisted in subjects completing 3000 steps on
a stepper. Oxygen placebo was given to participants via an oxygen mask connected
to an oxygen supply with no real oxygen inside. Results from this study highlighted
that placebo oxygen alone was effective in reducing fatigue; however no significant
changes were reported in relation to headache at rest, post-exercise headache, HR,
PGE2, and SO2 [4]. Differently, when placebo administration was preceded by oxygen preconditioning, whereby real oxygen was administered for several sessions in
a row and then replaced by sham (placebo) oxygen on the last test session, not only
fatigue was found to be reduced but also post-exercise headache, HR, and PGE2.
However, no changes were observed for headache at rest as well as for SO2. The
most interesting finding of this study is the influence that placebo administration
had on peripheral mechanisms such as PGE2, though without any increase in SO2,
showing how the placebo effect is not only a psychological but also a biological
phenomenon. This notwithstanding, this study also sheds light on the limits of a
placebo treatment, in that a placebo without a prior preconditioning procedure is
incapable of affecting biological pathways [4]. Moreover, in no case a placebo had
the power of reducing pre-exercise headache, suggesting the effectiveness of an
“anti-headache placebo” if and only if headache is induced or enhanced by means
of physical exercise [4].
In a different study, hypobaric hypoxia headache was investigated in the context
of two different modalities of placebo administration, namely, placebo oxygen
inhaled through an oxygen mask and placebo aspirin pills [3]. Headache and physiological parameters were first assessed at sea level (240 m) during the first day and
then at 3500 m on the same day and on the two following days [3]. The following
measurements were taken: headache, SO2, minute ventilation (Vmin), blood pH,
salivary PGD2, PGE2, PGF2, PGI2, and TXA2. Performance was evaluated by asking subjects to complete 3000 steps on a stepper. Participants were divided into four
5
The Special Case of High-Altitude Headache
61
groups: (a) no treatment; (b) placebo oxygen, with real oxygen preconditioning; (c)
placebo aspirin, with real aspirin preconditioning; and (d) “mixed” placebo, in
which preconditioning with oxygen was followed by the administration of placebo
aspirin. The oxygen placebo group showed reduction of headache, Vmin, blood
alkalosis, and PGE2, yet with no increase in SO2. Differently, in the placebo aspirin
group, reduction of headache pain was associated with the inhibition of all products
of cyclooxygenase, PGD2, PGE2, PGF2, PGI2, and TXA2, whereas ventilation and
blood alkalosis were not affected. These results seem to both corroborate and extend
what was previously shown by Benedetti and his team in 2015; they emphasize how
the placebo effect is not a unitary phenomenon: different placebos interact and
affect different physiological pathways; specifically, placebo oxygen influences the
ventilation-alkalosis pathway, whereas placebo aspirin affects the COX-PG pathway [3].
One of the core strengths of the hypobaric hypoxia model is that it allows to
investigate not only the placebo but also the nocebo effect, though still without
encountering important ethical limits. For example, Benedetti et al. [5] investigated
nocebo and placebo effects in high-altitude headache and at the level of the COX-PG
pathway. A model of interindividual communication was used to induce nocebo
responses. Precisely, one subject, the “trigger,” was informed by the researchers of
the likelihood of experiencing severe headache because of the lower oxygen concentration at high altitude. In the following weeks, the researchers were contacted
by other participants of the study asking for more information about the possibility
of experiencing high-altitude headache. This indicated that the trigger subject had
spread the information across some subjects, who then spread the information
across others, and so on. The experimental group consisted of subjects who were
informed about the risk of headache by the trigger, whereas the control group consisted of subjects who were unaware of such risk. An increase of headache pain and
salivary COX products (PGD2, PGE2, PGF2, PGI2, TXA2) was found in the nocebo
compared to the control group [5]. In addition, aspirin placebo was given to all subjects suffering from headache, both in the control and in the experimental group. It
was shown that placebo administration ameliorated headache pain and inhibited
prostaglandins synthesis in headache sufferers in the experimental group but not in
the control group. In other words, both aspirin and placebo reduced pain in the
socially affected individuals. The difference in the placebo response between the
two groups is ascribable to the different baseline values of headache pain and prostaglandins—e.g., PGE2—induced by the dissemination of negative information. A
placebo effect was observed only for the “infected” individuals who found themselves at an underprivileged nocebo baseline of increased pain, with the placebo
acting as a neutralizer of the nocebo component of the prostaglandin and pain
increase. Therefore, this study suggests that placebos could be effective only on the
nocebo-related component of pain.
It is worth noting how this study again shows that, similarly to a placebo, also a
nocebo is both a psychological and biological phenomenon capable of modulating
different biochemical pathways involved in headache pain.
62
5.4
D. Barbiani et al.
Conclusions
Research at high altitude has proven itself to be an extraordinary model, useful
to overcome some of the key issues in placebo and nocebo studies. One of the
main boons of this approach is that it permits to create a borderline condition
between the experimental and the clinical setting, thus allowing us to study a
clinical condition which is induced experimentally by simply bringing subjects
to high altitude. Moreover, high-altitude research has given a significant contribution to the development of our understanding of placebo and nocebo phenomena, showing, for instance, how fatigue is very sensitive to a placebo alone,
without the requirement of a preconditioning procedure. This suggests that positive expectations induced by positive verbal suggestions alone are sufficient to
trigger a placebo response in those more “psychologically susceptible” parameters such as fatigue. On the other hand, a preconditioning procedure prior to
placebo administration seems to be necessary in order to observe changes in
physiological parameters—ventilation, blood pH, heart activity, prostaglandins,
and TXA2—as well as in post-exercise headache. Interestingly, such changes
occur independently from the variation of SO2. These findings suggest that
learning mechanisms play a crucial role in placebo responses and often represent
the necessary condition in order to have a placebo response. One of the most
intriguing aspects of this line of research is the effect that a placebo has on an
array of different parameters despite no changes in SO2, suggesting that psychobiological mechanisms may, at times, be as important as the oxygen level in the
body. Moreover, there is growing evidence showing how placebo responses vary
depending on the type of placebo administered: placebo aspirin and placebo oxygen interact and affect different physiological pathways, suggesting that the placebo effect is not a unitary phenomenon, affecting both psychological and
physiological parameters. In addition, nocebo mechanisms have been shown to
act in a similar manner as placebo mechanisms. For example, in headache pain,
negative expectations lead to changes both at the psychological level, such as
increased headache perception, and at the physiological level, such as increased
salivary COX products.
Taken all together, these findings indicate how the biological factor alone, that is
hypobaric hypoxia, is only partially responsible for the changes observed at high
altitude. Indeed, psychological factors (expectations) and learning mechanisms
(conditioning) seem to play a fundamental role in the amelioration (placebo) or
generation (nocebo) of symptoms, as well as in the biochemical changes associated
to hypoxia.
Despite the large contribution that the high-altitude model has offered so far,
further research is required for a more in-depth understanding of this complex and
multiform area of investigation. First, research must address the question of how
physiological placebo responses occur and how they manage to bypass the oxygen
shortage in the body. Second, research should investigate other body functions that
may be affected by placebos and explore other physiological and biochemical
5
The Special Case of High-Altitude Headache
63
parameters. Third, it may be challenging to study the extent to which placebo
responses can push themselves forward, for example, by investigating what happens
with oxygen reductions that go beyond 50%.
References
1. Bartsch P, Baumgartner RW, Waber U, Maggiorini M, Oelz O. Comparison of carbondioxideenriched, oxygen-enriched, and normal air in treatment of acute mountain sickness. Lancet.
1990;336:772–5.
2. Benedetti F. Perspective placebo effects: from the neurobiological paradigm to translational
implications. Neuron. 2014;84:623–37.
3. Benedetti F, Dogue S. Different placebos, different mechanisms, different outcomes: lessons
for clinical trials. PLoS One. 2015;10(11):e0140967.
4. Benedetti F, Durando J, Giudetti L, Pampallona A, Vighetti S. High altitude headache: the
effects of real versus sham oxygen administration. Pain. 2015;156:2326–36.
5. Benedetti F, Durando J, Vighetti S. Nocebo and placebo modulation of hypobaric hypoxia
headache involves the cyclooxygenase-prostaglandins pathway. Pain. 2014;155(5):921–8.
6. Burtscher M, Likar R, Nachbauer W, Philadelphy M. Aspirin for prophylaxis against
headache at high altitudes: randomised, double blind, placebo controlled trial. Br Med J.
1998;316:1057–8.
7. Busse R, Fosterman U, Matsuda H, Pohl U. The role of prostaglandins in the endotheliummediated vasodilatory response to hypoxia. Pflugers Arch. 1984;401:77–83.
8. Davis RJ, Murdoch CE, Ali M, Purbrick S, Ravid R, Baxter GS, et al. EP4 prostanoid receptormediated vasodilation of human middle cerebral arteries. Br J Pharmacol. 2004;141:580–5.
9. Fredericks KT, Liu Y, Rusch NJ, Lombard JH. Role of endothelium and arterial K+ channels
in mediating hypoxic dilation of middle cerebral arteries. Am J Physiol. 1994;267:H580–6.
10. Imray C, Wright A, Subudhi A, Roach R. Acute mountain sickness: pathophysiology, prevention and treatment. Prog Cardiovasc Dis. 2010;52:467–84.
11. International Society for Mountain Medicine. Non-Physician Altitude Tutorial. 2005. Archived
from the original on 2011-06-06. Retrieved 22 Dec 2005.
12. Kawabata A. Prostaglandin E2 and pain—an update. Biol Pharm Bull. 2011;34:1170–3.
13. Leaf DE, Goldfarb DS. Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness. J Appl Physiol. 2007;102(1):313–22.
14. Marmura MJ, Hernandez PB. High-altitude headache. Curr Pain Headache Rep.
2015;19(5):483.
15. Messina EJ, Sun D, Koller A, Wolin MS, Kaley G. Role of endothelium-derived prostaglandins in hypoxia elicited arteriolar dilation in rat skeletal muscle. Circ Res. 1992;71:790–6.
16. Porcelli MJ, Gugelchuk GM. A trek to the top: a review of acute mountain sickness. J Am
Osteopath Assoc. 1995;95:718–20.
17. Ray CJ, Abbas MR, Coney AM, Marshall JM. Interactions of adenosine, prostaglandins
and nitric oxide in hypoxia-induced vasodilatation: in vivo and in nitro studies. J Physiol.
2002;544:195–209.
18. Richalet JP, Hornych A, Rathat C, Aumont J, Larmignat P, Rémy P. Plasma prostaglandins,
leukotrienes and thromboxane in acute high altitude hypoxia. Respir Physiol. 1991;85:205–15.
19. Sutton JR, Coates G, Houston CS, Oelz O. The Lake Louise consensus on the definition and
quantification of altitude illness. In: Sutton JR, Coates G, Houston CS, editors. Hypoxia and
mountain medicine. Burlington: Queen City Printers; 1992. p. 327–30.
20. West JB. The physiologic basis of high-altitude diseases. Ann Intern Med. 2004;141:789–800.
21. Wilson MH, Newman S, Imray CS. The cerebral effects of ascent to high altitudes. Lancet
Neurol. 2009;8:175–91.
Chapter 6
Placebo Response in Human Models
of Headache
Jakob Møller Hansen and Messoud Ashina
6.1
Introduction
Migraine is a complex neurovascular disorder characterized by recurrent episodes
of headache with associated features [14] and is one of the most prevalent [32] and
disabling neurological disorders [23].
A key feature of migraine is that various factors can trigger an attack, and this
phenomenon provides a unique opportunity to investigate disease mechanisms by
experimentally inducing migraine attacks [6]. Because migraine attacks are fully
reversible and amendable to therapy, the headache- or migraine-provoking property
of endogenous signaling molecules can be tested in a human model which offers
unique possibilities to study mechanisms responsible for migraine and to explore
the mechanisms of action of existing and future anti-migraine drugs [25].
Like all other interventions, participant expectations, content and delivery of
information, and unspecific effects of the intervention may exert a placebo or
nocebo effect on the outcomes.
In this chapter, we summarize the recorded placebo responses from human
experimental headache studies and discuss how placebo responses may be mitigated in future experimental human migraine studies.
J. M. Hansen · M. Ashina (*)
Department of Neurology, Danish Headache Center, Rigshospitalet, Glostrup, Denmark
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
e-mail: [email protected]
© Springer Nature Switzerland AG 2019
D. D. Mitsikostas, F. Benedetti (eds.), Placebos and Nocebos in Headaches,
Headache, https://doi.org/10.1007/978-3-030-02976-0_6
65
66
6.2
J. M. Hansen and M. Ashina
he Rationale for Using Human Experimental Migraine
T
Studies
In vitro studies have contributed in the characterization of receptors in cranial blood
vessels and the identification of new possible anti-migraine agents. Animal models
enable the study of vascular responses, neurogenic inflammation, and peptide
release and thus provided leads in the search for migraine mechanisms. So far, however, animal models cannot predict the efficacy of new therapies for migraine.
Human models of migraine can be used to test whether endogenous signaling
molecules or other putative trigger factors provoke migraine in humans; provocation of an attack suggests involvement of the triggering factor in the mechanisms of
spontaneous migraine attack. Experience has shown that if a factor induces migraine
in patients with migraine, the same factor will also induce a milder headache in
people without migraine; therefore, a first step in establishing a migraine-inducing
effect is to test for any headache-eliciting effect in healthy volunteers. The fact that
patients with migraine are more prone than healthy volunteers to experience
migraine attacks in response to these triggering factors suggests the existence of a
migraine threshold phenomenon [10, 36].
Experimental pain studies based on well-controlled study conditions and uniform outcome assessments are necessary to increase our understanding of basic
disease processes. The subjects may well be subject to placebo effects, caused by
conditioning, expectations, and the endogenous opioid system. This should be taken
into account when designing human provocation studies.
Provocation studies can be tailored to examine specific hypotheses; if the focus
of the study is to identify imaging or biochemical markers of migraine, scans and
blood samples are collected at baseline, at predefined intervals during the study
when effects are expected, and after treatment intervention (Fig. 6.1). With the addition of other imaging modalities such as high-field MRI, even more detailed information can be collected on the vascular response of the cephalic circulation.
6.3
Placebo Response in Human Experimental Models
For this chapter we selected experimental human studies where a placebo group was
included. Migraine provocation studies should preferably be double-blind crossover
studies and typically involve random assignment of participants to receive intravenous infusion of either the putative triggering factor or a placebo. This is also helpful for blinding purposes.
The placebo effects reported in human experimental studies are summarized in
Table 6.1. It is notable that both controls and patients report headache and also
migraine after provocation with placebo. Mostly, however, the placebo response is
modest.
6
Placebo Response in Human Models of Headache
67
Fig. 6.1 The human provocation model, modified from [25]. In the main version of this model,
patients with migraine are randomly allocated to receive intravenous infusion (25 min) of “target
substance” or placebo (isotonic saline) in a double-blind, crossover design. Headache intensity is
recorded on a verbal rating scale from 0 to 10 (0, no headache; 1, a very mild headache (including
a feeling of pressing or throbbing); 5, moderate headache; 10, worst imaginable headache). At
predefined intervals hemodynamic variables are recorded (mean velocity of blood flow in the middle cerebral artery by transcranial Doppler with hand-held 2-MHz probes; diameter of the frontal
branch of the superficial temporal artery by a high-resolution ultrasonography unit). Data on headache occurrence are captured in a headache diary [28]; headache scores are filled in during the
infusion and hourly after discharge. All characteristics of headache and symptoms that accompany
it are recorded in the diary. The diary included headache characteristics and accompanying symptoms necessary to classify the headache according to ICHD-III
6.4
lacebo in Relation to Vascular Effects in Human
P
Experimental Studies
Arterial dilatation may cause headache [24], and glyceryl trinitrate (GTN) infusion does cause a more pronounced dilation of extra- and intracerebral arteries in
migraine patients than in controls [33]. In a randomized, placebo-controlled,
double-blind, crossover study, 1.5-T magnetic resonance angiogram (MRA) was
combined with GTN infusion in healthy volunteers, to report a vasodilation of the
middle cerebral artery (MCA) that was significantly larger after GTN than placebo. Still, placebo led to a 1–2% increase in diameter and cross-sectional area
[12]. The vascular effects of calcitonin gene-related peptide (CGRP) infusion in
healthy volunteers were investigated with high-resolution 3-T magnetic resonance imaging (MRI): CGRP causes significant dilation of the extracerebral middle meningeal artery (MMA) but not of the intracerebral MCA compared with
placebo [3].
68
J. M. Hansen and M. Ashina
Table 6.1 Human experimental headache studies of various signaling molecules, where a placebo
group was included (selected)
Compound
Design
Glyceryl
Double-blind,
trinitrate (GTN) placebo-
controlled,
crossover trial
Study
population
Migraine
n = 12
Glyceryl
Randomized,
trinitrate (GTN) double-blind,
placebo-
controlled
crossover study
Chronic
tension-
type
headache
n = 16
Glyceryl
Double-blind,
trinitrate (GTN) placebo-
controlled,
crossover trial
Migraine
n = 28
Carbachol
Controls
n = 12
Carbachol
Vasoactive
intestinal
peptide (VIP)
Randomized,
double-blind,
placebo-
controlled
crossover study
Randomized,
double-blind,
placebo-
controlled
crossover study
Migraine
n = 18
Controls
Randomized,
n = 12
double-blind,
placebo-
controlled
crossover study
Headache
reported
(active vs.
placebo)
Migraine:
8/10 (80%)
after GTN
vs. 1/12 (8%)
after placebo
Delayed
headache:
15/16 (94%)
after GTN
vs. 11/16
(69%) after
placebo
Migraine:
16 (57.1%)
after GTN
vs. 0% after
placebo
Comment
Ref.
Thomsen
et al. [34]
Area under the
headache curve
larger after GTN
than after placebo
Ashina
et al. [5]
Perrotta
GTN (0.9 mg
et al. [26]
sublingual)
GTN leads to
facilitation of the
temporal processing
of the nociceptive
inputs at spinal
level, without a
notable placebo
effect
Schytz
Headache:
et al. [31]
9 (75%) after
carbachol vs.
3 (25%) after
placebo
Schytz
Marked placebo
Headache:
response precluded et al. [30]
15 (83%)
further studies in
after
carbachol vs. carbachol
8 (44%) after
placebo
Migraine:
8 (44%) after
carbachol vs.
6 (33%) after
placebo
Hansen
Side effects
Headache:
et al. [11]
7 (58%) after Heat sensation
VIP: 10/12
VIP vs. 3
(25%) after Placebo 3/12
placebo
6
Placebo Response in Human Models of Headache
69
Table 6.1 (continued)
Compound
Vasoactive
intestinal
peptide (VIP)
PDE 3
(Cilostazol)
Design
Randomized,
double-blind,
placebo-
controlled
crossover study
Randomized,
double-blind,
placebo-
controlled
crossover study
Study
population
Migraine
n = 12
Controls
n = 12
PDE 3
(Cilostazol)
Migraine
Randomized,
n = 14
double-blind,
placebo-
controlled
crossover study
PDE 5
(Sildenafil)
Controls
Randomized,
n = 10
double-blind,
placebo-
controlled
crossover study
PDE 5
(Sildenafil)
Migraine
Randomized,
n = 12
double-blind,
placebo-
controlled
crossover study
Calcitonin
gene-related
peptide
(CGRP)
Migraine
Randomized,
n = 12
double-blind,
placebo-
controlled
crossover study
Headache
reported
(active vs.
placebo)
Headache:
10 (83%)
after VIP vs.
4 (33%) after
placebo
Headache:
11 (92%)
after
cilostazol vs.
3 (25%) after
placebo
Migraine:
12 (86%)
after
cilostazol vs.
2 (14%) after
placebo
Comment
Side effects
Heat sensation
VIP: 12/12
Placebo 3/12
Patients reported
that the attacks
mimicked their
usual migraine
attacks and that
cilostazol-induced
attacks responded to
their usual migraine
treatment
Headache and
Headache:
9 (90%) after migraine caused by
sildenafil vs. sildenafil was not
3 (30%) after accompanied by
changes in plasma
placebo
levels of CGRP,
cGMP, and cAMP
compared to placebo
[17]
Delayed migraine-
Migraine:
10/12 (83%) like headache
without initial
after
sildenafil vs. dilatation of the
middle cerebral
2/12 (16%)
after placebo artery
Headache:
12 (100%)
after CGRP
vs. 1 (8%)
after placebo
Migraine:
3 (33%) after
CGRP vs. 0
(0%) after
placebo
Ref.
Rahmann
et al. [27]
Birk et al.
[7]
Guo et al.
[9]
Kruuse
et al. [19]
Kruuse
et al. [18]
Lassen
et al. [20]
(continued)
70
J. M. Hansen and M. Ashina
Table 6.1 (continued)
Compound
Hypoxia
Study
Design
population
Migraine
Randomized,
n = 15
double-blind,
sham-
controlled
crossover study
Pituitary
adenylate
cyclase-
activating
polypeptide
(PACAP-38)
Controls
Randomized,
n = 12
double-blind,
placebo-
controlled
crossover study
Pituitary
adenylate
cyclase-
activating
polypeptide
(PACAP-38)
Migraine
Randomized,
n = 12
double-blind,
placebo-
controlled
crossover study
Prostaglandin
I2
Randomized,
double-blind,
placebo-
controlled
crossover study
Randomized,
double-blind,
placebo-
controlled
crossover study
Prostaglandin
I2
Controls
n = 12
Migraine
n = 12
Headache
reported
(active vs.
placebo)
Migraine:
8 (53%)
during
hypoxia vs. 1
(7%) during
sham
Comment
Two patients
experienced
migraine without
aura-like attacks 5
and 8 h after
initiation of sham
procedure
Side effects:
Headache:
Heat sensation
12 (100%)
after PACAP PACAP: 11/12
vs. 2 (17%) Placebo 4/12
after placebo
Migraine:
2 (17%) after
PACAP vs. 0
(0%) after
placebo
PACAP38 infusion
Headache:
caused headache,
11 (92%)
after PACAP vasodilatation, and
vs. 3 (25%) delayed migraine-
after placebo like attacks
Heat sensation
Migraine:
7 (58%) after PACAP: 12/12
PACAP vs. 0 Placebo 0/12
(0%) after
placebo
Area under the
Headache:
headache curve
11 (92%)
after PGI(2) larger after PGI2
than after placebo
vs. 0 after
placebo
Area under the
Headache:
headache curve
12 (100%)
after PGI(2) larger after PGI2
vs. 3 (25%) than after placebo
after placebo
Migraine:
6 (50%) after
PGI(2) vs. 2
(17%) after
placebo
Ref.
Arngrim
et al. [2]
Schytz
et al. [29]
Schytz
et al. [29]
Wienecke
et al. [38]
Wienecke
et al. [37]
6
Placebo Response in Human Models of Headache
71
Table 6.1 (continued)
Compound
Prostaglandin
E2
Prostaglandin
E2
6.5
Design
Randomized,
double-blind,
placebo-
controlled
crossover study
Randomized,
double-blind,
placebo-
controlled
crossover study
Study
population
Controls
n = 11
Migraine
n = 12
Headache
reported
(active vs.
placebo)
Headache:
11 (100%)
after PGE(2)
vs. 0 after
placebo
Migraine:
9 (75%) after
PGE(2) vs. 0
after placebo
Comment
Area under the
headache curve
larger after PGE2
than after placebo
Ref.
Wienecke
et al. [39]
Antonova
Migraine-like
attacks during, and et al. [1]
immediately after,
the PGE(2) infusion
contrast with those
found in previous
provocation studies
revention of Experimentally Induced Headache
P
and Migraine
Tvedskov and colleagues conducted two randomized placebo-controlled crossover
studies and found that valproate [35] and propranolol [36] had no effect on GTN-
induced headache and migraine. The ineffectiveness of a widely used migraine prophylactics limits the usefulness of the model and must be considered in future
testing of new migraine prophylactic and acute drugs [4].
Placebo response rate for headache relief in migraine trials is considerable [21]
but varies considerably from 6% [15] to 47% [8], with a reported mean of 29% in a
meta-analysis of 98 studies [22]. This observation underscores the importance of
including an adequate control group and blinding in all clinical trials of interventions for migraine.
6.6
Can the Placebo Response Be Mitigated?
In a large Cochrane review of placebo interventions, the authors concluded that
there is no evidence that placebo interventions in general have clinically important
effects. They also suggested that placebo interventions can influence patient-
reported outcomes, especially pain and nausea, though it is difficult to distinguish
patient-reported effects of placebo from biased reporting. Variations in the effect of
placebo were partly explained by variations in how trials were conducted and how
patients were informed [13].
72
J. M. Hansen and M. Ashina
This was also the subject for an elegant study that examined whether positive
information about active medication was a contributing factor in successful migraine
treatment [16]. In six subsequent migraine attacks, migraine patients were given
either placebo or active treatment, administered under three information conditions
ranging from negative to neutral to positive. Treatment order was randomized.
Active treatment was superior to placebo, and the efficacy of open-label placebo
was superior to that of no treatment. Relative to no treatment, the placebo, under
each information condition, accounted for more than 50% of the drug effect.
Increasing “positive” information incrementally boosted the efficacy of both placebo and medication during migraine attacks. The benefits of placebo persisted even
if placebo was honestly described.
6.7
Conclusion and Implications for Study Design
Human experimental migraine studies are in many ways not different from migraine
treatment trials: An investigator is testing the effect of an experimental intervention.
As such, it is to be expected that this intervention will yield some placebo responses.
Placebo responses are indeed found in experimental human migraine studies: We
report a modest placebo effect. With the use of an appropriate control intervention,
this effect may be mitigated and taken into account. We suggest that care should be
taken to minimize unspecific effects including placebo by standardizing experimental conditions.
References
1. Antonova M, Wienecke T, Olesen J, Ashina M. Prostaglandin E(2) induces immediate
migraine-like attack in migraine patients without aura. Cephalalgia. 2012;32:822–33.
2. Arngrim N, Schytz HW, Britze J, Amin FM, Vestergaard MB, Hougaard A, Wolfram F, de
Koning PJ, Olsen KS, Secher NH, Larsson HB, Olesen J, Ashina M. Migraine induced by
hypoxia: an MRI spectroscopy and angiography study. Brain. 2016;139:723–37.
3. Asghar MS, Hansen AE, Kapijimpanga T, van der Geest RJ, van der Koning P, Larsson HB,
Olesen J, Ashina M. Dilation by CGRP of middle meningeal artery and reversal by sumatriptan
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Chapter 7
Nocebo in Headache Treatment
Christina Deligianni and Dimos D. Mitsikostas
7.1
Introduction
Among primary headache disorders, migraine and tension-type headache (TTH)
are the most frequent with 1 year prevalence of 35 and 38%, respectively [36],
affecting 1.04 and 1.89 billion of people worldwide (the third and sixth most prevalent conditions among all medical ones, respectively) [11]. Additionally, migraine
is rating as the second leading condition causing disability after low back pain [11].
Although rare relatively (1‰), cluster headache damages severely personal life,
becoming the third most important primary headache [32]. All three conditions are
treatable, but due to safety and tolerability reasons, available preventive treatments
have often limited success, even in the right hands. One out of five patients treated
with any migraine preventive pharmaceutical agent will discontinue treatment
because of tolerability and safety reasons [13]. Moreover, adherence is poor in
migraine preventive treatments, as in most conditions requiring chronic therapy.
Only one out of four patients complies with treatment in chronic migraine when
treatment is required for 6 months, and this decreases to one out of five when treatment duration increases to 1 year [15]. Adherence seems similar among the oral
migraine preventative drugs except perhaps for amitriptyline, nortriptyline, gabapentin, and divalproex, which show significantly lower odds of adherence when
compared to topiramate; on the other hand, citalopram, fluoxetine, venlafaxine,
atenolol, and metoprolol show a trend toward an increased likelihood of adherence
compared to topiramate [15]. Other studies suggest that low adherence may be
attributed to a number of factors, including side effects and/or lack of efficacy of the
drug [16]. Previous experiences, personality, and a variety of cofactors modulate
nocebo, even the price of treatment [37, 38]. Pharmacophobia and nocebo are
C. Deligianni · D. D. Mitsikostas (*)
1st Neurology Department, Aeginition Hospital, National and Kapodistrian University of
Athens, Athens, Greece
e-mail: [email protected]
© Springer Nature Switzerland AG 2019
D. D. Mitsikostas, F. Benedetti (eds.), Placebos and Nocebos in Headaches,
Headache, https://doi.org/10.1007/978-3-030-02976-0_7
75
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C. Deligianni and D. D. Mitsikostas
additional cofactors that border adherence and treatment outcomes significantly
[21, 22]. Pharmacophobia refers to the irrational fear of medication, and nocebo
refers to the experience of adverse events related to patients’ negative expectation
that a treatment will harm most likely instead of help [21]. The frequency of adverse
events can dramatically increase by informing patients about the possible side
effects of the treatment and by negative expectations on the part of the patient [4,
5]. Patients who were told that they might experience sexual side effects after treatment with β-blocker drugs reported these symptoms between three and four times
more often than patients in a control group who were not informed about these
symptoms [34]. Nocebo varies by the condition, and it has been estimated in several
brain disorders such as migraine [1, 26], epilepsy [39, 40], fibromyalgia [25], multiple sclerosis [30], Parkinson’s disease [35], neuropathic pain [29], and restless
syndrome [33] and in patients with depression [10, 20, 27]. Within this context, all
available data on nocebo related to headache treatment is summarized and discussed in this chapter.
7.2
ethodology to Estimate Nocebos in RCTs for Primary
M
Headaches
Several researchers systematically searched for AEs in placebo arms in RCTs for
primary headache without using the term nocebo [1, 18, 31]. One important finding
was that the AEs in the placebo arms corresponded to those of the anti-migraine
medication against which the placebo was compared [1]. Additionally, those studies
showed the way to calculate nocebo in RCTs. In a following study, two specific
outcomes were used to assess nocebo in RCTs: nocebo AEs (meaning the percentage of patients treated with placebo and experienced at least one AE) and nocebo
dropouts (referring to the percentage of patients treated with placebo and discontinued treatment because of AE) [30]. These outcomes may represent the most pragmatic and clinically relevant ones for nocebo in RCTs and used in all subsequent
meta-analyses to estimate nocebo in several neurological and pain conditions [14,
20, 28, 33, 39].
7.3
Nocebos in RCTs for Primary Headaches
Reuter and colleagues [31] first investigated nocebo in RCTs for headaches and
found that up to one-third of migraineurs treated with placebo experience AEs. In
trials for symptomatic migraine treatment with triptans, one out of five placebotreated patients reported at least one adverse event. The adverse events were grouped
into three categories: migraine-related (such as nausea, photophobia, and phonophobia), drug-related (symptoms typical of the experimental compound such as
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Nocebo in Headache Treatment
77
chest pressure in response to triptans), and nonspecific or coincidental (e.g., sleep
disturbance). The adverse events 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 [31]. In another review aimed at estimating the
placebo response in migraineurs treated with oral triptans, it was found that almost
one out of four participants treated with placebo reported AEs. Fascinatingly, studies performed in North America showed a higher nocebo frequency than those conducted in Europe [18]. Amanzio and colleagues [1] published an extensive
systematic review of nocebo in clinical trials for migraine. This was the first attempt
to intensely investigate migraine-related nocebo effects. They investigated the
adverse events after placebo in RCTs testing NSAIDs, triptans, or anticonvulsants.
Their major finding was that nocebo AEs mirrored the adverse events expected of
the active medication studied precisely. For example, anorexia and memory difficulties, which are typical AEs of anticonvulsants, were present only in the placebo arm
of these trials. In other words, nocebo in migraine trials arose from patients’ distrust. This important meta-analysis aimed to investigate the mechanisms of nocebo
in particular, rather than to investigate the magnitude of nocebo in RCTs for
migraine, and migraine most likely was used as a vehicle pain condition in this
study. For instance, the investigators searched RCTs for migraine trials, both symptomatic and preventive, only if specific anti-migraine agents were tested.
Undoubtedly, the results of this meta-analysis confirmed their findings derived from
experimental human studies that expectations modulate both nocebo and placebo
(the expectation theory of placebo and nocebo) [5].
A meta-analysis of RCTs for all primary headache disorders [26], for both symptomatic and preventative treatments, including all medications used, revealed that
the nocebo AE and nocebo dropouts frequencies for symptomatic migraine treatment trials were 18.45% (95% CI 14.90–22.23%) and 0.33% (95% CI 0.19–0.53%),
respectively. In trials studying triptans exclusively, nocebo AEs 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 AEs and dropout frequencies were 19.82%
(95% CI 15.84–24.12%) and 0.33% (95% CI 0.17–0.55%). Forty-five trials for the
migraine prevention were analyzed. Nocebo AEs and nocebo dropout frequencies
were estimated to be 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 (BoTA) and
topiramate did not differ significantly except that nocebo dropouts in trials for BoTA
were significantly lower than the average for all other prophylactic anti-migraine
treatments (0.22% vs. 4.755%). In trials for TTH (only four trials were retrieved in
this meta-analysis), nocebo AEs and nocebo dropout frequencies were 23.99%
(95% CI 4.61–52.20%) and 5.44% (95% CI 1.32–12.12%). No sufficient data to
analyze trials for symptomatic treatment of TTH were found by the authors, as for
the preventive treatment of cluster headache. For symptomatic cluster headache
treatment, four trials were analyzed in this meta-analysis, and the nocebo AE was
estimated at 18.67% (95% CI 10.65–28.33%); insufficient data were gathered to
calculate the nocebo dropouts (Table 7.1) [26].
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C. Deligianni and D. D. Mitsikostas
Table 7.1 Nocebo in placebo randomized controlled studies for primary headache treatment
Condition
Migraine, symptomatic
Migraine, prevention
TTH, symptomatic
TTH, prevention
Cluster headache, symptomatic
Cluster headache, prevention
% Nocebo AEs (CI)
18.4 (14.9–22.2)
42.8 (34.7–51.4)
NA
24.0 (4.6–52.2)
NA
18.7 (1.6–28.3)
% Nocebo dropouts (CI)
0.3 (0.2–0.5)
4.7 (3.3–6.5)
NA
5.4 (1.3–12.1)
NA
NA
Nocebo AEs patients treated with placebo and experienced an adverse event, nocebo dropouts
patients treated with placebo and discontinued treatment because of adverse event; CI confidence
intervals, NA non-applicable, TTH tension-type headache [26]
Table 7.2 The Q-No questionnaire
Question
I read the summary of product characteristics (SPC) before taking a medication
I have discontinued a medication because of adverse effects in the past
I ask my physician for potential adverse effects of the medication he/she gives me
I take into account the adverse effects reported in the summary of product
characteristics (SPC) seriously
Total score
Rating
Rating: 1 = never, 5 = always; by using a cutoff at score 15, the Q-No predicts nocebo with 71.7%
specificity, 67.5% sensitivity, and 42.5% positive predictive value [23]
7.4
Q-No Questionnaire
To capture patients with potential future nocebo responses, a specific self-fulfilled
questionnaire (Q-No) was evaluated with 71.7% specificity, 67.5% sensitivity, and
42.5% positive predictive value [23]. Q-No is a four-item (rating range 4–20) questionnaire addressing issues related to nocebo in outpatients seeking neurological
consultation. When the total score is higher than 15 (Table 7.2), the physician should
educate the patient for nocebo to minimize the potential patients’ negative expectations. Because several unpredictable factors may influence patients’ expectations
during medical treatment, it is difficult to guess nocebo; thus this tool may help
physicians to uncover those patients and treat them appropriately. There are several
limitations of the Q-No evaluation, however. Specificity, positive predictive value,
and reliability are relatively low. Because participants in the evaluation of Q-No
have had discussed the nocebo phenomenon with the treating neurologists, they
were partially educated; thus nocebo responses may differ in this patients’ sample
comparing to naive patients. Besides these limitations, however, Q-No may serve as
a useful tool to predict potential nocebo responses in clinical practice. Capturing
these patients and educating and treating them closely may limit nocebo and its
obvious and severe consequences in outcome [23].
7
Nocebo in Headache Treatment
Table 7.3 Nocebo adverse
events in outpatients suffering
from primary headache
disorders
79
Headache disorder
Migraine
Episodic migraine
Chronic migraine
Tension-type headache
Episodic TTH
Chronic TTH
Cluster headache
Episodic cluster headache
Chronic cluster headache
Patients scored ≥15 in Q-No (%)
217/372 (58.3)
142/220 (64.5)
75/152 (49.3)
55/107 (51.4)
16/25 (64.0)
39/82 (47.6)
19/35 (54.3)
9/14 (64.3)
10/21 (47.6)
Ref. [24]
All
58,3
64,3
Migraine Episodic
Chronic
49,3
All
51,4
TTH Episodic
64
Chronic
47,6
All
54,3
Cluster Headache Episodic
64,3
Chronic
47,6
0
17,5
35
52,5
70
patients (%) scored ≥ 15 in Q-No
Fig. 7.1 Nocebo adverse events (%) in outpatients suffering from primary headache disorders.
Patients suffering from episodic forms showed increased prevalence for potential behaviors than
those suffering from chronic forms in all three primary headache disorders (score ≥ 15 in Q-No).
ΤΤΗ tension-type headache [24]
7.5
Nocebos in Headache Outpatient Sufferers
In a clinical observational study [24], 514 outpatients suffering from several headache disorders fulfilled the Q-No, and 291 (56.6%) scored more than 15 indicating
potential nocebo behaviors (Table 7.3 and Fig. 7.1). Those who were suffering from
episodic forms of all three primary headache disorders (migraine, TTH, and cluster
headache) displayed higher risk for nocebo behaviors compared to those who were
suffering from chronic forms: two out of three patients suffering from episodic
headaches scored more than 15 in Q-No compared to one out of two patients who
are suffering from chronic subtypes. Migraineurs also showed higher risk for nocebo
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C. Deligianni and D. D. Mitsikostas
than those who were suffering from TTH (58.3% vs. 51.4%) [24]. In addition,
nocebo influenced patients’ choices for the treatment. These data indicate that
nocebo effect may worsen pain outcomes in essential proportion of headache outpatients, raising the need for better understanding the origin and the factors controlling
nocebo.
7.6
Factors Influencing Nocebos in Headaches
Multiple factors, both internal and environmental, encompassed within a clinical
encounter create a context through which patients develop negative or positive
expectancies about treatments and clinical outcomes. Nocebo arises from negative
expectancies elicited through verbal suggestion, conditioning, and/or social observation [3]. Like in other pain conditions, nocebo in headache has the potential to
significantly influence pain pathways by triggering physiological changes that could
consequently affect not only pain perception but also pharmacological efficacy and
clinical outcomes in the context of pain management [8]. Human studies showed
that nocebo effects can be effectively minimized by positive expectation induction
and can even turn into placebo effects [2]. In Table 7.4 factors controlling nocebo are
listed. It has been shown that pretrial verbal suggestion directly changes the patients’
expectations [4]; thus close follow-up and patient education may limit nocebo [21].
These influences and many others unpredictable like social media or the Internet
information cannot be detected. Instead an individual’s negative expectation originating from internal psychological structures could be predicted. A previous experience of drug-related AEs and/or failed interventions are stable factors contributing
to nocebo [9, 21, 22]. Whether these previously experienced AEs were or not related
to nocebo may not change the risk for future nocebo responses. However, a negative
patient–doctor communication facilitates nocebo [12]. Additionally, affective and
cognitive traits could be important as well. Some personality traits and psychological factors, such as anxiety, harm avoidance and persistence, pessimism, and fear of
Table 7.4 Factors influencing nocebo
Modifiable
Patient’s expectations
Patient’s education
Pre-treatment verbal suggestions
Speed of treatment titration
Safety profile of treatment
Patient–doctor relation/communication
Close follow-up
Affective and cognitive traits
The appearance of medical devices
Pharmacophobia
Non-modifiable
Previous negative experiences
Personality
Cultural factors
Drug-related adverse events
Social media and the Internet information
Gender
Treatment price
Generic formulations
Age
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Nocebo in Headache Treatment
81
pain, may influence the responsiveness to nocebo [2]. Finally, there is data indicating that treatment price and gender may influence nocebo responses in human studies, women being linked to conditioning rather than to expectancy and men the
opposite, but this finding needs to be confirmed clinically [17, 37]. By applying the
Q-No in patients prior to consultation (e.g., in the waiting room), a physician treating headache patients can easily be informed for potential nocebo behaviors and
load specific and tailored approaches to limit them (see below).
7.7
Management of Nocebos in Clinical Practice
Not only physicians but also nurses, other health-care professionals, and allied health
services should be aware of their responsibility to avoid and reduce nocebo effects and
the detrimental consequences of these effects, from diagnosis to therapy to prognosis
[6]. The benefit of taking a medication (“this drug will reduce your migraine days from
8 you have now to 3 per month”) should always be included in patient information
about newly prescribed drugs. Alternatively, a physician may explain the treatment
benefit by using only positive outcomes, like “this drug will increase your headachefree days from 22 to 27 per month.” Drug treatment for primary headache disorders
can be started at a very low dose (half or one-quarter the recommended starting dose).
The potential advantages of this approach include a further decrease in the risk of
adverse events, enhanced patient participation, improved adherence, and reduced
long-term costs [19]. “Start low, go slow” approach when starting a new medication
also improves adherence in nocebo patients by minimizing the risk of AEs. Most
importantly physicians should use an authentic and empathic communication style,
providing adequate information regarding disease, diagnoses, treatments, and AEs.
Close follow-up and discussing patients’ anxieties, concerns, and expectations are
always required. Occasionally, it is very difficult to convince the patient, but it helps
much when the physician explains the origin and the prevalence of nocebo. Informing
the patient that he/she is not the only one who has this reaction (in headaches almost
half of patients report nocebo AEs) and understanding the brain mechanisms underlying nocebo make the patient feel comfortable (Box 7.1) [6, 9, 12, 21, 22].
Box 7.1 Tips to Limit Nocebo
Apply the Q-No questionnaire before consultation; if your patient scores ≥15,
put on the following:
• During the interview try to maximize placebo and minimize nocebo by being
positive, authentic, and empathic; having face contact optimizes treatment
expectation and expectation of adverse effects; ask for potential nocebo risk
factors (e.g., previous experiences of drug-related AEs; use of complementary/
alternative medicine treatments); explain the origin, the brain mechanisms,
and the prevalence of nocebo in general and in headaches in particular.
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C. Deligianni and D. D. Mitsikostas
• When prescribing a new medical treatment, select the ones with the better
safety profile, instead of those with the better efficacy; use positive outcomes to explain their benefits (e.g., “this treatment will increase your
headache-free days from 22 to 27 per month”); inform the patient only for
the most frequent potential adverse events always in relation to the treatment benefit; ask the patient to participate in the treatment choice by presenting different options; “start low, go slow” with new medication
treatment titration.
• Close follow-up to monitor potential adverse events (ask for a telephone
follow-up a month after).
• Be tolerant and persistent, because nocebo patients require more attention
and time to convince adhering than other patients do.
7.8
Conclusions
Collectively, nocebo effects could substantially reduce treatment efficacy and tolerability, and therefore patients’ adherence and compliance, and could play a major role
in their withdrawal from necessary treatment. On the other hand, placebo increases
treatments’ efficacy firmly and can be triggered by positive verbal pretrial suggestions. Because both nocebo and placebo may represent two opposite pathways that
coexist in humans, it is necessary to modify them, but one cannot remove them. The
placebo phenomenon may promote appetitive and safety behaviors, while nocebo
effects may favor perceptual mechanisms that are initiated to prevent dangerous
events and negative outcomes [7]. In general, physicians treating headaches should
acknowledge nocebo as a significant cofactor for treatment adherence and failure and
plan techniques to border nocebo, such as patients’ education and close follow-up.
Pragmatic but enthusiastic presentation of treatment options increases placebo and
limits nocebo. Most headache conditions share a genetic component that no treatment
can erase. On the other hand, some headache patients avoid preventative treatment
because they believe their headaches are untreatable. To recruit those patients, a long
interview is required to explain the treatment benefits over the potential risks. Even
for the worst case, there is a treatment that could improve the patient’s life quality. The
Q-No is a useful tool to capture other nocebo cases that need special management.
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Chapter 8
Placebos and Nocebos in Migraine:
Children and Adolescents
Vanda Faria and David Borsook
8.1
Introduction
The role of placebo and nocebo in pediatrics has received relatively little attention
compared with adults [35, 74, 86]. Migraine, known to have a high placebo response
rate, especially in children [29, 79], is an ideal disease state to study both the placebo and nocebo phenomena. While the specific pathophysiology of the disease is
still unknown, migraine has a number of attributes that allow a deeper investigation
of the underlying efficacy resultant from potential positive and motivational therapeutic interventions like placebo or potential harmful contributions like nocebo.
First, its intermittent nature (i.e., in episodic migraine, migraine attacks are present
for 14 or less days a month), with an apparent interictal period where patients are
overtly “normal” with no headache, provides an ideal avenue for evaluating placebo
and nocebo responses on sensory effects of the disease (i.e., headache) in patients
during a pain-free state vs. healthy controls. In other words, it allows the assessment
of the relative sensitivity of these patients to experimental manipulations such as
placebo and nocebo. For instance, patients with migraine seem to be more responsive to aversive stimuli [89] suggesting that they should be more responsive to
nocebo than healthy controls. Secondly, aside from the headache pain itself, there
are associated sensory phenomena such as photophobia, phonophobia, and osmophobia that provide further evaluator processes for placebo and nocebo measures.
Finally, episodic migraine provides a range of severity and frequency of attacks, i.e.,
from low to high, where the latter is considered to provide a brain state that is more
or less resistant to placebo responses with greater brain changes (functional and
structural) occurring in patients with the higher frequency of migraine.
V. Faria (*) · D. Borsook
Center for Pain and the Brain, Boston Children’s Hospital, Harvard Medical School,
Boston, MA, USA
e-mail: [email protected]; [email protected]
© Springer Nature Switzerland AG 2019
D. D. Mitsikostas, F. Benedetti (eds.), Placebos and Nocebos in Headaches,
Headache, https://doi.org/10.1007/978-3-030-02976-0_8
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Expectations of clinical benefit or clinical worsening seem to be central for placebo and nocebo responses [43]. Previous pharmacological and neuroimaging studies have been focusing on understanding how expectancies interact with distinct
biological systems to shape clinical responses [32]. However, the great majority of
these studies have been focusing on the beneficial aspects of expectancies, and only
recently, placebos counterpart, i.e., nocebos, started to receive wider attention from
the scientific community [45]. From a clinical perspective, both placebo and nocebo
effects play a central role into the clinical outcome. When it comes to migraine,
whereas positive expectancies of migraine treatment may lead to reductions in
migraine frequency and even complete migraine remission, negative expectations can
reduce the effectiveness of migraine therapies and even produce side effects, usually
consistent with the side effects observed with the actual migraine drug intake. Hence,
whereas placebo responses, when effectively harnessed, can be one of the best allies
of good clinical practice, nocebo responses are equally important in the optimization
of the clinical outcome. Negative expectations may trigger anxiety resulting in a cascade of adverse symptoms or experiences. Consequently, these adverse experiences
may strengthen the negative expectations, making the nocebo effect stronger [91]. It
becomes imperative to advance and to translate both the placebo and the nocebo
knowledge to improve clinical care, especially in pediatrics, where the use of alternative therapies, with no pharmacological long-term side effects, becomes even more
appealing. Moreover, the pediatric group may also provide a “naïve” population in
that their life experiences are more limited than adults and potentially more influenced by adult behavior [41, 81] (i.e., parental and clinician).
We begin this chapter by providing a brief overview of pediatric migraine, its clinical characterization, and current treatments. We then introduce placebos and nocebos
by reviewing placebo and nocebo effects in the field of pain with adults (its biological
underpinnings), in pediatric clinical trials, and in the pediatric migraine context.
Finally we provide a description of current insights into potential learning mechanisms underlying placebo and nocebo responses, its implications in the pediatric
migraine clinic, and ethics of placebo administration in the pediatric setting (i.e.,
Placebo and Nocebo Effects in the Pediatric Clinic). Our focus is on how to best optimize treatment outcomes in pediatric migraine practice in an ethical way by maximizing the placebo and minimizing the nocebo effects during therapeutic interventions.
8.2
8.2.1
Pediatric Migraine
linical Presentation of Migraine in Children
C
and Adolescents
Headache is the most common manifestation of pain in childhood occurring in up
to 75% of school-aged children [10]. Pediatric migraine is the most frequent
recurrent headache disorder occurring in up to 28% of older children [3].
Frequently starting in childhood and extending into adulthood, migraine has been
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Placebos and Nocebos in Migraine: Children and Adolescents
87
identified as the seventh highest specific cause of adult disability worldwide [26]
and is thought to be a common underdiagnosed cause behind recurrent headaches.
The estimated overall (i.e., data from 32 countries) mean prevalence of pediatric
headache is 54.4% (95% CI: 43.1–65.8) and 9.1% for pediatric migraine (95% CI:
7.1–11.1) [90].
Migraine is a complex neurological disorder affecting multiple cortical, subcortical, and brainstem areas regulating autonomic, affective, cognitive, and sensory
functions [17]. Hence, an effort to unravel the pathophysiology of migraine must
go beyond the simplistic view of “migraine generator” regions. The clinical presentation of pediatric migraine is comparable to that of adults, which is characterized
by recurrent intermittent headaches (1–14 headache days per month in episodic
migraine and >14 headache days in chronic migraine), lasting 4–72 h. However in
pediatric migraine, the attacks tend to be of shorter duration (i.e., 30 min to 48 h)
and bilateral. Besides, in children, non-headache and neurological symptoms,
characterized as migraine variants (i.e., gastrointestinal, autonomic, and non-nociceptive symptoms) [29, 40], may be more prominent than the actual headache. In
addition, migraine is associated with a number of comorbidities such as asthma,
allergies [1, 25, 52], sleep disorders [49], emotional and behavioral problems [78],
depression, and anxiety [62]. Migraine is more common in boys than in girls until
after the menarche, when it becomes more common in girls [77]. Neuroimaging
studies have started to provide some insights into developmental migraine sexrelated susceptibility and/or resilience [31]. There is no formal classification of
migraine specific to children, but the International Classification of Headache
Disorders (ICHD) from the International Headache Society (IHS) distinguishes
the variants of migraine in children (https://doi.org/10.1177/0333102413485658).
About 65–80% of the pediatric population with migraine will experience disruption of their normal life at home, in school, and in other social settings. Hence,
early recognition and successful management of the disorder becomes vital for the
affected children.
8.2.2
Treatment of Migraine in Children and Adolescents
An early diagnosis and a prompt therapy are imperative when it comes to the
success of migraine treatment. The successful management of migraine involves
recognizing the triggering factors, providing pain relief, and considering prophylaxis. It entails a multimodal or biopsychosocial approach combining abortive
and prophylactic pharmacological therapies and non-pharmacological therapies
such as behavioral and psychoeducational interventions (patient education and
lifestyle strategies) [28]. Whereas the treatment short-term goals are focused on
the symptoms (i.e., to relieve pain and nausea and to promote sleep), the longterm goals are focused on the patient’s quality of life (i.e., by reducing the frequency and severity of headaches) and on a long-term successful management of
the disorder.
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8.2.2.1
Pharmacological Therapies
When it comes to pharmacological interventions, most pediatric placebo-controlled
trials have failed to demonstrate effectiveness of drugs over placebo, mostly due to
the high placebo response rates [29, 79]. For instance, Powers et al. [66] recently
reported that a pediatric placebo-controlled trial was stopped following an interim
analysis showing no difference between amitriptyline and topiramate as compared
to placebo. Only two triptans (almotriptan and rizatriptan) have been approved by
the Food and Drug Administration (FDA) to be safe and effective for the abortive
treatment of pediatric migraine [55], and only one antiepileptic drug (topiramate)
and one antidepressant (trazodone) have been shown to be more effective than placebo when it comes to prophylactic treatments [29].
8.2.2.2
Non-pharmacological Therapies
Regarding non-pharmacological interventions, behavioral techniques such as cognitive behavioral therapy and stress management therapy have been shown to be
highly effective. In fact, stress management seems to provide a better clinical outcome than pharmacological intervention (i.e., the ß-blocker metoprolol) [71].
Complementary and alternative medicines such as acupuncture and homeopathic
interventions have also been reported to be as effective as, or even more effective
than, prophylactic pharmacological migraine treatments [24, 57]. Importantly, however, neither acupuncture nor homeopathic therapies seem to outperform placebos
in clinical trials [22, 72] suggesting that the observable therapeutic responses might
reflect the placebo effect, perhaps enhanced by different levels of elaborated rituals,
and a closer patient-practitioner interaction.
8.3
8.3.1
Placebo and Nocebo Effects
lacebo and Nocebo Analgesia: Insights from Adult
P
Studies
Even though the neurobiological mechanisms behind placebo effects have been
investigated for several conditions, analgesia is without a doubt the best-studied
placebo response [85]. Pain is a highly complex subjective experience with a vast
biological significance. The experience of pain is not linearly related to the nociceptive input; it contains both sensory and affective dimensions that are under the
influence of several factors [61]. Hence, pain experiences are mediated not only
by peripherally related bottom-up mechanisms but also via centrally related topdown processes. Psychosocial regulation of pain together with the possibility to
induce pain experimentally makes pain an excellent model for assessing placebo
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and nocebo responses. As for placebo effects, nocebo effects are best studied in
the field of pain [27]. However, the nocebo effect has been widely overlooked, and
only recently this equally important response started to gain visibility in the field.
Due to ethical constraints, it is not easy to gather empirical data to best comprehend this phenomenon. However, it has been suggested that nocebo hyperalgesia
can be considered as a stress response. Nocebo suggestions induce anxiety, which
in turn results in pain enhancement [19, 91]. Notably however, all this knowledge
comes from adult studies, and developmental differences between children and
adults (e.g., neurological, cognitive, and psychological) that might significantly
impact positive and negative analgesic responses in children haven’t been
considered.
8.3.1.1
iological Constructs (Brain Regions) of Placebo Analgesia
B
in the Developing Brain
Neuroimaging studies investigating the underlying neural mechanism of placebo
analgesia have shown the repeated involvement of brain regions including the
medial thalamus, anterior insula, dorsal anterior cingulate cortex, periaqueductal
gray, secondary somatosensory cortex, dorsal posterior insula, ventromedial prefrontal cortex, dorsolateral prefrontal cortex, lateral orbitofrontal cortex, nucleus
accumbens, ventral striatum, and rostroventral medulla [85]. Whereas some of the
regions are related to higher functions such as attention, thought, and consciousness
(e.g., prefrontal regions) and are thought to be involved in appraisal and in the generation of placebo-related expectancies (e.g., dorsolateral prefrontal cortex), other
regions are involved in sensory perception/pain intensity (e.g., S1/dorsal posterior
insula), salience (e.g., anterior insula), reward-aversion/motivational state, etc. [85].
Notably, these regions have been evaluated in adults and thus portray the neurophysiology of placebo analgesia in a mature brain. However, within a developing
brain, functional connectivity changes in childhood and adolescence [13, 73, 88].
With altered connectivity between different brain regions during development, the
placebo response may be changed just as placebos can change the brain [4]. In addition, the specific evolution of a particular brain region during development, for
example, the anterior cingulate, may alter the susceptibility to behavior [83]. Thus,
the placebo response may differ with development in childhood and adolescence
based on brain maturation. In fact, when it comes to expectancies and belief systems, children have the ability to approach a situation from an unbiased or naïve
perspective. They seem motivated to learn, have fewer prejudices and less experience, and show a less developed ability for inhibition in general [18]. A mature
prefrontal cortex, for instance, may hamper flexible thinking, due to prior experience that could affect and bias expectations. Children on the other hand have a
stronger appetitive system and weaker control system. Delayed prefrontal maturation makes children’s belief system more flexible and easier to shape [44]; hence,
they might be more open to follow suggestions from clinicians and/or parents as
compared to adults.
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8.3.2
V. Faria and D. Borsook
Placebo and Nocebo Effects in Pediatric Clinical Trials
The use of placebos in adult clinical trials has proven priceless in providing a baseline against which active new treatments are assessed. Until recently, most knowledge on pediatric pharmacological treatments has been based on evidence that
originated from adult clinical trials [76]. This, however, constitutes a major challenge for clinicians that have to prescribe safe and effective doses of therapeutic
agents in pediatric populations. Nevertheless, due to the increasing awareness that
children are not mere small adults and that developmental factors impact the pharmacokinetics and pharmacodynamics of drugs [69], FDA and NIH published, during the last decade of the past century, guidelines securing the inclusion of pediatric
groups in the study of new compounds with potential use in children [87].
Consequently, there have been an increasing number of pediatric trials testing the
superiority of active new drugs against placebos. However, as previously stated,
most of these trials are facing the challenge of high placebo response rates [36, 67,
79]. The fact that clinical relevant symptom improvements are observed after placebo administration poses major methodological difficulties for pediatric trials, as
significant differential outcomes between active interventions and placebo become
harder to detect.
As placebos, nocebos are seen as a significant burden in clinical trials. Nocebo
effects can be so significant that patients eventually drop out of the study [45]. In the
pediatric field, when comparing the frequency of adverse events between active
treatments and placebo treatments in clinical trials of depression, no differences
were found between both arms suggesting a considerable nocebo effect [68].
Importantly, as reported above, these adverse responses are commonly related not
only with high rates of dropouts but also with difficulty in assessing the efficacy and
the safety profile of drugs in clinical trials [45]. Negative expectations substantially
limit treatment’s improvement, not only by increasing the magnitude of adverse
events but also by decreasing the impact of improvement itself, or even by abolishing the beneficial drug effects [11, 33]. Regarding the experienced side effects, they
are usually consistent with the effects experienced with the actual drug being tested,
i.e., the adverse events expected by the patients and their physicians [50]. However,
it is not always easy to disentangle nocebo effects from real drug side effects, but it
is important to bear in mind that patients’ treatment expectations can have both
positive (placebo) and negative consequences (nocebo) when evaluating the outcomes of the trials.
8.3.3
Pediatric Placebo Analgesia in Migraine
The failure of pediatric pharmacological trials together with the success of nonpharmacological interventions highlights the importance of placebo in the management of headaches in children. In migraine trials, whereas placebo response rates
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Placebos and Nocebos in Migraine: Children and Adolescents
91
have been estimated to be around 35% in adults, pediatric trials have reported
response rates around 50% or higher [54]. Placebo analgesia seems to be an even a
greater burden for pediatric trials than for adult trials [79]. Studies suggest that placebo response rates are significantly more marked in children as compared to adults
across conditions [86]. Age seems to play a role in placebo responsivity with higher
placebo response rates among younger children [59]. There seems to be an inverse
relationship between age and placebo response [46]. Something happens in the
developmental process that makes placebo response decline and drug response
increase.
From a clinical perspective, especially in pediatrics, one cannot ignore the fact
that migraine symptoms significantly improve after placebo therapy in more than
half of the children [54]. Placebo pills have been reported to decrease the average
occurrence of headaches to fewer than three a month from a starting point of nearly
six a month [29]. Moreover, it has been suggested that placebo interventions result
in 32% of pediatric complete relief [39]. As reported above, however, it is important
to understand that placebos can also result in clinically negative effects. Hence, the
focus should be in understanding the mechanism behind successful pediatric placebo interventions to maximize the placebo benefits and minimize the nocebo
effects in the migraine clinic.
8.4
Placebo and Nocebo Effects in the Pediatric Clinic
8.4.1
ossible Mechanisms Underlying Placebo and Nocebo
P
Responses
Different forms of learning seem to underlie both placebo and the nocebo responses.
Verbally induced suggestions, conditioning, and modeling can be seen as vehicles
through which either positive (placebo) or negative (nocebo) expectations are
acquired.
8.4.1.1
Verbally Induced Suggestions
Verbally induced suggestions can influence the clinical experience positively or
negatively [2]. Regarding the experience of pain, when participants are directed
toward the analgesic properties of a treatment, analgesia is perceived, but when
participants are alerted to the hyperalgesic effects of a treatment, pain is perceived
[21]. The power of verbally induced suggestions has also been investigated in children [92]. Moreover, verbally induced expectations of no improvement (i.e., expecting a placebo pill when an active drug is given) may significantly reduce or abolish
the beneficial effect of the actual drug [33]. Hence, the same way that positive verbal suggestions produce beneficial effects, negative verbal suggestions may produce
harmful effects or disrupt the therapeutical beneficial effects.
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8.4.1.2
V. Faria and D. Borsook
Conditioning
With regard to conditioning, past experiences of pharmacological and non-pharmacological treatments create subsequent placebo and nocebo responses depending on
the positive or negative effects of the treatment. For instance, in a pediatric study of
ADHD, children responded well to half their regular medication dose but only when
given together with a placebo. Hence, pairing a conditioned stimulus, i.e., placebo
pill, with the active drug resulted in conditioned placebo responses that allowed
children with ADHD to be treated effectively with a lower dose of medication [7].
Hence, placebo substitution may be a promising way to harness the placebo effect
in the clinic. According to conditioning, placebo effects can be elicited on the basis
of a planned sequence of drug and conditioned stimuli. Importantly, however, conditioned placebo effects may also mimic the drug side effects i.e., nocebo effect
[15], so it becomes important to be aware of this phenomenon to emphasize the
beneficial aspects of the treatment in order to improve treatment outcomes in the
clinic.
8.4.1.3
Modeling
Modeling, or observing, and interacting with others also plays an important role in
the formation of both placebo and nocebo responses. Observing a beneficial treatment in another person elicits a stable placebo analgesia [20]. Importantly, the effect
size of observationally induced placebo analgesic (live or video) responses is comparable to those induced via a conditioning schedule [48]. Notably, it seems that
observation carries potential cues to induce expectations of benefit and activate specific mechanisms independently of the social interactions [48]. The information
drawn from modeling may create a self-projection into the future outcome increasing the expectation of analgesia or hyperalgesia, since the effects of observation
apply to nocebo effect as well [84]. Importantly, in modeling, responses are elicited
without direct experience, and these are essential aspects in the optimization of
learning in general but especially in children.
8.4.2
Implications for Pediatric Migraine Treatment
As noted above particular elements present themselves to enhance the placebo or
nocebo effects during every clinical encounter. In pediatric migraine clinic, where
placebo responses are particularly high [54, 79], awareness of the potential benefits
of successfully harnessing these effects can lead to the optimization of the context
surrounding the patient, in order to maximize the placebo component and minimize
the nocebo component which can be crucial in migraine therapeutic outcomes.
Knowledge of placebo and nocebo mechanisms can best be applied in pediatric
migraine practice to enhance the positive aspects and diminish the negative aspects
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93
of the patient-provider interaction to provide the additional therapeutic benefit and
to avoid unhelpful characteristics in order to optimize the treatment outcome.
Parent-child interactions are also critical in maintaining a positive process [12, 14,
35], so it becomes vital to educate the parents about the potential benefit and harm
of these effects.
8.4.2.1
Enhancing Effects in the Clinic
Since migraine is often triggered and/or aggravated by external factors such as anxiety and stress [14], it becomes crucial, in the clinical setting, to recognize and target
the child’s individual needs, beliefs, and surroundings. During the doctor-patient
encounter, the physician and the therapy are seen as possible rewards with the
potential to suppress the discomfort caused by migraine. Within the therapeutic
encounter, the physician must recognize and take the most of its role as being an
integral part of the cure. The doctor-patient interaction is crucial for increasing
treatment compliance and facilitating learning of new healthy behaviors [6] that
might play an important role in preventive migraine attacks.
Enhancing placebo effects in the pediatric migraine clinic may be considered as
optimizing the “ecosystem.” In a therapeutical encounter, the treatment interaction
is rather complex, and nowadays we have not yet reached an optimal manner of
providing treatments in an environment that may enhance both positive and motivational cognitive processes. The ecosystem may be considered in a number of
domains that are interconnected including:
(a) Clinic Design: Well-designed architecture can prove a compelling, exciting,
and “special place” to be. This has been an approach in Maggie’s Centers where
“uplifting buildings [[read ‘clinics’]] benefit both body and soul”
(www.e-architect.co.uk). The idea that placebo processes may be influenced by
the physical environment has not been fully evaluated and implemented in the
clinic. Just as social and cultural backgrounds may provide a bio-genomic basis
for placebo responsivity (see [9, 37, 80]), the design of a clinic—its level of
serenity, beauty, interactivity, and comfortability—may all contribute to the
“special nature” of the place of treatment intervention [16]. The issue is to
transform the treatment environment into a place that may further enhance the
subtle and not so subtle contributions to potentiate placebo responsivity.
(b) Behavioral Sciences: The need to introduce more robust processes that encompass the science behind the process of altering the brain to produce positive
thoughts. The complexities of adding behavioral processes such as utilization of
non-noxious perception [38] may contribute to alterations of attention and
expectation [30]. Thus targeting processes that involve specific brain regions
(e.g., prefrontal—parietal or temporal pole regions) through specific processes
(akin to exercise for motor strength or sensorimotor integration) (ref) or cognitive behavioral therapy (CBT [44, 64]) need to be further evaluated and
developed.
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(c) Virtual Reality: Virtual reality can help with many aspects of the migraine disease and help mitigate associated fears and enhance the overall clinical condition [60]. Live brain training with automated feedback using fNIRS/EEG
systems may become commonplace in the clinic to train the brain.
(d) Communication: The role of verbal and other forms of communication in the
clinic has been termed the “silent healer” [5, 8]. It is well known that specific
aspects of the doctor-patient communication influence patients’ well-being
such as treatment satisfaction, adherence to treatment, coping with the disease,
and ultimately quality of life and state of health [5, 8, 82]. To improve the state
of health or the therapeutic outcome, physicians are advised to deliver positive,
motivational, and understandable information, reaching both the child and the
parents. When it comes to providing information about the possible side effects
of the chosen therapy, physicians should focus on minimizing the negative
expectancies, i.e., nocebo effects, and the emphasis should be on the reasons
why the treatment was chosen. Involving the patient in the therapeutical choices
(i.e., patient-centered care) increases patients’ self-confidence and empowers
them, which in turn may result in a better treatment adherence and improved
healthcare outcomes (see [53, 63]). Empathy has the potential to set in motion
psychological mechanisms that optimize the placebo response. A strong doctorpatient interaction based on care and interest might double the therapeutic
response [52].
(e) Ongoing Interactions Through Social Media: The placebo effect has been getting more effective in clinical trials. A suggested reason or this relates to
improved access to information for the general public. Recent evaluation of
social media (e.g., Facebook) has been purported to be a process that may
enhance the placebo effect (https://www.lodestonelogic.com); however this
would need to be performed in a more targeted manner through clinics or support groups.
Placebo responses are integral elements of any therapeutic intervention, which
validates the significance of contextual and psychological factors in the healing
process. The placebo effect can be of service to physicians in many clinical situations; hence, it should not be denied its rightful place in the pediatric clinic.
8.4.2.2
Enhancing Effects with Parental Interactions
Migraine may be a difficult condition that may produce changes in children’s behavior that may be negatively or positively enhanced by their parents. It may create a
functionally disabling negative feedback process (“social nocebo”) [7, 84]. Parentchild interactions have profound effects on individual behavior including pain [65,
75]. In the pediatric clinic, the need for parental support for noninvasive interventions and minimal risk interventions is very important. Parents are intrinsically
motivated in the advancement of pediatric care and may display an emotional
response when they think that the treatment is beneficial even in the absence of any
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Placebos and Nocebos in Migraine: Children and Adolescents
95
therapeutical benefit. This psychological benefit to parents (i.e., relief from worry)
is called placebo by proxy [42]. Importantly, placebo by proxy and the placebo
effect may interact to create a positive or a negative outcome [42]. For example, if
parents feel empowered and optimistic about the treatment, there may occur a
change in the patient’s environment that can result in less stress and anxiety. Hence,
placebo by proxy may elicit changes in the patient’s psychosocial context that mediate the placebo effect and optimize the therapeutic outcome. The reverse can also
occur resulting in worsening of the environment, more anxiety and stress, and consequently poorer outcome. In fact, placebo by proxy may create a false sense that
the patient is benefitting from the treatment resulting in the prevention of a more
appropriate treatment or neglect of important symptomatology that indicates that
the patient is getting worse [42]. Hence, since placebo by proxy can interact with
the placebo effect, it can be used as a clinical tool. For that reason, clinicians should
be aware of placebo by proxy when making therapeutic decisions and involve the
parents in these decisions to boost the belief and enthusiasms for the therapy.
Importantly clinicians should also consider placebo by proxy when evaluating treatment response especially when parents are the primary source of therapeutic
feedback.
8.4.3
thics of True Placebo Administration
E
in the Pediatric Setting
Critics claim that prescribing placebo involves deception and therefore violates the
patient’s autonomy and informed consent. On the other hand, supporters argue that
the placebo response might be one of the most effective treatments available for
many chronic conditions, and that can be accomplished without deception [56]. In
pediatric populations with migraine, where there is still limited evidence supporting
the benefit of pharmacotherapies and the potential negative effects of continued
therapy on brain development are still considered a “black box,” the option of placebo therapy, shown to have high response rates, might be considered the most ethical choice.
Survey studies show that doctors are willing to take advantage of placebo
responses and prescribe placebo therapies in clinical practice [47], perhaps even
more in children. Children, however, require special considerations and parental
consent. Importantly, parents seem to consider the use of placebos acceptable in
pediatric care, but their acceptance seems to be affected by the doctors’ opinions
about the therapeutic benefits, the conditions for placebo use, safety, purity of placebos, and transparency [34]. Recent adult and pediatric trials have shown that clinically relevant placebo responses can be obtained in a nondeceptive, transparent
manner (i.e., open-label placebo) [50, 51, 70]. In fact, being transparent to children
and parents about the administration of placebo, as an adjuvant therapy for attention
deficit hyperactivity disorder, not only yielded equivalent therapeutic benefits, while
reducing the medication use, but also resulted in fewer side effects [70].
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V. Faria and D. Borsook
When it comes to headaches, studies have shown that overuse of abortive headache medication may lead to chronic daily headaches [58]. Hence, as described
above, by means of learning via classical conditioning, placebos (as conditioned
stimuli) might be alternated with the abortive headache medication (i.e., placebo
substitution) to reduce the intake of abortive medication in these children [70]. This
partial reinforcement method has been shown to produce fewer side effects without
affecting the success of the treatment. Modeling can also be used as a vehicle to
induce placebo analgesic responses in children with migraine in an ethical way. For
instance, attending meetings of support groups where children with migraine meet
other children with migraine and share experiences of how successful the therapies
worked for them.
Although our knowledge is limited by the lack of studies aimed at investigating
the placebo and nocebo effects in pediatric migraine, progress in field has the potential to provide clinicians with the tools to maximize placebo effects and minimize
nocebo effects in the clinic in an ethical way, and both doctors and parents seem
ready to move forward.
8.5
Conclusions
Despite the adverse impact of migraines on pediatric health, the current demand of
effective treatments, together with the remarkably high placebo analgesic responsivity in children, the translation and adaption of the placebo and nocebo knowledge
into the pediatric clinic of migraine is still in its infancy [35]. Migraine seems to be
an ideal disease model to evaluate pediatric placebo responses. Due to the underlying nature of expectancies of the disease (i.e., expecting for the next attack), environmental factors and psychological mechanisms may be crucial in controlling
migraine attacks [14]. Moreover, the pediatric brain is more plastic in terms of
development and perhaps more adaptive [41, 81] to placebo processes. Hence, disregarding expectancy-related tools during the therapeutic encounter can be regarded
as suboptimal care. Whereas positive expectations and beliefs lead to motivation
and the adoption of assertive beneficial therapeutical responses, negative expectancies leads to inhibition and augmented anxiety and stress that will result in poorer
therapeutical responses. By emphasizing the positive aspects of the treatment and
providing continuous support, doctors and parents will not only increase the likelihood of maximizing placebo responses but also decrease the likelihood of nocebo
responses [23]. Furthermore, there is some evidence that in adults migraine enhances
or sensitizes the brain to aversive stimuli in the interictal period, suggesting that
enhancing positive processes and removing negative ones should be a clear objective in the pediatric clinic [89].
Notably however, most of this knowledge comes from adult studies, and developmental differences between children and adults (e.g., neurological, cognitive, and
psychological) that might significantly impact pediatric positive and negative analgesic responses haven’t been considered. Hence, future empirical work should care-
8
Placebos and Nocebos in Migraine: Children and Adolescents
97
fully address these responses in the pediatric clinic to help physicians and parents to
optimize the therapeutical outcome and to provide these children with an additional
placebo benefit.
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Chapter 9
Placebos and Nocebos in Other Brain
Disorders
Panagiotis Zis
9.1
Introduction
The term placebo refers to any intervention with no therapeutic effect that is used as
a control in randomized controlled trials (RCTs). Treatment with placebo can produce a beneficial effect that cannot be attributed to the properties of the placebo
itself (since it is inactive) and must, therefore, be due to the patient’s belief about
treatment.
Respectively, nocebo refers to the phenomenon of reporting/observing adverse
events (AEs) when using a substance or treatment with no active therapeutic effect
(placebo). Nocebo is probably the result of negative expectations by patients that
medical treatment will probably harm rather than heal [17, 18]. Nocebo is associated with lower adherence to the therapeutic intervention, higher rates of treatment
withdrawal, as well as significant difficulty in assessing the efficacy and the safety
profile of a drug [1, 7]. Often, previous negative treatment experiences [2] along
with several psychological factors such as stress and anxiety [6, 9, 14] control
nocebo.
Nocebo has been studied and found to be very prevalent in various neurological
conditions, including epilepsy [33], motor neuron disease [24], multiple sclerosis
[20], headache [15, 16], neuropathic pain [21], fibromyalgia [17], diabetic peripheral neuropathy [9], Meniere’s disease [4], restless legs syndrome [25], Parkinson’s
disease [26], depression [18, 22], and Alzheimer’s disease [32]. This indicates significant implications for clinical practice related to treatment adherence and
outcomes.
In the present chapter, placebo and nocebo responses of non-traumatic brain disorders, other than headaches, are discussed. Only systematic previous and
P. Zis (*)
Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation
Trust, Sheffield, UK
© Springer Nature Switzerland AG 2019
D. D. Mitsikostas, F. Benedetti (eds.), Placebos and Nocebos in Headaches,
Headache, https://doi.org/10.1007/978-3-030-02976-0_9
103
104
P. Zis
Table 9.1 Classification of the non-traumatic brain disorders based on the ICD-10
Classification
Neoplastic
ICD-10
chapter
II
ICD-10
block(s)
C71
Psychiatric
V
F00-F99
Infectious
Degenerative
VI
G00-G09
G20-G32
Demyelinating
Episodic and paroxysmal
G35-37
G40-47
Systemic atrophies affecting the
brain
G10-G13
Vascular
I
I61-I63
Example(s)
Malignant neoplasm of the
brain
Schizophrenia (F20)
Depressive episode (F32)
Bacterial meningitis (G00)
Parkinson’s disease (G20)
Alzheimer’s disease (G30)
Multiple sclerosis (G35)
Epilepsy (G40)
Migraine (G43)
Hereditary ataxia (G11)
Motor neuron disease
(G12.2)
Intracerebral hemorrhage
(I61)
Cerebral infarction (I63)
 eta-analyses in the topic have been considered for the purposes of this chapter, as
m
such methodologies can provide the highest quality of evidence [3].
9.2
Classification of Brain Disorders
The non-traumatic brain disorders are broadly classified in demyelinating, degenerative, episodic, paroxysmal, infectious, neoplastic, vascular, systematic atrophies
affecting the brain and psychiatric [30]. Table 9.1 summarizes this classification.
Apart from headaches, published systematic reviews and meta-analyses to date are
available in depression, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, epilepsy, and motor neuron disease.
9.3
9.3.1
ynopsis of Nocebo Phenomena in Non-traumatic Brain
S
Disorders
Depression
In a meta-analysis of 21 RCTs of various antidepressants, conducted by Mitsikostas
et al. [18], the nocebo AE rate in depression was estimated to be 44.7%. The nocebo
dropout rate was estimated to be 4.5%. In that study, the difference between the
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Placebos and Nocebos in Other Brain Disorders
105
nocebo rates and the respective rates of the active drug arms (active drug AE rate
40.9% and active drug dropout rate 6.9%) was very narrow.
The univariate analysis identified three factors significantly correlating with the
dropout rate because of AEs, age, placebo response, and duration of depression; however multivariate analysis failed to identify any particular factor contributing to nocebo.
In a smaller meta-analysis [5] only of duloxetine RCTs, the nocebo AE rate was
estimated to be higher (63.9%), whereas the nocebo dropout rate was very similar
(4.7%). In that study, there was no evidence to support that reported AEs are influenced by the AEs mentioned in the clinical trial participant information and consent
forms or that reported AEs would be influenced by AE profiles of previous antidepressant medications used by these study participants. However, people who had
previously used complementary medications were more likely to report AEs [5].
9.3.2
Alzheimer’s Disease
In a meta-analysis, which included 20 RCTs and was conducted by Zis et al. [32],
the nocebo AE rate in Alzheimer’s disease (AD) was estimated to be 57.8%. The
nocebo dropout rate was estimated to be 6.6%. In that study, the difference between
the nocebo rates and the respective rates of the active drug arms (active drug AE rate
61.6% and active drug dropout rate 8.8%) was very narrow.
The univariate analysis showed that sample size, body mass index (BMI), and
Mini-Mental State Examination (MMSE) score were potential factors negatively
correlating to AEs and dropouts among the placebo-treated populations, whereas
age was a potential factor positively correlating to AEs and dropouts among the
placebo-treated populations. In addition year of publication was negatively correlating with nocebo AE rate, disease duration was positively correlating with nocebo
AE rate, and male gender was negatively correlating with nocebo dropout rate.
However, meta-regression analysis showed that only sample size was negatively
correlated with both the nocebo AEs and dropout rates.
9.3.3
Parkinson’s Disease
In a meta-analysis, which included 41 RCTs and was conducted by Stathis et al.
[26], the nocebo AE rate in Parkinson’s disease (PD) was estimated to be 64.7%.
The nocebo dropout rate was estimated to be 8.8%. In that study, the difference
between the nocebo rates and the respective rates of the active drug arms (active
drug AE rate 73.3% and active drug dropout rate 9.8%) was very narrow, showing
that nocebo is a very important confounding factor of the reported AEs in RCTs as
well as in the clinical practice when treating patients with AD. A very strong correlation was also found between the nocebo AEs and nocebo dropout rates and the
active drug AEs and active drug dropout rates, respectively.
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9.3.4
P. Zis
Multiple Sclerosis
Using a meta-analytic approach, Papadopoulos and Mitsikostas [20] estimated that
the pooled incidence of nocebo responses is 74.4% in disease-modifying treatment
(DMT) trials and 25.3% in symptomatic treatment (ST) trials in multiple sclerosis
(MS). The pooled nocebo dropout rate is 2.1% in DMT and 2.3% in ST trials.
Meta-regression analysis revealed a higher nocebo incidence in parallel design
ST studies compared to crossover ones and a higher nocebo dropout rate in phase II
ST studies compared to phase III ones. Nocebo dropout rate in DMT trials exhibited
an association with the year of study publication and the frequency of drug
administration.
9.3.5
Epilepsy
Zaccara et al. have investigated the nocebo effect by analyzing placebo-treated,
drug-resistant, focal epileptic patients in RCTs [31]. They estimated that the proportion of placebo-treated patients withdrawing because of AEs is 3.9%, and the proportion of patients with AEs is 60.3%. The drawback of this study was that the
majority of the included RCTs were studies where placebo was compared to an
active drug as an add-on treatment. Therefore, patients that were treated with placebo were already on one or more other antiepileptic drugs.
In an attempt to estimate the nocebo effect in patients not receiving any active
antiepileptic treatment, Zis et al. conducted a meta-analysis of four RCTs in refractory partial epilepsy during pre-surgical monitoring [33]. The authors reported that
the pooled estimate of the percentage of placebo-treated patients who withdrew
treatment was 76.8% and the pooled estimate of the percentage of placebo-treated
patients who withdrew treatment because of AEs related to treatment (other than
seizures, which were considered to be a disease-related event) was 3.2%. The pooled
estimate of the percentage of active drug-treated patients who withdrew treatment
was 52.1%, and the pooled estimate of the percentage of active drug-treated patients
who withdrew treatment because of AEs related to treatment was 8.3%.
9.3.6
Motor Neuron Disease
Motor neuron disease (MND) is a progressive degenerative disease, commonly
affecting both the upper and the lower motor neurons. Thus, although it is not exclusively a brain disorder, MND can affect the motor cortex.
A meta-analysis of 12 RCTs conducted by Shafiq et al. showed that approximately 8 in 10 placebo-treated patients (78.3%) report at least 1 AE, and approximately 1 in 12 placebo-treated patients discontinue placebo treatment because of
9
Placebos and Nocebos in Other Brain Disorders
107
AEs other than death (8.4%). The respective rates for the active treatment groups are
84.7% and 12.6%. The fact that these differences are very narrow demonstrates that
nocebo is an important confounding factor of reported AEs in MND trials [24].
9.4
Placebo Effects in Non-traumatic Brain Disorders
In the majority of RCTs for the treatment of major depressive disorder, at least one
third of patients assigned to the placebo arm show clinically significant improvement [19]. It has been found that recovery from depression in placebo groups correlates with changes in frontal and cingulate cortical activity [29], suggesting that
placebo is centrally driven. In depression, placebo and nocebo responses correlate
significantly [18]. Similarly, in Alzheimer’s disease, Zis et al. showed that the
nocebo AE incidence is positively correlated with the cognitive scores (using the
ADAS-Cog tool), meaning that the more effective the placebo is, the more AEs and
more dropouts occur [32].
In Parkinson’s disease, clinicians have been describing placebo effects in their
patients for decades [13]. Significant placebo effects have been observed in pharmacological and non-pharmacological (i.e., deep brain stimulation and stem cell
implantation) RCTs. Neuroimaging studies have demonstrated that placebos stimulate the release of dopamine in the striatum of patients with Parkinson’s disease and
can alter the activity of dopamine neurons [13].
In multiple sclerosis, it has been shown that patients on placebo show a decreased
frequency of relapses during follow-up (in relapsing remitting cases) and decreased
rate of progression of the disability (in progressive cases) compared to the pre-trial
periods [12]. Although a possible explanation for this is the fact that in some RCTs
the patients are selected based on their progression rate (selection bias) and the phenomenon of “regression toward the mean” can occur, an actual placebo effect is also
very likely [12]. Interestingly, placebo effects have also been observed in immunological responses, such as the natural killer cell activity [11]. The possible mechanism for this is unknown; however it is unlikely that a clinical improvement driven
by the placebo effect is related to the transient increase in NK cell activity [11].
In epilepsy, the placebo effect has also been observed in RCTs, as placebo interventions can reduce the seizure activity of the patients [8]. Some seizure reduction
traditionally attributed to placebo effect, however, may reflect the natural course of
the disease itself [8].
9.5
Nature of AEs Across the Brain Disorders
Table 9.2 summarizes the nature of the AEs across brain disorders other than headache, where meta-analyses have been performed to date. It is clear that across all
disorders, the nature of AEs reported in the placebo-treated subjects mirrors those
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P. Zis
Table 9.2 Adverse events (AEs) reported in placebo-treated groups (nocebo AEs) and activetreated groups across brain disorders other than headache, where available
Depression [18]
Alzheimer’s disease [32]
Parkinson’s disease [26]
Epilepsy [33]
Motor neuron disease [24]
Placebo-treated patients
Headache
Nausea
Somnolence/sedation
Diarrhea
Headache
Urinary tract infection
Nausea
Dizziness
Dyskinesia
Headache
Dizziness
Fatigue/asthenia
Respiratory disorders
Dysphagia
Active drug-treated patients
Dizziness
Somnolence/sedation
Headache
Diarrhea
Headache
Dizziness
Nausea
Dizziness
Dyskinesia
Headache
Nausea
Dizziness
Respiratory disorders
Fatigue/asthenia
Dysphagia
The three commonest AEs are mentioned in each disorder (most common on top)
reported by active drug-treated subjects, suggesting that awareness of drug side
effect profiles might have influenced patient expectations and, thus, nocebo
responses [24]. However, the inherent difficulty in attributing non-specific symptoms (i.e., headache and dizziness) has to be recognized as a potential source of bias
in these meta-analyses.
An important observation is that it can be difficult to distinguish whether AEs
arise subsequent to drug administration or as a consequence of disease worsening.
In particular, dyskinesias reported in both the placebo and the active-treated patients
with Parkinson’s disease, urinary tract infections reported in the placebo-treated
patients with Alzheimer’s disease, and all the commonest AEs reported across both
the placebo and the active-treated patients with MND may as well be part of the
disease or the disease progression. Theoretically, the only way to estimate genuine
nocebo rates would be by comparing a group of patients not treated at all with a
group of patients treated with an inactive substance (placebo). The difference of the
rates of new symptoms occurring during such a study, between the two arms, would
be the true nocebo effect. However, since there are available treatments in these
diseases, such studies are unethical and therefore unrealistic [24].
9.6
Comparison Among Brain Disorders
Although direct comparison with other neurological diseases is difficult because of
the reasons related to trial populations, primary end points, severity, progression,
and pathophysiology, it can give an overall picture of nocebo magnitude across the
various brain disorders.
9
Placebos and Nocebos in Other Brain Disorders
109
Table 9.3 Nocebo AE rates and nocebo dropout rates in all brain disorders where nocebo effect
has been studied to date
Disorder
Motor neuron disease [24]
Multiple sclerosis [20]
Disease-modifying trials
Symptomatic therapy trials
Parkinson’s disease [26]
Refractory partial epilepsy [33]
Alzheimer’s disease [32]
Depression [18]
Headache [16]
Preventative treatment
Symptomatic treatment
AE rate (%)
78.3
74.4
25.3
Dropout rate (%)
8.4
2.1
2.3
64.7
60.8
57.8
44.7
42.8
18.5
8.8
4.0
6.6
4.5
4.8
0.3
AE adverse event
Table 9.3 summarizes the nocebo AE rates and nocebo dropout rates in all neurological disorders where nocebo effect was studied, using identical methodology.
The highest nocebo dropout rate has been observed in Parkinson’s disease [26].
Human experimental evidence suggests that negative expectations could result in
motor deterioration in patients with PD [23]. PET studies showed that high placebo
responses were associated with greater dopamine (DA) and opioid activity in the
nucleus accumbens, whereas nocebo responses were associated with a deactivation
of DA and opioid release [23]. Both systems modulate a number of processes,
including the regulation of reward and affective states. Thus, increased nocebo
should be expected in PD, although DA replacement therapy results in changes in
many aspects of neural activity within the entire basal ganglia cortical networks that
are not yet fully understood [10, 27].
Not considering the nocebo dropout rate during symptomatic treatment for headache and MS, which are short-lived interventions, the lowest nocebo dropout rate
has been observed during disease-modifying treatments in multiple sclerosis [20]. A
possible explanation for this observation is that trial participants are not necessarily
representative of the general population of MS patients as the wide range of available MS treatments today have reduced the pool of untreated, potentially recruitable
patients for trials. Those MS patients who decide to participate in trials are likely to
be more motivated and committed to adhere to the treatment regime [20].
The highest nocebo AE rate has been observed in MND [24]. Although AEs that
are reported in RCTs are classified as drug-related, a potential source of bias is that
it can be difficult to distinguish whether symptoms arise subsequent to placebo
administration or as a consequence of disease worsening. Especially AEs of respiratory origin, which have been documented as drug-related in the respective RCTs,
might as well be a disease complication per se [24].
The lowest nocebo AE rate has been observed during symptomatic treatment for
headaches [16], closely followed by the nocebo AE rate during symptomatic treatment for multiple sclerosis. An interesting finding was that the nocebo AE rate
110
P. Zis
during disease-modifying treatment is almost three times higher compared to
symptomatic treatment for MS. This may reflect the fact that that meta-analysis
included RCTs of already licensed drugs for symptomatic treatment [20].
9.7
Directions for the Future
Although the main brain disorders have been studied to date (headache, Parkinson’s
disease, Alzheimer’s disease, depression, epilepsy, multiple sclerosis, and motor
neuron disease), there are still unexplored areas, which should be investigated further. These include psychiatric (i.e., schizophrenia and bipolar disorder), vascular
(i.e., acute ischemic stroke, vascular dementia), degenerative (i.e., frontotemporal
dementia, Lewy body dementia), and other systemic atrophies of the brain (i.e.,
hereditary ataxias). Studying nocebo in neoplastic and infectious brain disorders is
an unrealistic aim since there are already available treatments for such disorders,
and, therefore, conducting new RCTs with a pure placebo arm is raising ethical
issues.
The wide range of nocebo AEs and nocebo dropout rates across the disease
suggests that nocebo is a disease-specific phenomenon. Nocebo is clearly affected
by the underlying pathophysiology of the disease and the patients’ expectations
and is strongly linked to the disease’s natural history and the availability of treatments. Therefore, meta-analyses of RCT of specific medications or group of medications (i.e., antiepileptics or antidepressants) that can target different disorders
(i.e., neuropathic pain and epilepsy, neuropathic pain and depression) are of limited value.
9.8
Conclusions
Nocebo has been found to be very prevalent in various brain disorders including
headache, Parkinson’s disease, Alzheimer’s disease, depression, epilepsy, multiple
sclerosis, and motor neuron disease. There are still unexplored areas, which should
be investigated further, given the significance of nocebo.
The consequences of nocebo in clinical practice are important, as current treatments are based upon evidence confounded by the nocebo effect. The available
meta-analyses do not provide any direct evidence for nocebo in clinical practice,
but, as long as RCT findings predict the effectiveness and the safety of a treatment
in clinical practice, the post hoc safety analyses may provide important considerations relevant to daily clinical practice as well. In any case, clinicians should be
aware that drug intolerance and treatment failure might be caused by nocebo and
recruit individualized strategies to limit it.
Nocebo has, however, implications for RCT design. Modifying informed consents for the tested pharmaceutical agents to include the chance of nocebo, blinding
9 Placebos and Nocebos in Other Brain Disorders
111
the investigators to the analysis of recorded AEs, paying more attention to the AEs
reported by the participants, and requesting more detailed safety reports by the
investigators are potential interventions in future RCTs.
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Chapter 10
Implications of Placebos and Nocebos
in Clinical Research
Luana Colloca and Nathaniel Haycock
10.1
he Dilemma of Clinical Trial Designs
T
and Placebo Effects
Distinguishing placebo responses from placebo effects is the key to avoid confusion in interpreting findings and advance clinical research designs and outcomes
[21]. These terms often appear in published articles interchangeably but they do
not have the same meaning. When a drug is given, the effectiveness of a treatment
can be determined by comparing the changes observed in patients receiving the
drug (treatment response) with those receiving placebo (placebo response). The
placebo effect—effect of expectancy in clinical outcomes—is the difference
between the placebo and no-intervention arm allows scientists to account for any
changes that would have been observed without any treatment (natural history) or
through spontaneous remission, regression to mean, and the Hawthorne effect
[23]. The placebo effect describes any improvements that are over and above these
nonspecific, confounding changes that may occur in a no-intervention arm. Thus,
in order to talk about the placebo effect, we need clinical trials that include a
L. Colloca (*)
Department of Pain and Translational Symptom Science, University of Maryland School of
Nursing, Baltimore, MD, USA
Departments of Anesthesiology and Psychiatry, University of Maryland School of Medicine,
Baltimore, MD, USA
Center to Advance Chronic Pain Research, University of Maryland, Baltimore, MD, USA
Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA
e-mail: [email protected]; [email protected]
N. Haycock
Department of Pain and Translational Symptom Science, University of Maryland School of
Nursing, Baltimore, MD, USA
© Springer Nature Switzerland AG 2019
D. D. Mitsikostas, F. Benedetti (eds.), Placebos and Nocebos in Headaches,
Headache, https://doi.org/10.1007/978-3-030-02976-0_10
113
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L. Colloca and N. Haycock
no-intervention arm along with a placebo arm in order to distinguish changes seen
in an untreated group from the treated arms.
Although the no-intervention arm is one way to estimate the placebo effect, it is
often quite difficult to propose the kind of clinical trial design in which waiting list
arms are included as the control group for placebo effects. Alternative clinical trial
designs such as the sequential parallel comparison design can bring the need to
disentangle placebo effects into harmony with ethical principles of research [34].
Another approach that may help detect placebo effects in the context of clinical
trials (and practice) is a systematic assessment of participants’ expectations. There
is evidence that expectations (e.g., of pain relief) influence a variety of medical
conditions [9, 37]. For example, patients’ expectations can positively influence both
long-term mortality [8] and response to surgical interventions [7]. They can also
potentially predict long-term postoperative walking performance following hip and
knee arthroplasty [74] as well as patients’ satisfaction following total joint arthroplasty [53]. Laboratory research has demonstrated that expectations, which are
often shaped by open-hidden paradigms, can impact the response to medication
such as morphine, anxiolytic diazepam, deep brain stimulation [for a review, see
[25]], i.v. remifentanil [14], topical lidocaine/capsaicin [62], and acupuncture [51].
Therefore, it is very useful to measure expectations and related factors (e.g., credibility and perception of effectiveness).
Measures for expectations range from single questions to multi-item scales.
One common question is: “What do you expect your level of pain intensity to
be?” [75]. Questions such as this can be corroborated with other single questions dealing with credibility of the clinician and treatment, such as “How effective do you think this treatment will be?” [29]. Another important measurement
to collect is perceived effectiveness of the treatment [see, [41, 61]]. Three items
such as these are easy to administer to placebo and medication arms within
clinical trials. It remains problematic, however, to assess them in a natural history arm.
10.2
rug and Placebo Effects: Additive
D
and Interaction Effects
The relationship between drug and placebo responses (and placebo effects if the
natural history is included) is highly relevant for clinical research given that the gold
standard of efficacy in randomized clinical trials, when drug responses outperform
placebo responses, is based on the specious assumption that drug and placebo
responses are additive [see 17 for a review].
A 2 × 2 balanced placebo design with instructions about the drug (told drug versus told placebo) as one factor and actual drug (given drug versus given placebo) as
the other factor can allow to test interactions between drug and placebo responses.
This design, in combination with neuroimaging, has been helpful to explore both
additive and interaction effects [42, 76, 77].
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Implications of Placebos and Nocebos in Clinical Research
115
Both additive and interaction effects between drugs and placebo responses have
been reported. Significant fMRI activity associated with the main effect of instructions as well as an apparent interaction with treatment in the bilateral inferior frontal
gyrus and left medial frontal gyrus has been found by Kong et al. [47], who used
verbal instruction (positive instruction vs. neutral instruction) alongside acupuncture (real vs. sham).
A balanced placebo and an open-hidden design were used by Atlas et al. [6] to separate the effect of remifentanil and instruction in a pharmacokinetic model. Remifentanil
and instructions both reduced pain ratings, but the effect of remifentanil on pain reports
and fMRI activity did not interact with verbally induced changes. In contrast, the effect
of lidocaine/prilocaine on pain ratings and brain signaling in the anterior insula rACC,
the anterior insula, and the ventral striatum showed an interactive effect in a study by
Schenk et al. [69] using fMRI. The study utilized a within-subjects design and balanced placebo (received lidocaine/prilocaine versus received control cream) with an
instruction manipulation (told lidocaine/prilocaine versus told control cream). Clinical
findings have also suggested that placebo and drug effects may not be merely additive
[25]. The additive versus interactive effect may depend on the mechanisms of action of
the given treatment. Future research with in vivo receptorial radiotracers and PET
imaging techniques (e.g., PET with carfentanil radiotracers) may help illustrate this
aspect with relevant implication for clinical and translational research.
10.3
Silencing the DLPC to Reduce Placebo Effects
Placebo- and nocebo-pain signaling have been associated with brain regions such as
the thalamus, primary and secondary somatosensory cortex (S1/S2), anterior cingulate cortex (ACC), and insula [3, 64, 65]. Namely, reduced activity has been documented in the ACC, insula, and thalamus [32, 66, 78]. Further, a meta-analysis of
fMRI placebo and pain studies has identified the insula, dorsal ACC, thalamus,
amygdala, and right lateral prefrontal cortex as less active during placebo analgesic
effects [5] with a few trends in opposite directions [46]. The dorsolateral prefrontal
cortex (DLPFC) has been linked to the generation and maintenance of placebo analgesia over time [48, 52, 78, 80, 82]. Anticipation of placebo analgesia seen during
fMRI in the DLPFC, which is involved in emotion regulation [56], working memory [63], and cognitive control [54], correlates with the magnitude of individual
placebo effects [52, 78].
Evidence of the role of the DLPFC also stems from experiments using transcranial magnetic stimulation (TMS) to momentarily silence the function of left and
right DLPFC [48] and from a study with impairment of the DLPFC in patients with
Alzheimer’s disease that had loss of prefrontal executive functions [13]. Importantly,
these studies suggest that it is potentially feasible to modulate placebo and nocebo
effects by changing the transient excitability of the rDLPFC using tDCS [31] and
TMS. This approach can be of help to advance research on treatment efficacy since
silencing the DLPFC can minimize placebo effects.
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10.4
L. Colloca and N. Haycock
he Inner Pharmacy: Potentials for Future
T
Biomarkers?
Studies suggest that distinct systems, namely, the dopamine, opioid, serotonin,
endocannabinoid, oxytocin, vasopressin, and cholecystokinin systems, influence
placebo and nocebo effects.
The most robust and well-established notion is that the opioid system is heavily
involved in the formation of placebo analgesic effects [1, 32, 50, 58].
Pioneering studies have demonstrated that placebo analgesia is antagonized by the
opioid antagonist naloxone [1, 32, 50]. Functional coupling of the rostral ACC (rACC)
and the periaqueductal gray (PAG) (Eippert, Bingel et al. 2009) was reduced when
naloxone (0.15 mg/kg) was administered before the test phase of a study with a classical conditioning paradigm using placebo. Opioid signaling has been well-documented with in vivo human PET studies and the μ-opioid receptor-selective radiotracer
[11C]carfentanil studies [57, 61, 70, 79, 82]. The activation of opioid neurotransmission has been explored along with the dopaminergic system during a placebo administration using carbon 11 [11C]-labeled raclopride (and [11C] carfentanil) in the PET
[70]. Despite negative results in shaping placebo analgesia using dopamine antagonist
haloperidol (2 mg) and the agonist levodopa/carbidopa (100/25 mg) to test the
involvement of dopamine [71], dopaminergic activation prevailed in the nucleus
accumbens and accounted for 25% of the variance in placebo responders and nonresponders [70]. The concept of placebo responders and nonresponders may sound controversial (e.g., is a person a responder to a variety of treatments and manipulations);
however being able to split study participants into responders and nonresponders has
advantages for describing behavioral, objective, and clinical phenotypes.
Recently, the CB1 receptor antagonist, rimonabant, has been used to block conditioned analgesic effects when non-opioid pharmacological conditioning with the
nonsteroidal anti-inflammatory drug (NSAID) ketorolac is performed [11], which
suggests an involvement of the cannabinoid system. By blocking the CCK A and B
receptors with the nonselective A/B receptor antagonist proglumide, placebo analgesia can be enhanced [10] probably by reversing nocebo-induced hyperalgesia [12].
The concept of enhancing placebo effects opens up new approaches that leverage
the use of agonists. Oxytocin agonists given intranasally enhanced placebo analgesia in men [43], and a nonselective vasopressin agonist for both Avp1a and Avp1b
receptors enhanced placebo effects in women [27]. Avp1a and Avp1b vasopressin
receptors largely expressed within the central nervous system regulate social
behaviors, stress, conciliatory behaviors [35, 68], and social communication

responses [72, 73].
Pharmacological studies indicate the existence of a sort of “inner pharmacy” that
is in turn activated to trigger placebo and nocebo effects. Future efforts should be
made to understand the contribution of specific receptor expressions and functions
within each system using selective antagonists and agonists and potential biomarkers. This knowledge is guiding research on the role of distinct genetic variants (see
next section).
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Implications of Placebos and Nocebos in Clinical Research
10.5
117
I s There a Genetic Biomarker of Placebo Analgesic
Effects?
Emerging studies on “the placebome,” or the genetic variants that influence the
placebo effect [18, 40], promise to increase our understanding of the mechanisms
underlying placebo analgesia and nocebo hyperalgesia and potentially help advance
clinical research. In fact, understanding how specific genetic variants influence the
placebo effect may allow clinical researchers to tailor treatments and study design
(e.g., randomized clinical trials) to individuals to maximize outcomes and to disentangle treatment effects from placebo effects.
Namely, results from studies relating SNPs of the catechol-O-methyltransferase
(COMT) gene [39, 81], the monoamine oxidase A (MAO-A) X-linked gene [49], the
dopamine beta-hydroxylase (DBH) gene [4], and the brain-derived neurotrophic
factor (BDNF) gene [60] provide evidence that polymorphisms which reduce dopaminergic activity may be linked with decreased placebo response. Genetic variants
that affect dopamine pathways appear to affect the placebo effect and may eventually serve as biomarkers to differentiate placebo responders from nonresponders.
Serotoninergic pathway genes (e.g., TPH2, 5-HTTLPR, 5-hydroxytryptamine transporter SLC6A4 SNP rs4251417, HTR2A SNPs rs2296972 and rs622337) may also
be involved in placebo analgesia [33, 36], although further research is needed to
provide conclusive evidence.
In addition, studies by Pecina and colleagues on analgesia [59] suggest that
genes involved in the cannabinoid and opioid systems may be two of the strongest
mediators of placebo responses and effects. The investigators found that the magnitude of placebo analgesia and improved mood was greatest for individuals homozygous for the common Pro129/Pro129 genotype of the fatty acid amide hydrolase
(FAAH) gene and directly linked the opioid system with the cannabinoid system in
the context of placebo analgesia suggesting that different systems may play a role
when a placebo analgesic effect is observed.
So far, the strongest evidence linking genetic variants with the placebo effect
comes from studies of opioidergic pathways and placebo analgesia. For example, aspartic acid (G) allele carriers for the rs1799971 functional polymorphism
in the μ-opioid receptor gene (OPRM1) showed reduced opioid receptor expression, function, and density as well as lower placebo effects, in the nucleus
accumbens during placebo analgesia [58]. In that same study, using positron
emission tomography (PET) and selective radiotracers to label μ-opioid and
dopamine receptors (D2/D3), Pecina et al. found that AA homozygotes had
greater baseline availability of μ-opioid receptors than G allele carriers in the
anterior insula, amygdala, nucleus accumbens, thalamus, and brainstem.
Interestingly, G allele carriers demonstrated higher NEO-Neuroticism personality scores indicating that exploring psychological traits along with genetic variants may help identify critical phenotypes of placebo responders and
nonresponders [57]. Clearly, variation in OPRM1 is involved with individual
differences in response to pain and placebo.
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L. Colloca and N. Haycock
Despite these results, the existence of many mechanisms underlying placebo
effects suggests that it is unlikely that single polymorphisms can, by themselves,
explain why placebo analgesia and hyperalgesia occur. However, these correlations
do promise to uncover a set of common alleles that may interact to influence complex traits related to placebo effects.
10.6
atient-Doctor Communication and Nocebo Effects:
P
A Self-Fulfilling Prophecy
In clinical research, nonspecific symptoms and complaints in patient populations,
medication nonadherence, and need for additional drug prescriptions are often
related to nocebo effects. For example, the mere mention of headaches as a common
side effect during the informed consent process of studies on antidepressants and
other medications can increase the likelihood that headaches are experienced during
the study [15, 19, 20, 45].
Informing study participants about the occurrence of adverse effects leads to
withdrawal from the study. For example, mentioning gastrointestinal side effects
during the consent process in a randomized, double-blind, placebo-controlled trial
that examined the effects of either aspirin, sulfinpyrazone, or both drugs for the
treatment of unstable angina pectoris induced a sixfold increase of gastrointestinal
symptoms and elicited consequent patient-initiated cessation of therapies [55].
Discontinuation and lack of adherence to statin drugs have been also reported in
population-based studies. In statin trials performed from 1994 to 2003, placebo
arms showed a variety of symptoms including (but not limited to) headache (0.2–
2.7%) and abdominal pain (0.9–3.9%). These adverse events were even higher in
the general population when statins moved from phase III to phase IV [67]. The
large lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial
recently published showed that 10 mg open-label atorvastatin and placebo induced
an excess rate of muscle-related adverse events in the non-blinded non-randomized
3-year follow-up phase but not in the blinded initial 5-year phase. In the non-blinded
phase, public claims about side effects may have caused patients and physicians to
expect to experience the alerted adverse events [38].
Nocebo effects thus contribute to the occurrence of side effects and shape both
clinical outcomes and patients’ adherence to medication [24]. Preventing deleterious communication while still protecting patients’ rights and preferences is therefore critical. Since medical-informed consent documents have great potential to
modify patient expectations, empirical work has been conducted regarding risk and
benefit communication, with special emphasis on the effect of different framing
strategies on shared decision-making processes. Benefits and risks can be provided
verbally or numerically [16].
Information can be framed as relative, as opposed to absolute risks or “numbers needed to treat (NNT)”, in a way that appears convincing and, in the clinical
context, may facilitate adherence [30]. Moreover, risks or benefits can be framed
10
Implications of Placebos and Nocebos in Clinical Research
119
as gains or losses. Accordingly, negatively framed side effects focus on the number of patients experiencing a given risk (e.g., 38 out of 100 study participants
taking antidepressants will experience headache), while positively framed information focuses on the number of participants not experiencing the adverse effect
(e.g., 62 out of 100 participants will not experience headache). It seems intuitively
plausible that the second wording will lead to a less negative-risk perception.
However, the negative framing remains the current standard for informed consent
procedures [28]. Clearly, framing effects may be moderated by psychological factors including the recipient (participant)’s disposition and prior therapeutic experiences (see below).
10.7
I mpact of Positive and Negative Prior Therapeutic
Experiences
Positive and negative previous therapeutic experiences may not only confound the
results of crossover designs but also shape expectancies and treatment responses.
Learned placebo and nocebo effects can be elicited in healthy participants as well as
in participants suffering from pain and other disorders.
Prior analgesic experiences can increase the response to a subsequent placebo,
and negative hyperalgesic experiences can decrease the magnitude of placebo
effects. Colloca and Benedetti [22] performed a study in which one group received
a placebo intervention after being exposed to an intensity of painful stimulations
that was surreptitiously decreased and a second group received a placebo after
another treatment was made ineffective (e.g., no manipulation of the intensity of
painful stimulation was performed). Both groups were tested for placebo analgesic
effects after a time lag of 4–7 days. Placebo effects following the effective procedure were remarkably higher than those following the ineffective treatment. These
findings suggest that placebo effects may be moderated by prior experience (either
positive or negative) and that the effect of initial treatment does influence the magnitude of subsequent placebo effects even days after being exposed to them [22].
Similarly, Kessner et al. introduced a new analgesic treatment after randomization of healthy study participants to two arms exposed to effective and ineffective
(actually always inert) patch treatment, to test for the effect of treatment history
[44]. As anticipated, the therapeutic response to the tested treatment was lower in
the negative compared to the positive treatment history arm. The negative treatment
history induced a higher activation of the bilateral posterior INS, and a lower activation of the right DLPFC, which is involved in inhibitory modulatory processes for
placebo as described above [44].
There is a relationship between the effect of prior positive and negative experiences and the magnitude of placebo and nocebo effects. The greater the exposure to
negative and positive treatment experiences, the higher the nocebo and placebo
effects, respectively [26]. Similar results have been observed in pain patients.
André-Obadia et al. demonstrated in a crossover study design aimed at evaluating
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L. Colloca and N. Haycock
the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) that
the size of placebo analgesia in patients suffering from chronic neuropathic pain
depends on prior experience of either successful or unsuccessful treatments [2].
These findings deserve further investigation for the potential to improve the design
of clinical trials and, likewise, optimize therapeutic strategies.
10.8
Conclusions
Knowledge of placebo and nocebo responses can help improve clinical research.
By incorporating natural history groups as well as placebo groups into RCTs and
keeping individual differences in placebo effects in mind, researchers can control a
variety of confounds including natural history and regression to the mean, among
others. Doing so will lead to an increase in the design of more rigorous, reliable,
and valid studies. Beyond controlling for confounding factors, knowing what individual and contextual factors (e.g., prior experiences effects and framing effects)
contribute to placebos and nocebos can enable researchers to harness those effects
to yield optimal treatment outcomes.
Acknowledgments Work reported here was supported by grants of the National Institute of
Dental and Craniofacial Research (R01DE025946 to LC) of the National Institutes of Health. This
work was supported also by the MPowering the State, a grant from the State of Maryland (LC).
The content is solely the responsibility of the authors and does not necessarily represent the official
views of the funding agencies. The authors report no conflict of interest. The funding sources had
no role in study design; the collection, analysis, and interpretation of data; the writing of the report;
or the decision to submit the chapter for publication.
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of expectation on the brain metabolic responses to methylphenidate and to its placebo in nondrug abusing subjects. NeuroImage. 2006;32(4):1782–92.
77. Volkow ND, Wang GJ, Ma Y, Fowler JS, Zhu W, Maynard L, Telang F, Vaska P, Ding YS,
Wong C, Swanson JM. Expectation enhances the regional brain metabolic and the reinforcing
effects of stimulants in cocaine abusers. J Neurosci. 2003;23(36):11461–8.
78. Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose
RM, Cohen JD. Placebo-induced changes in FMRI in the anticipation and experience of pain.
Science. 2004;303(5661):1162–7.
79. Wager TD, Scott DJ, Zubieta J-K. Placebo effects on human μ-opioid activity during pain.
PNAS. 2007;104(26):11056–61.
80. Watson A, El-Deredy W, Iannetti GD, Lloyd D, Tracey I, Vogt BA, Nadeau V, Jones
AKP. Placebo conditioning and placebo analgesia modulate a common brain network during
pain anticipation and perception. Pain. 2009;145(1–2):24–30.
81. Yu R, Gollub RL, Vangel M, Kaptchuk T, Smoller JW, Kong J. Placebo analgesia and reward
processing: integrating genetics, personality, and intrinsic brain activity. Hum Brain Mapp.
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82. Zubieta J-K, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, Nichols TE, Stohler
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2005;25(34):7754–62.
Chapter 11
Implications of Placebos and Nocebos
in Clinical Practice
Dimos D. Mitsikostas
11.1
Introduction
The shadowy phenomenon known as nocebo describes negative expectancies for
medical treatment resulting in experience of unpleasant symptoms. In contrast, positive expectancies trigger placebo that results in treatment outcome improvement. In
evolutionary terms, nocebo and placebo coexist in humans to favor perceptual mechanisms that anticipate threat and dangerous events (nocebo) or promote appetitive
and safety behaviors (placebo) [10, 11]. In clinical trials placebo and nocebo are
powered mainly by pre-trial suggestions’ positive and negative ones, respectively, all
of them delivered during the informed consent process [9]. In clinical practice however, multiple factors, both internal and environmental, encompassed within a clinical encounter create a context through which patients develop negative or positive
expectations for treatments and clinical outcomes. Positively influencing patients’
beliefs about therapeutic success is one way to maximize placebo [2]. However,
being too optimistic is also ethically problematic and can be construed as disingenuous if one is not cautious [7]. Manipulating a patient’s expectations may not necessarily require lying or deceiving. In studies of irritable bowel syndrome and migraine,
patients were informed they were being treated with placebo and still developed a
positive clinical response [21, 22]. But the emphatic and enthusiastic physicians’
presentation of clinical data in a patient certainly declares empathy from the physician’s site that in turn develops trust to the patient’s site, which consequently
upsurges adherence and treatment outcome. Adherence is limited in conditions
requiring chronic daily treatment that are associated with potential adverse events
(AEs), in chronic pain disorders in particular [12]. Headache, the most common pain
condition, remains one major health problem underestimated by all sites, patients,
D. D. Mitsikostas (*)
1st Neurology Department, Aeginition Hospital, National and Kapodistrian University of
Athens, Athens, Greece
e-mail: [email protected]
© Springer Nature Switzerland AG 2019
D. D. Mitsikostas, F. Benedetti (eds.), Placebos and Nocebos in Headaches,
Headache, https://doi.org/10.1007/978-3-030-02976-0_11
125
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families, doctors, media, and health-care decision-makers. Among several headache
types, migraine and cluster headache [41] represent the most disabling primary
headache disorders. Migraine in particular is rating as the second leading condition
causing disability after low back pain worldwide, affecting 1.04 billion [17]. Tensiontype headache (TTH) is the most frequent headache disorder in the world with 1-year
prevalence 38% [45] and 1.89 billion of people suffering from it (the third most
prevalent condition among all medical ones) [17]. All headache disorders are treatable, but due to safety and tolerability reasons, available preventive treatments have
often limited success, even in the right hands. Low adherence and comorbidity are
key chains in the vicious cycle of chronic migraine therapeutics [19, 20, 49].
In this article the role of placebo and nocebo in headache therapeutics will be
discussed with emphasis to techniques that improve the balance of placebo over
nocebo.
11.2
Methodology to Estimate Nocebos in Clinical Practice
While estimating nocebo response in controlled randomized clinical trials (RCTs)
is easy, simply by referring to the AEs observed in the placebo-treated arm [1], in
clinical practice it is almost impossible to estimate nocebo accurately and securely.
The same stands for the placebo response. In RCTs two specific outcomes are used
to assess nocebo: nocebo AEs (meaning the percentage of patients treated with placebo and experienced at least one AE) and nocebo dropouts (referring to the percentage of patients treated with placebo and discontinued treatment because of AE)
[38]. But in clinical practice no such an assessment could be done. To overcome this
pragmatic complexity, a questionnaire was evaluated to capture patients with potential future nocebo responses. This is a specific self-fulfilled questionnaire (Q-No),
with 71.7% specificity, 67.5% sensitivity, and 42.5% positive predictive value for
nocebo [32]. Q-No is a four-item (rating range 4–20) questionnaire addressing
issues related to nocebo in outpatients seeking neurological consultation. When the
total score is higher than 15 (Table 11.1), the physician should educate the patient
for nocebo to minimize the potential patients’ negative expectations. There are
Table 11.1 The Q-No questionnaire
Question
I read the summary of product characteristics (SPC) before taking a medication
I have discontinued a medication because of adverse effects in the past
I ask my physician for potential adverse effects of the medication he/she gives me
I take into account the adverse effects reported in the summary of product
characteristics (SPC) seriously
Total score
Rating
Rating: 1 = never, 5 = always; by using a cutoff at score 15, the Q-No predicts nocebo with 71.7%
specificity, 67.5% sensitivity, and 42.5% positive predictive value (Mitsikostas and Deligianni
2015 [32])
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Implications of Placebos and Nocebos in Clinical Practice
127
several limitations of the Q-No evaluation, however. Specificity, positive predictive
value, and reliability are relatively low. Because participants in the evaluation of
Q-No have had discussed the nocebo phenomenon with the treating neurologists,
they were partially educated; thus nocebo responses may differ in this patients’
sample comparing to naive patients. Besides these limitations, however, Q-No may
serve as a useful tool to predict potential nocebo responses in clinical practice.
Capturing these patients and educating and treating them closely may limit nocebo
and its obvious and severe consequences in outcome [32].
In a clinical observational study [33], 514 outpatients suffering from several
headache disorders fulfilled the Q-No, and 291 (56.6%) scored more than 15 indicating potential nocebo behaviors. Post hoc analysis showed that those who were
suffering from episodic forms of all three primary headache disorders (migraine,
TTH, and cluster headache) displayed higher risk for nocebo behaviors compared to
those who were suffering from chronic forms: two out of three patients suffering
from episodic headaches scored more than 15 in Q-No compared to one out of two
patients who were suffering from chronic subtypes. Migraineurs also showed higher
risk for nocebo than those who were suffering from TTH (58.3% vs. 51.4%) [33].
In addition, nocebo influenced patients’ choices for the treatment. These data indicate that nocebo may worsen pain outcomes in an essential proportion of headache
outpatients, raising the need for establishing techniques to boundary nocebo’s consequences in practicing, mainly by controlling the doctor-patient communication.
11.3
Placebo in Headache Treatment
Even in an emotionally sterile patient-doctor communication, still the prototype
placebo/nocebo behaviors do exist. In a sophisticated human experiment [21], the
investigators tested the hypothesis that, in acute migraine, clinical outcomes with
both placebo and medication treatment would increase monotonically as the pretreatment verbal information varies from negative (0% chance of receiving active
medication) to uncertain (50% chance of medication) to positive (100% chance).
They used migraine headache as a model because migraine is a naturally recurring
neurological disorder of unilateral throbbing headache associated with variable
incidence of aura, nausea, photophobia, allodynia, fatigue, and irritability. The
recurring nature of migraine allowed the investigators to compare within each subject the efficacies of treatment and placebo over consecutive attacks using varying
conditions of information. By manipulating the information provided to subjects,
the primary analysis showed that the magnitude of headache relief induced by rizatriptan (a triptan for symptomatic migraine treatment), as well as placebo, was lowest when pills were labeled as placebo and higher when pills had uncertain labeling
or were labeled as active medication. The effect was monotonic for placebo and
nearly monotonic for rizatriptan. Interestingly, placebo treatment mislabeled as
rizatriptan reduced headache severity as effectively as rizatriptan mislabeled as placebo, and open-label placebo treatment was superior to no treatment. Based on
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D. D. Mitsikostas
these findings, the authors concluded that (1) raising the likelihood of receiving
active treatment for pain relief significantly contributes to increased success rate of
triptan therapy for migraine, (2) open-label placebo treatment may have an important therapeutic benefit, and (3) placebo and medication effects can be modulated by
expectancies [21]. As in migraine, a therapeutic benefit of open-label placebo vs. no
treatment has also been reported for subjects with irritable bowel syndrome in a
randomized controlled study [22] and in a pilot study in depression [23]. All together
these data indicate that any single treatment contains placebo inevitably and in a
reverse manner nocebo as well, which is in line with the hypothesis that both predispositions coexist in humans to favor perceptual mechanisms [9]. In practice,
these perceptual mechanisms are triggered as soon as the physician suggests any
treatment. But the kind of treatment and the way of suggestion along with several
additional environmental and individual factors influence essentially the balance
between these two opposite brain tendencies and control the final reaction. In clinical research for migraine, placebo-controlled studies are still the gold standard [13,
46], although the above data question this strategy.
11.4
Nocebo in Symptomatic Migraine Treatment
Reuter and colleagues first investigated the AEs in patients treated with placebo in
RCTs for the symptomatic treatment of migraine. In trials for symptomatic migraine
treatment that tested the therapeutic efficacy of triptans, 21.9% of control patients
reported at least one AE although treated with placebo. Symptoms were grouped
into three categories: migraine-related (symptoms such as nausea, photophobia, and
phonophobia), drug-related (symptoms typical of the experimental compound such
as chest pressure in response to triptans), and nonspecific or coincidental (symptoms such as 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 [40]. 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 AEs.
Interestingly, studies performed in North America showed a higher nocebo frequency than those conducted in Europe [27].
Consequently, Amanzio and colleagues [1] published an extensive systematic
review of nocebo in clinical trials for migraine. This was the first attempt to intensely
investigate migraine-related nocebo effects. They investigated the AEs after placebo
in RCTs testing NSAIDs, triptans, or anticonvulsants. Their major finding was that
nocebo AEs mirrored the AEs expected of the active medication studied precisely. For
example, anorexia and memory difficulties, which are typical AEs of anticonvulsants,
were present only in the placebo arm of these trials. In other words, nocebo in migraine
trials arose from patients’ distrust [1]. However, this important meta-analysis aimed to
investigate mechanisms of nocebo in particular, rather than to investigate the magnitude of nocebo in RCTs for migraine. Migraine most likely was used as a vehicle pain
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Implications of Placebos and Nocebos in Clinical Practice
129
condition in this study. For instance, the investigators searched RCTs for migraine
trials, both symptomatic and preventive, only if specific anti-migraine agents were
tested. Undoubtedly, the results of this meta-analysis confirmed their findings derived
from experimental human studies that expectations modulate both nocebo and placebo (the expectation theory of placebo and nocebo) [1].
In another more recent meta-analysis of RCTs for all primary headache disorders, 56 RCTs published in the last decade were analyzed to estimate the frequency
of patients treated with placebo who experience any AE (nocebo AE ratio) or discontinued treatment due to AE (nocebo dropout ratio) [36]. In this meta-analysis, all
RCTs using any compound, either for acute or for chronic treatment, were included.
The aim was to estimate the magnitude of nocebo in headaches in the most clinically relevant manner for both the clinicians and trial designers. In symptomatic
treatments, nocebo dropout ratio was limited (0.33%), but in chronic preventive
treatments was increased up to 5%, showing that 1 out of 20 patients treated for
migraine prophylaxis discontinues treatment due to nocebo AEs. Practitioners
should be aware of this fundamental nocebo effect, trial designers as well [30, 31,
36]. Stratified analyses in migraine studies revealed that:
1. Nocebo AEs and nocebo dropout ratios were higher in preventive trials than in
symptomatic trials (P < 0.001).
2. Nocebo AE ratio 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).
3. Nocebo may change with route administration (e.g. botulin toxin A).
4. No differences were found between studies performed in North America compared with Europe.
5. Dropout ratio was lower in the placebo group than in the active drug group (mean
difference, 7.09%; 95% CI, 4.1%–10.1%; P < 0.0001).
6. Nocebo rates did not vary with the drug tested, with headache type, or by continent, with one exception (botulin toxin A) [36].
For symptomatic cluster headache treatment, four trials were analyzed in this
meta-analysis, and the nocebo AE was estimated at 18.67% (95% CI 10.65–28.33%);
insufficient data were gathered to calculate the nocebo dropouts in RCTs for cluster
headache and tension-type headache [36].
11.5
What Does Control Placebo and Nocebo?
Several factors control placebo and nocebo, some of them being modifiable and
some others not (Table 11.2). Previous experiences, personality, and a variety of
cofactors modulate nocebo, even the price, the packing, or the tablet/capsule [37,
38, 48]. Pharmacophobia and nocebo are additional cofactors that border adherence
and treatment outcomes significantly [30, 31]. Pharmacophobia refers to the
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D. D. Mitsikostas
Table 11.2 Factors influencing nocebo
Modifiable
Patient’s expectations
Patient’s education
Pre-treatment verbal suggestions
Speed of treatment titration
Safety profile of treatment
Patient-doctor relation/communication
Close follow-up
Affective and cognitive traits
Pharmacophobia
Non-modifiable
Previous negative experiences
Personality
Cultural factors
Drug-related adverse events
Social media and internet information
Gender
Treatment price
Generic formulations
Age
The appearance of drugs or medical devices
irrational fear of medication, and nocebo refers to the experience of adverse events
related to patients’ negative expectation that a treatment will harm most likely
instead of help [30]. The frequency of adverse events can dramatically increase by
informing patients about the possible side effects of the treatment and by negative
expectations on the part of the patient [4, 5]. Patients who were told that they might
experience sexual side effects after treatment with β-blocker drugs reported these
symptoms between three and four times more often than patients in a control group
who were not informed about these symptoms [43]. Nocebo varies by the condition,
and it has been estimated in several brain disorders such as migraine [1, 36], epilepsy [50, 51], fibromyalgia [34], multiple sclerosis [38], Parkinson’s disease [44],
neuropathic pain [37], and restless syndrome [42] and in patients with depression
[14, 29, 35]. Many other unpredictable factors like social media or Internet information cannot be detected. Instead an individual negative expectation originating from
internal psychological structures could be predicted. A previous experience of drugrelated AEs and/or failed interventions are stable factors contributing to nocebo [8,
30, 31]. Whether these previously experienced AEs were or not related to nocebo
may not change the risk for future nocebo responses. However, a negative patientdoctor communication facilitates nocebo [18]. Additionally, affective and cognitive
traits could be important as well. Some personality traits and psychological factors,
such as anxiety, harm avoidance and persistence, pessimism, and fear of pain, may
influence the responsiveness to nocebo [3]. Finally, there is data indicating that
treatment price, generic medicines [15, 16], and gender and age may influence
nocebo and placebo responses in human studies, women being linked to conditioning rather than to expectancy and men the opposite, but this finding needs to be
confirmed clinically [24, 47]. Children and adolescents show much higher placebo
responses in headaches, up to 61% in studies for prevention of migraine [39], making treatments with proven efficacy in adults (e.g., topiramate and amitriptyline)
unable to achieve a more effective clinical trial endpoint than placebo in the prevention of migraines in patients less than 18 years of age [25, 26]. There is no evidence
for nocebo responses in children; but in trial with amitriptyline and topiramate [39],
only 1.5% of patients treated with placebo discontinued treatment because of AEs
vs. 5% in adults [36], indicating that children may display lower nocebo rates. By
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Implications of Placebos and Nocebos in Clinical Practice
131
applying the Q-No in adult patients prior to consultation (e.g., in the waiting room),
a physician treating headache patients can easily be informed for potential nocebo
behaviors however and load specific and tailored approaches to limit them.
11.6
Persuading Patients
Not only physicians but also nurses, other health-care professionals, and allied
health services should be aware of their responsibility to avoid and reduce nocebo
effects and the detrimental consequences of these effects, from diagnosis to therapy
to prognosis [6]. The benefit of taking a medication (“this drug will reduce your
migraine days from 8 you have now to 3 per month”) should always be included in
patient information about newly prescribed drugs. Alternatively, a physician may
explain the treatment benefit by using only positive outcomes, like “this drug will
increase your headache-free days from 22 to 27 per month.” Drug treatment for
primary headache disorders can be started at a very low dose (half- or one-quarter
the recommended starting dose). The potential advantages of this approach include
a further decrease in the risk of adverse events, enhanced patient participation,
improved adherence, and reduced long-term costs [28]. “Start low, go slow”
approach when starting a new medication also improves adherence in nocebo
patients by minimizing the risk of AEs. Most importantly physicians should use an
authentic and empathic communication style, providing adequate information
regarding disease, diagnoses, treatments, and AEs. Close follow-up and discussing
patients’ anxieties, concerns, and expectations are always required. Occasionally, it
is very difficult to convince the patient, but it helps much when the physician
explains the origin and the prevalence of nocebo. Informing the patient that he/she
is not the only one who has this reaction (in headaches almost half of patients report
nocebo AEs) and understanding the brain mechanisms underlying nocebo make the
patient feel comfortable (Box 11.1) [6, 8, 18, 30, 31].
Box 11.1 Tips to Increase Placebo and Limit Nocebo
• During the interview, be positive, authentic, and empathic; having face
contact with the patient optimizes treatment expectation and expectation of
adverse effects. Patients who have tried several alternative treatments
before generally may dislike pharmaceutical interventions.
• When prescribing a new medical treatment, use positive outcomes to
explain their benefits (e.g., “this treatment will increase your headachefree days from 22 to 27 per month”), and encourage the patient not to
Google for potential adverse events but to ask you. Go low and slow with
the drug titration. Discuss the nocebo phenomenon.
• Close follow-up to monitor potential adverse events (ask for a telephone
follow-up a month after) or to reduce patient’s awareness.
• Be tolerant, reachable, and persistent, in general.
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11.7
D. D. Mitsikostas
Conclusions
Both placebo and nocebo are cognitive responses to all but therapies that coexist in
humans and control outcomes radically. Physicians should acknowledge the mechanisms and factors controlling both reactions and plan individual strategies to change
the balance of placebo in their practicing. Because personality powers both
responses, physicians must certainly get the patient’s picture before decision-making and respect his/her principles. There are currently available several pharmaceutical and non-pharmaceutical treatment options in headaches that are being enriched
substantially lately, enlarging the patients’ right of choice. One implication of
respect for persons is a respect for personal autonomy, that is, acknowledging the
moral right of every individual to choose and follow his or her own plan of life and
actions. Given that one single adverse event does not cause the same implications
among individuals nor patients share a common perception for it, doctors should
describe the potential adverse events in their patients but in relation to treatment
benefits. Treatment outcomes presented in a positive way affect patients significantly; thus a long interview may be required only for explaining the treatment
benefits. Having in mind that even the worst headache case can be improved with a
particular treatment, the physician should play a magic role to capture and convince
suspicious patients who are not adhering, partly because previous physicians have
not respected, or have not spent enough time to explore, their own individual choices
for life.
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43. Silvestri A, Galetta P, Cerquetani E, Marazzi G, Patrizi R, Fini M, Rosano GM. Report of erectile dysfunction after therapy with beta-blockers is related to patient knowledge of side effects
and is reversed by placebo. Eur Heart J. 2003;24(21):1928–32.
44. Stathis P, Smpiliris M, Konitsiotis S, Mitsikostas DD. Nocebo as a potential confounding
factor in clinical trials for Parkinson's disease treatment: a meta-analysis. Eur J Neurol.
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Goadsby PJ. Comparative tolerability of treatments for acute migraine: a network meta-analysis. Cephalalgia. 2017;37(10):965–78.
47. Tinnermann A, Geuter S, Sprenger C, Finsterbusch J, Büchel C. Interactions between brain
and spinal cord mediate value effects in nocebo hyperalgesia. Science. 2017;358(6359):105–8.
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Seizure. 2017;45:95–9.
Chapter 12
Informed Consent and the Ethics
of Placebo-Based Interventions
in Clinical Practice
Marco Annoni and Franklin G. Miller
12.1
Introduction
In recent years a converging series of empirical studies has begun to unravel the
psychobiological mechanisms of placebo and nocebo effects [13]. These studies
have demonstrated that placebo effects may significantly modulate a plethora of
symptoms in highly prevalent conditions such as pain, depression, irritable bowel
syndrome, and migraine [5, 19].
For instance, in an experiment by Kham-Hansen et al., patients with recurring
migraine were randomized using a 2 × 3 balanced placebo design to receive either
a placebo or an effective medication (Maxalt) under three information conditions:
truthful disclosure (“Maxalt” or “placebo”), blinded treatment (50% chance of
receiving Maxalt or placebo), and deceptive disclosure (told “Maxalt” but given
placebo; told “placebo” but given Maxalt) [17]. The study demonstrated that Maxalt
was more efficacious than placebo across all information conditions. However, the
study also found that Maxalt mislabeled “placebo” was nearly as effective as a placebo mislabeled “Maxalt” and that the effect of a truthful placebo was superior to
no treatment. Remarkably, the placebo effect “was significant under each labeling
condition relative to no treatment, amounting in magnitude to >50% of Maxalt
effect under the corresponding labeling condition” [17]. These findings suggest not
only that placebo effects may enhance the therapeutic benefits of both placebos and
proven therapies but also that different information disclosures may elicit different
magnitudes of placebo effects, presumably through the modulation of patients’
expectations.
M. Annoni (*)
Consiglio Nazionale delle Ricerche, Istituto di Tecnologie Biomediche, Rome, Italy
e-mail: [email protected]
F. G. Miller
Weill Cornell Medical College, New York, NY, USA
e-mail: [email protected]
© Springer Nature Switzerland AG 2019
D. D. Mitsikostas, F. Benedetti (eds.), Placebos and Nocebos in Headaches,
Headache, https://doi.org/10.1007/978-3-030-02976-0_12
135
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M. Annoni and F. G. Miller
Other treatments for migraine and other forms of headache have been found to have
similarly strong placebo components, most notably acupuncture. A 2016 Cochrane
review sampled 22 trials with 4985 participants in total to ascertain whether acupuncture was more effective than no treatment, sham acupuncture, and prophylactic treatment to reduce migraine frequency [21]. This comprehensive study found that
acupuncture was associated with a moderate reduction of migraine frequency over no
acupuncture and with a small but statistically significant reduction in frequency over
sham after treatment and at follow-up [21]. Acupuncture reduced migraine frequency
significantly more than drug prophylaxis after treatment, and patients receiving acupuncture were less likely to report adverse side effects and to discontinue participation
in trials as compared with patients receiving conventional treatments. Based on these
results, this review concluded that acupuncture may be “considered a treatment option”
for migraine patients, even though most of its benefits may be due to placebo effects.
Collectively, these and other studies suggest that placebo effects may account for
a significant part of the benefits of conventional and complementary treatments currently prescribed to treat or prevent migraine. These empirical findings, however,
raise a host of ethical issues regarding whether and how clinicians could ethically
promote placebo effects and minimize nocebo effects with the aim of maximizing
therapeutic benefits without compromising informed consent [24].
In particular, it is possible to distinguish three ways in which clinicians may
mobilize placebo effects for therapeutic purposes, each raising a different set of
moral considerations. First, clinicians may resort to paternalistic deception—for
instance, recommending or administering a placebo as if it were an effective medication (e.g., “Maxalt”). According to one view in medical ethics, paternalistic
deception may sometimes be morally permissible, but only when its prospective
benefits outweigh the potential risks, the infringement of patient’s autonomy, and
the threatening of the bond of trust [1, 4, 20]. Second, clinicians may attempt to
prescribe placebos without deception—i.e., “open-label placebos.” In principle, this
option sidesteps the ethical hurdles of using deception. However, the evidence supporting the efficacy of open-label placebos is still limited to a few pilot studies [28].
Furthermore, there is an ongoing debate about whether and how an open-label placebo can be transparently prescribed without equivocation [3, 6, 16].
While these scenarios have been already analyzed in some depth elsewhere, in
this chapter we focus on a third category of morally relevant and less explored
cases: the one regarding the prescription of treatments that, like acupuncture, has
been proven to be slightly more effective than placebos and yet significantly better
than no treatment or the standard or care—a class of remedies that we shall henceforth label as “placebo-based interventions.”
12.2
The Ethics of Prescribing Placebo-Based Interventions
Under which conditions could doctors prescribe placebo-based interventions? In
order to answer this preliminary question, let us consider again the case of recurring
migraine—a highly prevalent, painful, and potentially disabling condition. While
12 Informed Consent and the Ethics of Placebo-Based Interventions in Clinical Practice
137
there are several proven pharmacological and non-pharmacological therapies for
treating and preventing migraine, in each case the prescription may vary considerably
depending on patients’ preferences and clinical features of the attacks [23]. Moreover,
some individuals with recurring migraine are refractory to guideline-based treatment,
while others cannot be treated with pharmacological remedies due to comorbidities,
the severity of side effects, or the risk of medication overuse [22, 29].
Thus, there are conceivable cases in which, based on the available evidence, acupuncture may be the only, or the most, effective clinical option for a patient. In these circumstances, we argue, there is no reason why doctors should not consider the prescription of
an effective treatment, even though most of its benefits are due to placebo effects, as long
as (1) no other comparable clinical option is available; (2) no deception is involved; (3)
the benefits outweigh the risks; (4) the costs are proportioned to the benefits; and (5) the
treatment is in line with patients’ needs. (By extension, this argument can also be generalized to the prescription of other placebo-based interventions in other conditions prone
to placebo modulation, such as pain or irritable bowel syndrome.)
However, while these threshold conditions apply to all prescriptions, intentionally recommending a placebo-based intervention requires additional caution for
three reasons. First, despite recent scientific advancements in the characterization of
their underlying mechanisms, placebo and nocebo effects remain elusive phenomena [5, 26, 27]. Placebo effects may vary considerably from one context to another
and across individuals [15]. Hence, it is difficult to anticipate the magnitude of the
benefit that placebo-based treatments might have in each case.
Second, some placebo-based interventions may be contrary to patients’ preferences and beliefs. For instance, patients may be skeptical or opposed to complementary and alternative remedies. Hence, it is crucial to probe in advance patient’s
attitudes toward the recommended placebo-based intervention. Additionally, this
might allow patients to better match their preferences and beliefs with available
therapeutic options, enhancing their sense of control—a factor that has been shown
to positively contribute to the modulation of clinical outcomes [14].
Finally, it is important for physicians to be more aware and educated about placebo and nocebo effects [7]. As several empirical studies have demonstrated, the
quality of the therapeutic interaction and the features of the clinician delivering the
therapy may all be important variables of placebo modulation [5, 21]. Being aware
of such determinants of placebo effects might lead physicians prescribing a placebo-based treatment such as acupuncture to recommend a particular practitioner,
thus indirectly enhancing the placebo component of the proposed therapy.
12.3
lacebo-Based Interventions and the Ethics of Informed
P
Consent
Provided the former conditions are met, the next relevant ethical issue is how doctors should communicate when recommending placebo-based interventions. In particular, should doctors disclose that most of the benefits of the prescribed treatment
may be due to placebo effects?
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M. Annoni and F. G. Miller
This question suggests an ethical dilemma. On the one hand, clinicians have a
duty of beneficence. This moral obligation entails that doctors must act to serve
patients’ best interests. The primary purpose of prescribing a placebo-based intervention is to alleviate patients’ symptoms mostly through beneficial placebo effects.
However, as evidence suggests, the strength of patients’ expectations may correlate
with the magnitude of the placebo effects [5]. Disclosing that the prescribed treatment is “placebo-based” might hinder patients’ expectations, thus leading to weaker
placebo effects and suboptimal clinical outcomes.
On the other hand, clinicians have a duty of respecting patient’s autonomy and
right to informed consent. This moral obligation entails that clinicians have a
prima facie duty of veracity in all their professional communications: other things
being equal, doctors must be honest and tell the truth to patients. The duty of
veracity, in turn, can be further understood as the conjunction of two more specific
duties: the negative duty not to lie and deceive and the positive duty to provide all
the necessary information to respect and foster patients’ autonomous agency [2,
4]. For simplicity, let us call the former the duty of truthfulness and the latter the
duty to inform.
Clearly, a physician introducing acupuncture by saying (a) “this treatment has
been proven effective to reduce the frequency of migraine attacks” would not violate the duty of truthfulness, as this statement is factually true. It is, however, less
clear whether this statement alone violates the duty to inform or whether the clinician should add (b) “…although most of its benefits may be due to placebo effects.”
In our view, while deciding in such scenarios, doctors should adopt a pragmatic
criterion and add sentence (b) only if it would make a conceivable difference for
patient’s decisional autonomy; otherwise they can omit it out of consideration of
beneficence.
Consider, for example, the case of a patient suffering from recurring migraine
who is refractory to pharmacological treatments. For this patient acupuncture may
represent the only clinical option to reduce the frequency of future disabling attacks.
If the doctor concludes, after probing patient’s views and preferences, that he would
be willing to try any treatment that could help, then he might introduce acupuncture
using only statement (a). In this case, we argue, adding statement (b) would likely
not enhance patient’s autonomy in any significant way, and yet it will possibly
diminish the benefits of undergoing the treatment. In this case, since (a) is a truthful
statement, and (b) does not obviously fall under the duty to inform, a doctor introducing acupuncture using only (a) would not violate his general duty of veracity.
After all, the benefits of many effective treatments—from analgesics to antidepressants—are thought to be due to pharmacological and placebo effects, and yet
doctors have no duty of informing patients while prescribing these treatments that
the final outcome may in part be due to a non-pharmacological cause.
By contrast, consider the case of a doctor who ponders chiropractic spinal
manipulative therapy (CSMT) as a treatment for a patient in the same conditions.
This doctor is aware of a recent three-armed, single-blinded, placebo, randomized
controlled trial in which the efficacy of CSMT has been evaluated versus placebo
(“sham chiropractic”) and control (usual pharmacological management) [8]. (“Sham
12 Informed Consent and the Ethics of Placebo-Based Interventions in Clinical Practice
139
chiropractic” was a sham push maneuver that had been validated by a previous
study as a legitimate placebo control [9].) This study found that migraine frequency
was significantly reduced in all three groups from baseline to posttreatment.
However, while the effects persisted in both the CSMT and the placebo group at
follow-up, they returned to baseline in the control group. With respect to all endpoints, no significant difference was found between CSMT and placebo. Hence, this
study suggests that CSMT is an “effective” treatment for migraine, although only
because of placebo effects, and that both CSMT and sham chiropractic may be
superior to usual pharmacological management over the medium term.
Thus, differently from the case of acupuncture, and assuming these empirical
findings to be correct, CSMT has no specific efficacy for migraine and operates only
through placebo effects. Importantly, this difference impacts how doctors should
introduce CSMT in order to achieve a valid, nondeceptive, informed consent. In
fact, if a doctor introduces CSMT by saying (c) “this treatment has been proven
effective to reduce the frequency of migraine attacks,” then (c) could qualify as a
deceptive statement if it is meant to instill in the patient the false belief that CSMT
is “effective” in the same sense in which therapies like Maxalt are “effective”—i.e.,
superior to placebo. Yet, the term “effective” is slightly ambiguous, as it might be
intended in a more ordinary sense as meaning that a treatment is “beneficial and
superior to no treatment.” In this latter sense, (c) would arguably be true, and thus it
would not formally violate the duty of truthfulness.
However, even if we concede that the term “effective” may be intended in the
latter sense, introducing CSMT without adding that its benefits may be (entirely)
due to placebo effects would still violate clinicians’ duty to inform. This is demonstrated by the fact that (c) could likewise be used to prescribe/recommend placebo
pills or sham acupuncture, as both have been demonstrated to be “effective”—i.e.,
superior to no treatment—in controlled studies. Yet, intentionally prescribing/recommending a placebo treatment without patient’s informed consent represents a
clear failure to uphold clinicians’ duty of respecting patient’s autonomy. If the
patient later discovers that the recommended treatment (a pill, acupuncture, or chiropractic) was “just a placebo,” legitimately, he may feel duped and manipulated by
the doctor in a way that is incompatible with the respect of his decisional autonomy.
Furthermore, this may also lead to harmful consequences for the therapeutic relationship and the bond of trust.
Of course, one could argue that, given the expected benefits, sometimes it might
be ethical to prescribe deceptively a placebo-based treatment—or even a placebo
treatment—in violation of the duty of veracity. It is important, however, to underscore that, in this case, the doctor would resort to paternalistic deception, a practice
that is incompatible with the provision of a valid informed consent and that might
be justifiable only in exceptional cases [2, 18].
In general, the acupuncture and CSMT examples illustrate how complex it is for
doctors to achieve a valid informed consent and respect patient’s autonomy when
the recommended treatment has a dominant or exclusive placebo component.
A final issue concerns the possible harm that informed consent may cause due
to nocebo effects. Clinicians’ duty to inform covers also the possible side effects
140
M. Annoni and F. G. Miller
of prescribed therapies and procedures. Some of these side effects may be amenable to nocebo modulation, such as headache or insomnia [25]. In disclosing
these possible effects, clinicians may inadvertently increase the likelihood of
patients experiencing nocebo-related side effects. With respect to this issue,
scholars have suggested three strategies. The first strategy is to override the duty
to inform, considering “nondisclosure in the case when a nocebo effect is likely to
occur” [12]. This solution, however, may be appropriate only in those rare cases
in which the possible harm of nocebo effects is so severe as to justify a breach of
clinicians’ duty of veracity [10, 11]. A second strategy, then, is that of minimizing
nocebo effects without forestalling the duty of veracity. This can be accomplished
by informing patients about nocebo effects, and offering them the possibility of
voluntarily waiving to receive side-effect information [25], and by using framing
effects to reduce possible nocebo side effects [12]. Clinicians may resort to this
second strategy in those cases in which the prescription of a placebo-based intervention includes the disclosure of information that may cause mild and reversible
nocebo effects. Finally, a third strategy is to educate patients (and clinicians) more
about nocebo effects, so as to help them “understand and contextualize the potential for anxiety and other psychophysiological mechanisms that could lead to the
occurrence of unwanted nocebo effects” [10].
12.4
Conclusion
Placebo effects may modulate clinical outcomes in many symptomatic conditions,
including headache and migraine. However, the intentional manipulation of placebo
effects in clinical settings poses the ethical question of how clinicians ought to communicate with patients in order to maximize their therapeutic benefits while at the
same time securing a valid informed consent.
This ethical issue is particularly thorny when it regards the prescription of placebo-based treatments, i.e., of remedies that have been found slightly more effective
than placebos in controlled experiments and yet better than no treatment or the
standard of care.
With respect to this kind of treatment, in this chapter we have argued that doctors
may ethically prescribe placebo-based interventions in nondeceptive ways, provided that no other comparable clinical option is available; the benefits outweigh the
risks; the costs are proportional; and the treatment is in line with patients’ needs,
values, and preferences.
Finally, we have contended that, while prescribing placebo-based interventions,
doctors may ethically omit to mention that most of the benefits of the prescribed
treatment are due to placebo effects out of considerations of beneficence, but only
in those cases in which the treatment has been proven more effective than a comparable placebo, and this information would not make a conceivable difference for
patients’ autonomy.
12 Informed Consent and the Ethics of Placebo-Based Interventions in Clinical Practice
141
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