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PLACEBO AND
PAIN
FROM BENCH TO BEDSIDE
Edited by
Luana Colloca
National Institutes of Health, Bethesda, MD, USA
Magne Arve Flaten

Department of Psychology, University of Tromsø, Trondheim, Norway
Karin Meissner
Institute of Medical Psychology, Ludwig-Maximilians-University, Munich, Germany
AMSTERDAM • BOSTON • HEIDELBERG • LONDON

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SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO
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therefore copyright protection is not available in the United States for such portions of the book pursuant to
17 U.S.C. Section 105. (Preface, Chapter 15, Chapter 22)
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Preface
It is with great enthusiasm that we present Pain and have paved the way to several of the most relevant
Placebo, a book outlining key aspects of research on neurobiologic discoveries, and have led the discourse
placebo-induced modulation of experimental and clini- about challenges, controversies and potentials of these
cal pain, explaining the most important mechanistic advances, while providing stimulating and innovative
advances, while discussing the impact of these findings perspectives. Undoubtedly, we could not cover all top-
for clinical researchers and health practitioners. ics or involve all researchers in the field in this volume.
This is the first book that offers a comprehensive view This field of research is growing at such a rapid rate as to
of the themes of pain, placebo and nocebo. Although parts make a complete treatise of placebo and pain impossible.
of these topics have been presented in a few books, there The Editors wish to thank all the authors for their
was a compelling need for a book specifically devoted contributions and acknowledge the support they have
to pain, placebo and nocebo research encompassing the received from their funders. Luana Colloca would like to
realms of both basic science and clinical viewpoints. For thank the Intramural Research Program of the National
this reason, we present this compendium that explains Center for Complementary and Alternative Medicine
the bases for placebo-induced modulation of pain, with (NCCAM), the National Institute of Mental Health
an emphasis on clinical perspectives, and their implica- (NIMH), and the Department of Bioethics, Clinical Cen-
tions for clinical trials and practices. ter at the National Institutes of Health for their valuable
The first part of the book is devoted to the description source of support for her activities. Magne Arve Flaten is
of the mechanisms underlying placebo-induced media- grateful to the Bial Foundation and the Research Council
tion and modulation of pain. Our expectation is that of Norway for continuous support, and Karin Meissner
these sections will be of particular interest to not only thankfully acknowledges the German Ministry of Edu-
scientists in the fields of medicine, psychology, and other cation and Research and the Schweizer-Arau Founda-
health sciences, but also scientists in basic disciplines tion for their support.
such as neuroscience, physiology, pharmacology, and We trust that this book provides a valuable contribu-
biochemistry. Conversely, the second part of the book tion in promoting future discoveries, providing mate-
has been structured to be a helpful tool for senior-level rial for critical discussions, and educating readers about
healthcare providers including, but not limited to, anes- this fascinating and promising field. Our ultimate hope
thesiologists, internists, neurologists, neurosurgeons, is that by improving the general understanding of the
neuroscientists, psychologists, nurses, and palliative mechanisms of placebo and pain, this book offers a step
care providers. towards a path of relief for patients in pain.
Our vision for this prodigious undertaking could
certainly not be accomplished in isolation, and hence, Luana Colloca
we are honored and privileged to have engaged scien- Magne Arve Flaten
tists whose valuable contributions have advanced and Karin Meissner
elucidated these areas of research. These researchers
ix
Contributors
Per M. Aslaksen Department of Psychology, University of Randy L. Gollub Psychiatry Department, Massachusetts
Tromsø, Tromsø, Norway General Hospital and Harvard Medical School, MA, USA
Fabrizio Benedetti Department of Neuroscience, University Jian-You Guo Key Laboratory of Mental Health, Institute of
of Turin Medical School, and National Institute of Neurosci- Psychology, Chinese Academy of Sciences, Beijing, P. R. China
ence, Turin, Italy Martin Ingvar Cognitive Neurophysiology Research Group,
Ulrike Bingel NeuroImage Nord, Department of Neurology, Stockholm Brain Institute, Osher Center for Integrative
University Medical Center Hamburg-Eppendorf, Hamburg, Medicine, Karolinska Institutet, Stockholm, Sweden
Germany Karin Jensen Department of Psychiatry, Massachusetts
Christopher Brown Human Pain Research Group, Univer- General Hospital/Harvard Medical School, Charlestown,

sity of Manchester, Manchester, UK MA, USA
Christian Büchel Department of Systems Neuroscience, Wayne B. Jonas Samueli Institute, Alexandria, VA, USA
University Medical Center Hamburg-Eppendorf, Hamburg, Anthony Jones Human Pain Research Group, University of
Germany Manchester, Manchester, UK
Ben Colagiuri School of Psychology, University of Sydney, Regine Klinger Outpatient Clinic of Behavior Therapy,
Sydney, Australia Department of Psychology, University of Hamburg, Ham-
Luana Colloca National Center for Complementary and burg, Germany
Alternative Medicine (NCCAM), National Institutes of
Sibylle Klosterhalfen Department of Psychosomatic Medi-
Health, Bethesda, MD, USA, National Institute of Mental cine, University Hospital Tübingen, Tübingen, Germany
Health, National Institutes of Health, Bethesda, MD, USA,
Leonie Koban University of Colorado, Boulder CO, USA
Department of Bioethics, Clinical Center, National Institutes
of Health, Bethesda, MD, USA Jian Kong Psychiatry Department, Massachusetts General
Hospital and Harvard Medical School, MA, USA
Cindy Crawford Samueli Institute, Alexandria, VA, USA
Klaus Linde Institute of General Practice, Klinikum rechts
Bettina K. Doering Department of Clinical Psychology
der Isar, Technische Universität München, Munich, Germany
& Psychotherapy, Philipps University Marburg, 35032
Marburg, Germany Peter F. Lovibond School of Psychology, University of New
South Wales, Australia
Falk Eippert Centre for Functional Magnetic Resonance
Imaging of the Brain (FMRIB), University of Oxford, Oxford, Fei Luo Key Laboratory of Mental Health, Institute of Psy-
UK chology, Chinese Academy of Sciences, Beijing, P. R. China
Wael El-Deredy Department of Psychological Sciences, Uni- Peter S. Lyby Department of Psychology, University of
versity of Manchester, Manchester, UK Tromsø, Tromsø, Norway
Paul Enck Department of Psychosomatic Medicine, Univer- Serge Marchand Université de Sherbrooke, Faculté de méde-
sity Hospital Tübingen, Tübingen, Germany cine Centre de recherche clinique Étienne-Le Bel du CHUS
Sherbrooke, Québec, Canada
Damien Finniss Pain Management R esearch Institute,
University of Sydney Royal North Shore Hospital, Sydney, Karin Meissner Institute of Medical Psychology, Ludwig-
Australia; School of Rehabilitation Sciencess, Griffith Uni- Maximilians-University Munich, Munich, Germany
versity, Queensland, Australia Franklin G. Miller Department of Bioethics, Clinical Center,
Arnstein Finset Department of Behavioral Sciences in Medi- National Institutes of Health, Bethesda, MD, USA
cine, Institute of Basic Medical Sciences, Faculty of Medi- Daniel E. Moerman William E. Stirton Professor Emeritus of
cine, University of Oslo, Oslo, Norway Anthropology, University of Michigan-Dearborn, MI, USA
Magne Arve Flaten Department of Psychology, Norwegian Marta Peciña Department of Psychiatry and Molecular and
University of Science and Technology, Trondheim, Norway Behavioral Neuroscience Institute, University of Michigan,
Herta Flor Department of Cognitive and Clinical Neurosci- Ann Arbor, MI, USA
ence, Central Institute of Mental Health/Medical Faculty Gitte Laue Petersen Danish Pain Research Center, Aarhus
Mannheim, Heidelberg University, Mannheim, Germany University Hospital, Aarhus, Denmark
Elisa Frisaldi Department of Neuroscience, University of Predrag Petrovic Cognitive Neurophysiology Research
Turin Medical School, and National Institute of Neurosci- Group, Stockholm Brain Institute, Osher Center for Integra-
ence, Turin, Italy tive Medicine, Karolinska Institutet, Stockholm, Sweden
xi
xii CONTRIBUTORS
Donald D. Price Division of Neuroscience, Department of Oral Harald Walach Institute of Transcultural Health Studies,
and Maxillofacial Surgery, University of Florida, Florida, USA European University Viadrina, Frankfurt (Oder), Germany
Winfried Rief Department of Clinical Psychology & Psy- Jin-Yan Wang Key Laboratory of Mental Health, Institute
chotherapy, Philipps University Marburg, 35032 Marburg, of Psychology, Chinese Academy of Sciences, Beijing, P. R.
Germany China
Luka Ruzic University of Colorado, Boulder CO, USA Katja Weimer Department of Psychosomatic Medicine,
Lene Vase Department of Psychology and Behavioural University Hospital Tübingen, Tübingen, Germany
Sciences, School of Business and Social Sciences, Aarhus Jon-Kar Zubieta Department of Psychiatry and Molecular
University, Aarhus, Denmark and Behavioral Neuroscience Institute, and Department of
Tor D. Wager University of Colorado, Boulder CO, USA Radiology, University of Michigan, Ann Arbor, MI, USA
C H A P T E R
1
Historical Aspects of Placebo Analgesia
Damien Finniss
Pain Management Research Institute, University of Sydney & Royal North Shore Hospital, Sydney, Australia; School of
Rehabilitation Sciences, Griffith University, Queensland, Australia
INTRODUCTION phrase seems to have been mistranslated to ‘I will please

the Lord,’ with the word ‘placebo’ therefore meaning ‘to
Placebos and placebo effects have been an interesting please.’6 This slight mistranslation was the foundation
component of medicine and health care for hundreds for the meaning and application of the word for many
of years. The topic area of ‘placebo’ is one that has been centuries.
appealing to professionals from a wide range of back- By the late 1300s, the word placebo had taken on a
grounds, ranging from clinical and laboratory fields to disparaging meaning, where hired mourners were said
broader anthropologic and sociocultural disciplines. to ‘sing placebos’ of false praise to flatter the dead.2 Simi-
Inherent in this topic area lay a multitude of perspectives larly, around the same time, in one of Geoffrey Chau-
and approaches to understanding the meaning of placebo cer’s Canterbury tales (The Merchant’s Tale), a character
and how it might relate to health care and broader human- ‘placebo’ was depicted as a sycophant.7 In another of
ity. On this basis, it could be argued that the study of pla- Chaucher’s tales (The Parson’s Tale), flatterers were
cebo is an important pillar in the practice of medicine. described as the Devil’s chaplains, always singing
Recently, significant attention has been given to a mod- placebo.8 It seems clear that even in these early times,
ern conceptualization of placebos and placebo effects in there were some subtle variations in the use and mean-
an attempt to progress understanding of the area. This has ing of the word. Although the literal translation of the
been particularly important in moving the field forward word was ‘to please,’ its actual use seemed to be more
and advancing the study of placebo. However, it is impor- negative, and these early applications of placebo may
tant to appreciate a historical perspective as this provides well have shaped the direction of its use for many years
an understanding of the origin of the word and the initial to come.
framework in which it was used. Much of the modern The use of the word ‘placebo’ in a medical context
view of placebo is still shaped by its lengthy history. seems to have been due to the work of a British physi-
cian, William Cullen.9 In the year 1772, Cullen delivered
a series of lectures in which he used the word placebo in
DEFINITIONS AND the medical context. He conceptualized giving a placebo
CONCEPTUALIZATION as an attempt to comfort or please a particular patient
who had incurable disease, and wrote that ‘… I did not
The word ‘placebo’ seems to have first appeared trust much to it, but I gave it because it is necessary to give a
in a religious context around the time of the 13th cen- medicine, and as what I call a placebo.’2 This is a particularly
tury, in the setting of an early Latin translation of the interesting paper in the history of placebo as it presented
Hebrew Bible.1,2 It is believed that the word placebo (a placebo in a somewhat positive way, identifying it as a
Latin word) was actually the result of a mistranslation useful tool for both the physician and for the patient.
from the ancient Hebrew word ‘ethalech,’ which means In fact, the notion that placebo may reduce a patient’s
‘I shall walk.’3 In the opening phrase of the Vespers for symptoms (by pleasing them) during the course of an
the Dead (Psalm 116, 9th verse), the biblical phrase reads incurable disease introduces the idea that placebo effects
‘Placebo Domino in regione vivorum,’ which translated may be meaningful in certain therapeutic contexts,
means ‘I shall walk before the Lord.’4,5 However, this particularly when symptomatic improvement is an
Placebo and Pain. http://dx.doi.org/10.1016/B978-0-12-397928-5.00001-5 1 Copyright © 2013 Elsevier Inc. All rights reserved.
2 PLACEBO AND PAIN
important goal. This insightful paper may have been the the rods in a blinded manner. He first implanted
impetus for the first documentation of the term ‘placebo’ ‘imitation’ rods (made from wood), and four of the five
in a medical dictionary in 1785 (Motherby’s New Medi- patients gained relief. The procedure was then repeated
cal Dictionary).8 In this dictionary, placebo was defined with the genuine Perkins Tractors, with the same result.
as ‘a common placebo method or medicine’; this is not Haygarth quotes ‘an important lesson in the physic is here
entirely in keeping with the original translation of the to be learnt, the wonderful and powerful influence of the
word, or even Cullen’s initial use, but it nonetheless passions of the mind upon the state and disorder of the body.’7
acknowledged ‘placebo’ as an entity in the medical set- Together, these trials were the first in the medical field to
ting. However, it was not much later (1811) that a clearer use a placebo in the setting of a control for the purposes
definition was provided in Hooper’s Medical Diction- of assessing the validity of a treatment. Furthermore, the
ary, which defined a placebo as ‘any medicine adapted conclusions of these trials would shape interpretation
more to please than benefit the patient,’ and therefore of placebo-controlled trials to the current day. Frankin,
this definition was more representative of the origin of Lavoisier and Haygarth all came to similar conclusions
the word.8 Despite many minor modifications over the as to a ‘response’ to the placebo treatment. First, this
years, this has arguably remained the foundation of both demonstrated a lack of evidence for the intervention in
the definition and meaning of placebo that has persisted question. Second, response to placebo was a construct
to recent times. of the ‘imagination,’ and therefore was quite separate
to an effect that existed in the body. Haygarth, however,
did make an important link between mind and body,
PLACEBOS AS CONTROLS which seems to have been an advanced appreciation for
the time.
At a similar time to the first use of the word in the
medical literature, the notion of using a placebo as a
control in the medical setting was presented. In 1784, PLACEBOS AS A TREATMENT
what is believed to be the first placebo-controlled exper-
iment was conducted by Benjamin Franklin and Antione The assessment of placebo use as a treatment is some-
Lavoisier.10 The trial was conducted as a result of Louis what complex as it depends on whether one assesses
XVI appointing a Royal Commission to investigate the the validity of a given treatment, using a modern scien-
work of Franz Anton Mesmer, who had claimed to have tific framework, or attempts to understand the intention
discovered a new curative technique. This technique of the clinician in prescribing treatments. For the latter,
was called ‘mesmerism,’ and was founded on the belief one is particularly reliant on the literature, although it
that humans had certain internal channels of fluid, a is entirely possible that, despite frequent use of place-
property Mesmer called ‘animal magnetism,’ and that bos in routine clinical practice, this was not presented in
targeting these fluid channels with therapy could alle- the medical literature due to the negative connotations
viate many bodily symptoms. Initial results from the surrounding placebo use. Regardless of the approach
elaborate rituals of mesmerism suggested profound to assess placebo use clinically, this has been a dif-
effects, and it was on this basis that the controlled trial ficult task even for experienced anthropologists and
was established.10 In this trial, patients were exposed historians.13–15
to genuine ‘mesmerized’ objects (as described by Mes- The analysis of ‘prescientific’ medicine using a current
mer) and objects which were reportedly mesmerized, scientific framework has led some authors to propose the
but which had been secretly swapped and were simply idea that the history of prescientific medicine may actu-
a ‘dummy.’ As a significant number of patients would ally be the history of the placebo effect.15 Such a view
respond to both objects, the commission concluded is constructed on the assessment of the many different
that there was no scientific evidence of Mesmer’s treatments presented in the literature and in a variety
theories, and that any effects were due to a patient’s of pharmacopias. For example, some remedies sighted
‘imagination.’10 in the London Pharmacopoeia include ‘Usnea’ (the
It was not long after that another placebo-controlled moss from the skull of a victim of a violent death) and
trial was conducted, this time in the setting of surgery. In Gascoyne’s powder (bezoar, amber, pearls, crabs’ eyes,
1799, a British physician by the name of John Haygarth claws and coral).14,16 Other common remedies included
decided to perform a trial on a treatment which involved unicorn horn (usually from an elephant) and bezoar
surgical implantation of metallic rods (‘Perkins Trac- stones (allegedly formed from the tears of a deer bitten
tors’).11 It was believed that the metallic properties of the by a snake, but actually animal gallstones).17 In fact, it
tractors were able to alleviate the symptoms of disease.12 has been estimated that there were at least 5000 ancient
In this small trial of five patients, Haygarth implanted remedies with over 16 000 different prescriptions.14
HISTORICAL ASPECTS OF PLACEBO ANALGESIA 3
Another way of assessing the use of placebo as a treat- PLACEBO IN THE EARLY 20TH CENTURY
ment has come with the study of Native Americans, who
used an incredible number of medicinal plants in differ- Placebos continued to be used in the first half of
ent prescriptions for many ailments. It has been assessed the 20th century, primarily as controls in experiments.
that over 219 different cultures of Native Americans used This was essentially a progression from the previously
more than 2800 species of medicinal plants in over 25 000 described trials some 100 years before. However, there
ways.15 However, this line of sociocultural research had possibly been a shift in the interpretation of pla-
places less focus on assessment of scientific validity of cebo effects in the setting of trials. This may have been
these remedies (the actual content) than on their cultural shaped by work some years before, such as a small trial
meaning. To this extent, placebo was conceptualized conducted by an American physician, Austin Flint, in
more by the use of remedies as part of a symbolic healing 1863. In this study, a placebo was given (a diluted rem-
ritual, one which modern medicine would identify as a edy) for the management of articular rheumatism. The
placebo (by the so-called inert nature of the remedy).18 conclusion was that the placebo would not actually alter
However, it is important to keep in mind that s o-called the natural course of the disease, rather it would provide
‘healing rituals’ have not been isolated to specific cul- symptomatic relief as the disease progressed through
tures, with procedures such as ‘Royal Touch’ dating its natural history.7,20 In this instance, response to a pla-
back many hundreds of years. This relatively common cebo was not deemed to be in one’s ‘imagination,’ or not
procedure involved laying one’s hands on a patient as a genuine response, rather it was seen as an observed
a treatment for illness, and was one of the most persis- response to the administration of a placebo treatment.
tent methods of healing that extended into contempo- Therefore, one could assess the symptomatic response to
rary times.17 Both qualitative assessment of the content a placebo and compare it to the response to the interven-
of treatments, and assessment of the broader ritualistic tion in question (or index intervention). The difference
nature of healing using a modern framework, suggest between symptomatic relief to placebo and to that of the
that, by modern definition, these practices resembled index intervention represented the additional effects of
the use of placebo as a means of alleviating symptoms the index treatment, which were presumably more spe-
of disease. cific to the disease process. It is therefore possible that
The assessment of specific placebo use is also difficult such shifts in thinking may have shaped the introduc-
and open to interpretation, particularly from a definition of blinded trials using placebos, several of which
tional perspective. Many of the above treatments may were conducted in the early 1900s.20
have been believed to be specific for the cure of disease, The use of placebos in the clinical trial setting
rather than simply a treatment to ‘please’ the patient increased in the early 20th century, with the first clini-
(using the very original definition of a placebo). In other cal blinded study conducted in 1913.21 Soon after, sev-
words, the intention of the clinician may not have been eral trials using what was called ‘the blind method’22
to prescribe a placebo, as he or she may have believed were conducted, some with numbers approaching 1000
that the treatment was a cure for a disease, even if a pla- subjects, such as the trial conducted by Adolf Bingel in
cebo was actually given. Although the word placebo is 1918.14 In this particular trial, researchers tested an ‘anti-
not often used, there are cases where one may interpret toxin’ and a placebo for the treatment of diphtheria. Bin-
the intention of the physician as being ‘pleasing’ rather gel made a specific point of using colleagues who were
than focused on curing the disease. For example, in 1807, blinded to the allocation as assessors of the treatment,
Thomas Jefferson was recorded as stating what he termed underscoring his beliefs about the importance of con-
‘pious fraud’ when a successful physician reported trols and blinding in evaluation of treatments. After sev-
that he used more bread pills, drops of coloured water eral years of limited use, controlled blinded trials were
and powders of hickory ashes than all other medicines again reported, firstly in the setting of assessing different
combined.7 Similarly, others have noted that part of the types of ether preparation23 and then in the assessment
practice of medicine was to learn to give placebo, bread of aminophylline for angina pectoris.24 In fact, over this
pills, subcutaneous water and other devices.19 Although period of time, Gold and his colleagues introduced the
there is not a great amount of literature using such direct ‘placebo-controlled double-blind trial’ to modern medi-
language about placebo use, it does suggest that the cine, which is still in use today.14 This method was made
practice of using placebos with the specific intention of famous when it was used to study a treatment (Khellin)
bringing comfort (and not fixing pathology) may have for angina pectoris in 1950.25 It was felt that controlling
been quite widespread, although, as mentioned previ- the placebo effect in the study of a treatment was impor-
ously, the negative connotations surrounding placebo tant for understanding the effect of the drug above the
use may have resulted in a lack of desire to publish on response to placebo administration. This paradigm was
the area. slowly adopted as standard for both research-funding
4 PLACEBO AND PAIN
bodies, and later extended to the approval for new drugs post-operative pain, and therefore represented one of
in several countries. the first attempts to use placebo to improve clinical out-
comes. In this study of 97 patients, researchers investi-
gated pain scores and total analgesic medication use in
PLACEBO AS MORE THAN JUST AN two groups of patients post-operatively. The first group
EXPERIMENTAL CONTROL was treated in a standard manner. The second group, or
‘special care’ group, received additional attention (both
Throughout the first half of the 20th century, there in content and time) and advice from the physician
were limited publications on the clinical use of placebo. regarding management of post-operative pain. At this
Nonetheless, there were papers such as the one written time, such an intervention was deemed to be ‘a placebo’
by Houston in 1938 which was titled ‘The Doctor Himself as any benefit was not attributable to a specific phar-
as a Therapeutic Agent.’26 Although not strictly report- macologic action of a medicine. Researchers found that
ing placebo use, this paper described the effect of the the total analgesic drug dose was significantly lower in
therapeutic relationship or environment on the patient, the ‘special care’ group than in the routine group, con-
implying that factors other than the prescribed therapy cluding that the physician interaction was an important
were also powerful in patient outcomes. Papers such component of a therapeutic outcome (Fig. 1.1). This
as this one started to evolve thinking about the various was an important initial paper in linking the doctor–
components of the therapeutic encounter and how this patient interaction with placebo effects and the ability to
might result in improvements in patients’ symptoms. It improve clinical practice.
was not long after that Wolf and colleagues published Perhaps the most significant paper published in many
a paper advocating the use of placebos in the clinical years came in 1955, in that it drew attention to the results
setting.27 In this paper, the authors suggested that if a of the placebo group in placebo control trials, and, in
patient was ‘pleased’ by receiving a placebo, then this doing so, estimated the power of ‘the placebo effect.’29
was in fact a positive response to treatment. This paper
seems to have been the first paper that specifically used
the word placebo in the title and advocated use in the
routine clinical setting.
Further exploration of placebo in its own right was
seen in a pioneering paper by Lasagna and colleagues
in 1964. This paper investigated placebo analgesia in the
setting of post-operative pain, with the goal of under-
standing placebo responses and placebo responders.
Researchers studied 93 patients with post-operative
pain and administered alternating doses of placebo and
opioid analgesia (morphine). A clinically meaningful
effect was defined as 50% reduction in pain, and mul-
tiple alternating doses were able to be given to reach
this target. The repeated administration protocol per-
mitted an evaluation of initial and consistent responses
to placebo. Researchers found that only 14% of patients
responded consistently to placebo, with 31% of patients
consistently not responding. A large percentage (55%)
of patients were defined as inconsistent responders. An
additional qualitative analysis was performed, suggest-
ing that placebo responders may have had more somatic
symptoms, higher levels of anxiety, and a more positive
view of the hospital compared to non-responders. This
led the investigators to make some conclusions as to the
different psychologic and behavioral traits seen between
responders and non-responders. To this extent, this was
a pioneering paper in investigating placebo analgesic FIGURE 1.1 Figure reproduced from Egbert LD, Battit GE, Welch
responses in a clinical setting. CE, Bartlett MK. Reduction of postoperative pain by encouragement
and instruction of patients – a study of doctor–patient rapport. N Engl
In the same year (1964), another landmark paper was J Med 1964;270(16):825–827. Note the significant differences between
published.28 This paper assessed whether ‘active pla- total postoperative morphine use between the control and ‘special
cebo action’ could be used to improve management of care’ groups.
In this seminal paper, titled ‘The Powerful Placebo,’ effects) than in clinical trials (which are strictly controls),
Beecher analysed the results of 15 controlled trials and and that there are significant methodological issues in
pooled the results together to estimate the power of the treating the placebo effect as a single effect and assessing
placebo effect. The ‘effect’ was estimated at an average it across many different clinical settings. However, in the
of 35.2% (range of 21% to 58%).29,30 After so many years, bigger picture, these papers again brought the topic of
this paper finally took an empirical approach to quan- placebo to light and gained an extraordinary amount of
tifying just how important the placebo effect might be attention in medical literature and in the printed media.
in different medical settings. Although there are many
papers which question the interpretation of this trial,
it marked an important step in research on placebo, as THE EMERGENCE OF THE STUDY OF
people had become interested in what happened in the PLACEBO MECHANISMS
placebo group rather than just in the treatment group.
Although efforts to study placebo responses in clinical Although the recent history of placebo has been domi-
trials were already underway, e.g. in the setting of post- nated by assessment of placebo responses in clinical tri-
operative pain by Lasagna and colleagues, the paper by als, concurrent interest in the mechanisms of placebo
Beecher was pivotal in raising the profile of placebo in started in the 1960s with a series of elegant experiments
the medical community.31 studying psychologic conditioning in animals.39,40 This
With further use of placebo as a control in medical work was soon expanded to humans,41 and together
and surgical treatments, more interest was generated demonstrated that placebo analgesic effects may be
in challenging the current practice of medicine and also mediated by conditioning (or learning) processes.
appreciating the power of the placebo effect. Examples Despite uncovering the potential understanding of how
of the power of placebo effects were seen in a series of placebo effects may be mediated, research into placebo
trials in surgery for angina pectoris, conducted not long mechanisms only blossomed from this time, represent-
after the paper by Beecher. ing the start of a new era of research into placebo.
Internal mammary artery ligation, a surgical treatment In 1978 a landmark trial was conducted by Levine and
for angina pectoris, was performed as it was believed to colleagues, who tested the hypothesis that placebo anal-
increase blood flow to the myocardium. In turn, patients gesia may be mediated by endogenous opioids. In this
reported reduced symptoms.13,15 A series of placebo double-blinded study in post-operative pain, patients
or ‘sham’ controlled trials (where half of the patients received a placebo 2 hours post-surgery and were then
received the surgery and half were given only a skin categorized into ‘responders’ and ‘non-responders.’
incision) demonstrated significant responses to both the When a second drug administration was performed (the
placebo (or sham) procedure and the real procedure.32,33 opioid antagonist naloxone) in each of these groups,
As in the past, such a response to the placebo (or sham) there was no change in pain in the ‘non-responder’
operation questioned the validity of the actual surgery, group; however, there was an increase in pain in the
suggesting that the symptom relief was merely due to a ‘responder’ group. This was an elegant demonstration
placebo effect and not to the technical nature of the pro- that placebo analgesia could be significantly reduced by
cedure. Such demonstrations of response to placebo sur- naloxone, supporting the hypothesis that endogenous
gical procedures have continued over the course of the opioids mediate placebo analgesia.42
last 50 years, with similar powerful placebo responses In 1983, the role of endogenous opioids was extended
seen in very recent trials of surgery, such as for arthros- by Grevert and colleagues in another important study
copy for knee pain34 and vertebroplasty for spinal pain.35 of the mechanisms of placebo analgesia.43 In this study,
Even in recent times, interpretation of such powerful experimentally induced arm pain was created in 30 sub-
placebo responses has involved challenging the validity jects. Each subject received a placebo injection and was
of different surgical procedures, and although accepted subsequently divided into two groups. Forty minutes
as the ‘gold standard’ in empirical evaluation of a treat- after the first placebo injection, subjects in group one
ment, placebo responses in this context have still been received a hidden administration of naloxone, and those
somewhat negative, although for a different reason, as in group two received a hidden injection of saline. This
this can challenge contemporary medical practice. ‘open–hidden’ paradigm represented a novel way to
Continued use of placebo in both medical and surgi- assess the pharmacology of the drug without the psy-
cal trials resulted in further estimates of the power of the chosocial context (hidden administration) or the phar-
placebo effect. In the last 10 years, several papers have macology of the drug and the effects of the psychosocial
been published which have attempted to analyze the context (now conceptualized as placebo effects). In this
power of placebo effects in different settings.36–38 One study, hidden naloxone reduced the initial placebo anal-
of the key findings was that placebo effects were larger gesia whereas hidden saline did not, further supporting
in experimental trials (which aim to increase placebo the role of endogenous opioids in placebo analgesia.
6 PLACEBO AND PAIN
This new paradigm improved experimental valid- Gracely and colleagues in 1985, was seemingly designed
ity and was used again a year later (1984) by Levine & in a similar manner to previous studies investigating
Gordon.44 The hypotheses and results of this experiment placebo analgesia and the endogenous opioid system.48
were in fact similar to those of Grevert et al in 1983; how- However, the hypotheses were in fact different, and this
ever, this study was particularly important in that it repro- study aimed to assess placebo analgesia and the role
duced the above-mentioned findings with the inclusion of the therapeutic encounter. In this double-blinded
of a natural history (no treatment) group. The presence administration of placebo in post-operative dental pain,
of a natural history group allows for a more valid estima- patients were divided into two groups. Patients in both
tion of a response to a placebo injection as it controls for groups were told that they could receive an opioid
the natural history of the experimental pain and statisti- analgesic (fentanyl), a placebo, or an opioid antagonist
cal phenomena such as regression to the mean.45 Each (naloxone) and that this could either improve, worsen
of these studies conducted between 1978 and 1985 pro- or cause no change to their pain. However, the clini-
vided critical groundwork for exploration into the role cians were told that there would be no active analgesic
of the endogenous opioid system and placebo analgesia. available for administration in group one, but that there
Furthermore, by virtue of the fact that placebo analgesia would be a chance of delivering an opioid analgesic in
was not completely reversed by naloxone, these studies group two. Strict double-blinded conditions remained in
raised the possibility that other physiologic systems may place. When analysing the response of patients in both
also be involved in placebo analgesia. Together with fur- groups to placebo, researchers found that a significant
ther research on conditioning in humans, e.g.,46 and the placebo effect existed in group 2 (when the clinician
psychologic construct of expectancy, e.g.,47 there was a believed that a real analgesic could be given) com-
discrete field of work aimed at understanding the mech- pared with group 1 (when the clinician believed that the
anisms of placebo effects. patient could only receive placebo or naloxone). In fact,
One particularly important study took place at around the average effect in group 1 was negative, and patients
the same time as the described work into the mecha- reported increases in pain (Fig. 1.2). Whilst this experi-
nisms of placebo analgesia. This study, conducted by ment seemed to be designed to extend previous work on
8
(Pain Rating Index, McGill Pain Questionnaire)
6 Placebo (group PN)
4
CHANGE IN PAIN
–2
Placebo (group PNF)
–4
–10 0 10 60
MINUTES AFTER TREATMENT
Change in pain rating index between baseline (10 min before injection) and 10 and 60 min
after administration of placebo.
PN = group that could have either received placebo or naloxone.
PNF = group that could have received placebo, naloxone, or fentanyl (PNF).
FIGURE 1.2 Figure reproduced from Gracely RH, Dubner R, Deeter WD, Wolskee PJ. Clinicians’ expectations influence placebo analgesia.
Lancet 1985;5:43. Note that in the group PN, where there was no possibility of delivering active analgesia, subjects actually reported increased
pain compared with the group PNF, where clinicians believed that there was a possibility of delivering an active analgesic. A significant placebo
effect is seen in the PNF group.
opioid mechanisms, it was actually constructed to assess medical treatment.60 This is supported by very interest-
the interaction between the clinician and the patient. The ing research demonstrating differences in drugs when
authors concluded that the information given to they are given in a normal clinical manner or in a hid-
the clinicians may have resulted in subtle changes in den manner (which removes the treatment context or
the doctor–patient relationship (as double blinding ritual).61 In fact, when one gives a placebo, it is studying
prohibited exchange of any information) and that the the effect of the psychosocial context (which includes
clinician’s behaviors and gestures may have the ability concepts such as meaning and the treatment ritual) on
to modulate placebo analgesia. the patient without giving the actual treatment itself.45
In more recent times, research in placebo mechanisms Logic then decrees that any health-care encounter (as
has expanded exponentially. In 1995, Fabrizio Benedetti there is a psychosocial context) has the ability to activate
published a paper which demonstrated that placebo placebo mechanisms, and that these mechanisms may
analgesic effects were not only related to one system be very different according to the clinical situation. This
(the opioid system), but to another chemical (cholecys- reconceptualization draws on the previously mentioned
tokinin).49 This research group in Italy then drove the historical literature, some of which places less focus on
research agenda on placebo, discovering that there were ‘the placebo’ and more focus on the therapeutic ritual or
multiple psychologic and biologic mechanisms for pla- context.
cebo analgesic effects, e.g.50–52 Others supported this Taken together, there is a large transition from the use
work (which was primarily in the field of pain and anal- of placebo to test whether a treatment is real or ‘imag-
gesia) and expanded it to include novel imaging of the ined,’ or to see placebo in a negative light, to a modern
brain, e.g.,53,54 and studies of placebo in other conditions appreciation of a dynamic group of effects related to the
such as Parkinson’s disease.55,56 Of great importance was therapeutic ritual or context. This appreciation presents
that the mechanism literature prompted re-evaluation the notion that one should not deceptively give place-
of the concept of placebo, which still has strong links to bos but rather understand how placebo mechanisms can
both its biblical origins and early use in the clinical trial be activated when giving valid therapies to patients. It
setting. is now understood that it is not the content of the pla-
cebo that ‘pleases’ the patient, rather it is the psychoso-
cial context and ritual of receiving the placebo therapy
USING HISTORY TO FURTHER EXPLORE which changes the mind–brain–body interaction. After
PLACEBO ANALGESIA some hundreds of years, a new era in placebo research is
emerging: one that aims to better understand the mind–
Only recently has there been a concerted attempt to brain interaction through understanding placebo effects.
re-evaluate placebo in the context of clinical trials and Only then will one be able to look back and see how
clinical practice. Such examples include reviews of pla- something with such a negative origin has led to very
cebo mechanisms and their implications for clinical trials positive steps forward in health care.
and practice,57 and concerted attempts to reconceptual-
ize the topic area, e.g., Miller and Kaptchuk.58 Taken References
together, an analysis of the history of placebo coupled
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not one placebo effect, rather there are many, including
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161-165.
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Despite some of the unsavory connotations from the Hist. 1987;31:123-142.
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8 PLACEBO AND PAIN
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C H A P T E R
2
Neurochemistry of Placebo Analgesia: Opioids,
Cannabinoids and Cholecystokinin
Fabrizio Benedetti, Elisa Frisaldi
Department of Neuroscience, University of Turin Medical School, and National Institute of Neuroscience, Turin, Italy
INTRODUCTION Cholecystokinin (CCK) is an octapeptide which binds

to a couple of receptor subtypes: CCK-1 and CCK-2. The
Historically known for their analgesic effects, the distribution of CCK in the brain matches that of the opi-
endogenous opioid peptides are represented mainly by oid peptides at the spinal and supraspinal level,5 sug-
beta-endorphin, enkephalins and dynorphins. They are gesting a close interaction between the two systems.6
the natural ligands of the opioid receptors and, like their From a functional point of view, CCK inhibits the anal-
relative agonists (e.g. morphine) and antagonists (e.g. gesic effects of morphine7 and β-endorphin,8 so that it is
naloxone), they are not entirely specific for any one of the considered as an antagonist of the opioid system.6
receptor subtypes. In fact, different types of opioid recep- These three neurotransmitters have been found to
tors exist, all belonging to the G protein-coupled receptor powerfully modulate both placebo analgesia and nocebo
superfamily. The most studied and understood are μ hyperalgesia. Therefore, today they are considered to
(or MOR, from mu opioid receptor), δ (DOR) and κ (KOR). have a pivotal role in placebo and nocebo responses
The opioid receptors are found in a variety of brain (Fig. 2.1). In the following sections we describe how this
regions in different proportions, from the spinal cord to modulation takes place.
the cerebral cortex. Whereas MOR and DOR receptors
probably mediate both spinal and supraspinal analgesia,
KOR receptors are involved mainly in spinal analgesia.1 SOME TYPES OF PLACEBO ANALGESIA
The endogenous cannabinoids are closely related ARE MEDIATED BY ENDOGENOUS
to the active ingredients present in Cannabis sativa OPIOIDS
extracts. The endocannabinoids belong to the class of lipid
mediators, a series of arachidonic acid derivatives that Placebo-induced analgesia has been found to be
play pivotal roles in immune regulation, in self-defense, related to the activation of the endogenous opioid sys-
and in the maintenance of homeostasis in living systems. tems in some circumstances. The first study that tried
Ligands and receptors of this system are present at vari- to understand the biologic mechanisms of placebo anal-
ous levels in the pain pathways, from peripheral sensory gesia was aimed at blocking opioid receptors with the
nerve endings to spinal cord and supraspinal centers, in antagonist naloxone.9 This study was performed in the
a way that is parallel to, but distinct from, that involving clinical setting in patients who had undergone extrac-
opioid receptors.2 Like other lipid mediators (e.g. pros- tion of the third molar. The investigators found a disrup-
taglandins), they appear to be synthesized and released tion of placebo analgesia after naloxone administration,
locally on demand. The endocannabinoids in mammalian which indicates the involvement of endogenous opioid
tissues are mainly anandamide, 2-arachidonylglycerol systems in the placebo analgesic effect. One of the major
and 2-arachidonylglyceryl ether.2 They bind to a couple criticisms was the lack of adequate control groups, such
of distinct types of G-protein-coupled receptor, CB1 and as a natural history group, as well as the possibility that
CB2. The former is expressed mainly in the brain, while naloxone per se might have a hyperalgesic effect.10 From
the latter is expressed in peripheral tissues, such as the this perspective, the higher pain intensity following nal-
immune system.2–4 oxone administration would not be due to the blockade
10 PLACEBO AND PAIN
FIGURE 2.1 General schema of the involvement of opioid, cannabinoid and cholecystokinin systems in placebo analgesia and nocebo
hyperalgesia.
of placebo-induced activation of endogenous opioids, endogenous opioids in placebo analgesia was explained.
but rather to the hyperalgesic properties of naloxone. By using the model of experimental ischemic arm pain
This is a crucial point because naloxone must not have (tourniquet technique), it was definitely clarified that
any hyperalgesic effect in order to be used in the study of naloxone, which was tailored to individual weights,
the placebo effect. Despite these limitations, the study by does not affect this kind of pain, so that any effect fol-
Levine, Gordon and Fields9 represented the first attempt lowing naloxone administration could be attributed to
to give scientific credibility to the placebo phenomenon the blockade of placebo-induced opioid activation.15
by unraveling the underlying biologic mechanisms. Concurrently, the same authors tested the effects of pro-
Thus, this study represents the passage from the psycho- glumide, a non-specific antagonist for CCK-1 and CCK-2
logic to the biologic investigation of the placebo effect. receptors, on placebo analgesia. It was hypothesized
The years that followed the publication of the study by that, on the basis of the anti-opioid action of CCK, the
Levine et al9 were characterized by some attempts to ver- blockade of CCK receptors could enhance the opioids
ify and to reproduce these findings.11,12 However, in 1983, released by the placebo. Indeed, it was found that the
Gracely et al13 demonstrated that naloxone may indeed CCK-blocker enhanced placebo analgesia, which repre-
have hyperalgesic effects in postoperative pain, thus pos- sents a novel and indirect way to test the opioid hypoth-
ing some doubts on the opioid hypothesis of placebo anal- esis.15,16 Therefore, the model we have today to explain
gesia. Research in this field had a long pause from 1984 the analgesic effect following the administration of a pla-
to 1995, with the exception of a few isolated studies. For cebo involves two opposing neurotransmitter systems,
example, Lipman and collaborators14 studied chronic-pain opioids and CCK.
patients and found that those patients who responded to In 1984, Fields and Levine17 had hypothesized that
a placebo administration showed higher concentrations the placebo response may be subdivided into opioid
of endorphins in the cerebrospinal fluid compared with and nonopioid components. In particular, Fields and
those patients who did not respond to the placebo. Levine’s suggestion was that different physical, psy-
From 1995 until 1999, a long series of experiments chologic and environmental situations could affect the
with rigorous experimental designs were performed by endogenous opioid systems differently. This concept
Benedetti and collaborators. During these 5 years, many was further supported by the finding that the placebo
unanswered questions were clarified, and the role of analgesic effect is not always mediated by endogenous
NEUROCHEMISTRY OF PLACEBO ANALGESIA 11
opioids.13 This issue was partially addressed by Amanzio placebo administration was carried out in another study
and Benedetti,18 who showed that both expectation and which used noxious thermal stimulation.25 In these stud-
a conditioning procedure can result in placebo anal- ies, placebos affected opioid activity in a number of pre-
gesia. The former is capable of activating opioid sys- dicted opioid-rich regions that play central roles in pain,
tems whereas the latter activates specific subsystems. including periaqueductal gray, dorsal raphe and nucleus
In fact, if the placebo response is induced by means of cuneiformis, amygdala, orbitofrontal cortex, insula,
strong expectation cues, it can be blocked by the opioid rostral anterior cingulate, and lateral prefrontal cortex.
antagonist naloxone. Similarly, if a placebo is given after Connectivity analyses revealed that placebo treatment
repeated administrations of morphine (preconditioning increased connectivity between the periaqueductal gray
procedure), the placebo response can be blocked by nal- and the rostral anterior cingulate cortex.26
oxone. Conversely, if the placebo response is induced by The pharmacologic approach with opioid antago-
means of prior conditioning with a nonopioid drug, it is nists, such as naloxone,9,18,26,27 and with CCK antago-
naloxone-insensitive.18 nists, such as proglumide,15,16,28,29 has been crucial over
Specific placebo analgesic responses can be obtained the past years to understand the neurobiology of placebo
in different parts of the body,19,20 and these responses are analgesia. With a similar approach, Benedetti and collab-
naloxone-reversible.21 For example, if four noxious stim- orators used a CCK-2 receptor agonist, pentagastrin, in
uli are applied to the hands and feet and a placebo cream order to investigate how CCK hyperactivity affects the
is applied to one hand only, pain is reduced only on the placebo analgesic response in the experimental model of
hand where the placebo cream had been applied. This ischemic arm pain.30 In this study, placebo analgesia was
highly specific effect is blocked by naloxone, suggesting tested after morphine preconditioning, which is known
that the placebo-activated endogenous opioid systems to be mediated by endogenous opioids.18,27 As hypoth-
have a precise and somatotopic organization, probably esized, the activation of CCK-2 receptors by means of
at the central level.21 pentagastrin completely abolished placebo analgesia.
A common observation in all these studies is that the Therefore, a change in the balance between opioids
naloxone dose necessary to block placebo analgesia is as and CCK, which seems to be crucial in several condi-
large as 10 mg, which suggests the involvement of dif- tions,31,32 may influence placebo analgesia in opposite
ferent classes of opioid receptors, like the MOR, DOR directions, depending on the activity of these two neu-
and KOR. In fact, the binding affinity of naloxone for the rotransmitters: when CCK activity outweighs opioid
DOR and KOR receptors is about 10–15 times lower than activity, placebo analgesia is reduced, while the opposite
for the MOR receptors, thus large doses are supposed to situation leads to increased placebo analgesic responses.
involve DOR and KOR receptors as well. These effects have also been studied in mice by Guo
In 2002, Petrovic et al22 found that some brain regions et al.33 On the basis of Amanzio and Benedetti’s experi-
in the cerebral cortex and in the brainstem are affected ments,18 these researchers used the hot-plate test in an
by both a placebo and the rapidly acting opioid ago- attempt to measure the reaction time of mice to nocicep-
nist remifentanil, thus indicating a related mechanism tive stimulus (hot plate) after different types of phar-
of placebo-induced and opioid-induced analgesia. In macologic conditioning. This was performed by the
particular, the administration of a placebo induced the combination of the conditioned cue stimulus with the
activation of the rostral anterior cingulate cortex and the unconditioned drug stimulus, either the opioid mor-
orbitofrontal cortex. Moreover, there was a significant phine or the nonopioid aspirin. If mice were conditioned
covariation in activity between the rostral anterior cingu- with morphine, placebo analgesia was completely antag-
late cortex and the lower pons/medulla, and a subsignif- onized by naloxone, whereas if mice were conditioned
icant covariation between the rostral anterior cingulate with aspirin, placebo analgesia was naloxone-insensitive.
cortex and the periaqueductal gray, thus suggesting that These findings show that, also in mice, the mechanisms
the descending rostral anterior cingulate/periaqueduc- underlying placebo analgesia include both opiod and
tal gray/rostral ventromedial medulla pain-modulating nonopioid components and may depend on the previous
circuit is involved in placebo analgesia, as previously exposure to different pharmacologic agents.
hypothesized by Fields and Price.23
In 2005, the first direct evidence of opioid-mediated
placebo analgesia was published.24 By using in vivo ENDOCANNABINOIDS ARE INVOLVED
receptor-binding techniques with the radiotracer IN SOME TYPES OF PLACEBO
carfentanil, a MOR agonist, it was shown that a pla- ANALGESIA
cebo procedure activates MOR neurotransmission in
the dorsolateral prefrontal cortex, the anterior cingu- From the previous studies it is clear that the endog-
late cortex, the insula, and the nucleus accumbens. A enous opioid systems are not the only mechanisms
more detailed account of MOR neurotransmission after involved in placebo analgesia. When a nonopioid
12 PLACEBO AND PAIN
drug is administered for a few days in a row, and then anxiogenic procedure, for an inert treatment has to be
replaced with a placebo, the placebo analgesic response given along with negative verbal suggestions of pain
is not reversed by naloxone, which suggests that specific increase.
pharmacologic mechanisms are involved in a learned In 1997, a trial in postoperative patients was run
placebo response, depending on the prior exposure to with the CCK antagonist proglumide.28 This consisted
opioid or nonopioid substances.18,33 Another placebo of a post-surgical manipulation that induced expecta-
analgesic effect that is not mediated by opioids has been tions of pain worsening. It was found that proglumide
described in irritable bowel syndrome patients, indicat- prevented nocebo hyperalgesia in a dose-dependent
ing that in different medical conditions, and in different manner, even though it is not a specific painkiller,
circumstances, other systems may be recruited.34 thus suggesting that the nocebo hyperalgesic effect is
There is today accumulating evidence that nonsteroi- mediated by CCK. This effect was not antagonized by
dal anti-inflammatory drugs (NSAIDs), such as ketorolac naloxone. A dose of proglumide as low as 0.05 mg was
and aspirin, have effects that go well beyond the inhibi- totally ineffective, whereas a dose increase to 0.5 and
tion of cyclooxygenase and prostaglandin synthesis. In 5 mg proved to be effective. As CCK is also involved in
fact, NSAIDs have been found to interact with endocan- anxiety mechanisms, it was hypothesized that proglu-
nabinoids, a class of lipid mediators, both in vivo and mide affects anticipatory anxiety.1,28 However, due to
in vitro,35,36 and cyclooxygenase-2 has been shown to ethical limitations in these patients, these effects were
utilize endocannabinoids as substrates.37 Therefore, the not investigated further.
endocannabinoid system may play a pivotal role in both In order to better understand the mechanisms under-
the therapeutic and adverse effects of NSAIDs38 as well lying nocebo hyperalgesia and to overcome the ethical
as in NSAID-induced placebo responses.18,33 constraints that are inherent in the clinical approach, a
On the basis of all these considerations, Benedetti and similar procedure was used in healthy volunteers by
collaborators39 induced opioid or nonopioid placebo inducing experimental pain.29 The oral administration
analgesic responses and assessed the effects of the of an inert substance, along with verbal suggestions of
CB1 receptor antagonist rimonabant. Unlike n aloxone, hyperalgesia, was found to induce both hyperalgesia
rimonabant had no effect on opioid-induced placebo and hyperactivity of the hypothalamic–pituitary–adrenal
analgesia following morphine preconditioning, whereas axis, as assessed by means of adrenocorticotropic hor-
it completely blocked placebo analgesia following mone (ACTH) and cortisol plasma concentrations.
nonopioid preconditioning with ketorolac. These f indings Both nocebo-induced hyperalgesia and hypothalamic–
indicate that those placebo analgesic responses that are pituitary–adrenal hyperactivity were blocked by the
elicited by conditioning with NSAIDs are m ediated by benzodiazepine diazepam, which suggests the involve-
CB1 cannabinoid receptors. ment of anxiety mechanisms. By contrast, administration
Although the site where the CB1 receptors are acti- of the mixed CCK-1/2 receptor antagonist proglumide
vated cannot be established, recent in vivo studies in blocked nocebo hyperalgesia completely, but had no
baboons40 and humans41 indicate that CB1 receptors are effect on the hypothalamic–pituitary–adrenal hyperac-
abundant in the basal ganglia, for example in the stria- tivity, thus suggesting a specific involvement of CCK in
tum, which has been found to have a key role in the pla- the hyperalgesic but not in the anxiety component of the
cebo response. In fact, the nucleus accumbens, a part of nocebo effect. Interestingly, both diazepam and proglu-
the ventral striatum which belongs to the dopaminergic mide did not show analgesic properties on baseline pain,
reward system, is activated after placebo administra- as they acted only on the nocebo-induced pain increase.
tion.42,43 Therefore, a key question for future research These data suggest that a close relationship between
will be to understand where in the brain the endocan- anxiety and nocebo hyperalgesia exists, but they also
nabinoids are activated during placebo analgesia and indicate that proglumide does not act by blocking antici-
how they possibly interact with other systems such as patory anxiety, as previously hypothesized,1,28 but rather
the opioid network. it interrupts a CCKergic link between anxiety and pain.
Therefore, unlike the anxiolytic action of diazepam,
proglumide blocks a CCKergic pro-nociceptive system
NOCEBO HYPERALGESIA IS MEDIATED which is activated by anxiety and is responsible for
BY CHOLECYSTOKININ anxiety-induced hyperalgesia. Support for this view
comes from a study that used a social-defeat model of
Compared with placebo analgesia, much less is anxiety in rats, in which CI-988, a selective CCK-2 receptor
known about nocebo hyperalgesia, mainly due to ethi- antagonist, prevented anxiety-induced hyperalgesia.45
cal constraints. In fact, whereas the induction of placebo Nocebo hyperalgesia is thus an interesting model to
responses is acceptable in many circumstances,44 the better understand when and how the endogenous pro-
induction of nocebo responses represents a stressful and nociceptive systems are activated. The pro-nociceptive
NEUROCHEMISTRY OF PLACEBO ANALGESIA 13
and anti-opioid action of CCK has been documented placebos work across different diseases and therapeu-
in many brain regions,46–49 and CCK has been shown tic interventions, and we also need to test the effects
to reverse opioid analgesia by acting at the level of the of pharmacologic conditioning not only for painkill-
rostral ventromedial medulla50,51 and to activate pain- ers but also for other classes of drug as well, such as
facilitating neurons within the same region.52 The simi- immunosuppressive and hormone-stimulating agents.
larity of the pain-facilitating action of CCK, both on Another issue that requires further clarification is why
brainstem neurons in animals and on nocebo mecha- some subjects respond to placebos whereas other sub-
nisms in humans, is an interesting point that deserves jects do not, a critical point that is likely to be clarified
further investigation. by pursuing further research into both learning and the
It is worth pointing out that the discrepancy between genetics of neurotransmitters such as opioids, cannabi-
anxiety-induced hyperalgesia and stress-induced anal- noids and CCK.
gesia may be only apparent. In fact, stress is known to
induce analgesia in a variety of situations, in both ani-
mals and humans. Indeed, when we are under stress, the References
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15. Benedetti F. The opposite effects of the opiate antagonist naloxone
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nocebos. These include opioid, cannabinoid and CCK sia. Pain. 1996;64:535-543.
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will be to understand the interaction between a complex placebo analgesia: expectation-activated opioid systems versus
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However, many questions still remain unanswered. tribute to the magnitude of placebo analgesia in an experimental
For example, we need to know where, when, and how paradigm. Pain. 1999;83:147-156.
14 PLACEBO AND PAIN
21. Benedetti F, Arduino C, Amanzio M. Somatotopic activation of 41. Wong DF, Kuwabara H, Horti AG, et al. Quantification of cerebral
opioid systems by target-expectations of analgesia. J Neurosci. cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizo-
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C H A P T E R
3
Placebo Analgesia in Rodents
Jian-You Guo, Jin-Yan Wang, Fei Luo
Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, P. R. China
INTRODUCTION A likely candidate for the mediation of placebo-

induced analgesia is the opioid-related neuronal net-
Behavioral context can modulate neuronal activity in work in the brain.12 This hypothesis was supported
nociceptive and non-nociceptive somatosensory path- by a recent brain-imaging study in which the authors
ways.1,2 Placebo analgesia is one of the most striking found that the very same brain regions in the cerebral
examples of the cognitive modulation of pain percep- cortex and brainstem could be affected by either a pla-
tion. It represents a situation where the administration cebo or the rapidly acting opioid agonist remifentanil,
of an ineffective substance produces an analgesic effect thus indicating a related mechanism in placebo- and
when the subject is convinced that the substance is a opioid-induced analgesia.13 The direct demonstration
potent painkiller. It is not surprising then that a con- of placebo-induced release of endogenous opioids was
siderable effort has been committed over the last three obtained using in vivo receptor binding with positron
decades to the study of mechanisms that may account emission tomography by Wager et al14 and Scott et al.15
for placebo-induced analgesic effects. The neural basis Although neurochemical mechanisms have not yet been
of placebo analgesia was first established by Levine identified in nonopioid-meditated placebo, the possible
et al,3 who discovered that the placebo response could involvement of some neurotransmitters has been shown
be blocked by the opioid receptor antagonist naloxone. in some conditions. For instance, a specific CB1 cannabi-
This indicates the involvement of the endogenous opioid noid receptor antagonist could block nonopioid placebo
system. Following this finding, complex experimental analgesic responses but has no effect on opioid placebo
designs have elucidated several components underlying responses. These findings suggest that the endocan-
the placebo analgesic response, and other studies have nabinoid system has a pivotal role in placebo analgesia
subsequently confirmed this exciting and provocative in some circumstances when the opioid system is not
hypothesis.4–7 Significant placebo-induced activation of involved.16,17
μ-opioid receptor-mediated neurotransmission has been
directly observed in higher-order and subcortical brain
regions.8 THE PLACEBO EFFECT IN ANIMALS
Fields and Levine9 were the first to hypothesize that
placebo response may be subdivided into opioid and The placebo effect has been a topic of interest in sci-
nonopioid components. In particular, they suggested entific and clinical communities for many years, and our
that different physical, physiologic, and environmental knowledge of the mechanisms of the placebo effect has
situations could affect the endogenous opioid system been advanced considerably by human studies. How-
differently. This concept was further supported by the ever, animal models have been given less attention, and
finding that the placebo effect was not always mediated they have provided less information on this subject. For
by endogenous opioids.10 Thus, the conditions neces- the nonverbal animal, associative learning is consid-
sary for the activation of opioid systems needed to be ered to play a key role in the placebo effect. Originally
identified. This problem was addressed by Amanzio and demonstrated by Pavlov18 with animals, associative
Benedetti,11 who showed that expectation or a condition- learning was considered essentially as a pairing of two
ing procedure is capable of activating different types of stimuli. One, initially neutral in that, by itself, it elicits
placebo analgesia. no response, is called the conditioned stimulus (CS);
16 PLACEBO AND PAIN
the other, which consistently elicits a response, is called group was subjected to 45 minutes activity testing after
the unconditioned stimulus (US). The response elicited a saline injection. One week later all groups received the
by the pairing of the CS and the US is called the condi- untreated-run treatment. The DR group yielded signifi-
tioned response (CR). The formation of CRs may be due cantly more locomotion than did the UR group, while
to repeated association of the CSs with active medica- there was no difference between the DNR group and
tion, the USs. Pairing placebos with effective medication, the UR group. These results confirm the findings that a
followed by administering placebos without the medica- single administration of a drug may have consequences
tion, can produce a CR that is similar to the response to for later behavior over and above any direct actions of
medication.19 the drug; this apparent placebo effect might represent a
Pavlov and others reported the conditioning of some conditioned response.
of the effects of morphine on animals.18,20 Dogs were Pihl and Altman23 investigated whether the number of
given subcutaneous doses of morphine sulfate daily. A pairings between the active substance and introduction
small amount of morphine produces salivation in the into an experimental chamber affects the placebo effect in
dog and usually produces emesis and sleep. After seven rats. The experiment was run in three phases: a baseline
or eight daily administrations of morphine, these dogs phase, a drug phase, and a post-drug phase. In the base-
salivated profusely, and a few even vomited or slept line phase, all animals were placed in the experimental
while the experimenter was preparing the dogs for an chamber after administration of 0.1 mL saline (i.p.); these
injection. Presumably, events associated with the admin- animals received 10 1-hour trials in this baseline phase. In
istration of morphine become the conditioned stimuli for the drug phase, the animals were randomly divided into
some of the reactions that are characteristically induced four groups. Groups differed according to the number of
by the drug. The parallel to the placebo effect is clear, trials they received (put into the chamber after injection
but research has been restricted to morphine, and there of d-amphetamine sulfate solution). The three placebo
have not been enough controls to exclude other interpre- groups received 3, 9 and 15 trials, respectively. A control
tations. Herrnstein21 showed that saline injections mimic group received 15 trials (administered with saline). All
the effect of scopolamine hydrobromide (disrupting the animals were put into the chamber after drug or saline
learned behavior) in rats. In their schedule, a rat was injection. In the post-drug phase, all groups received
placed daily in a chamber that was insulated for light saline injection prior to 15 trials. The results of the post-
and sound and contained a lever and a feeding device. drug phase showed that the 15-trials group was sig-
The rat was hungry and was trained to depress the lever nificantly different from the 3-trials group and from the
by reinforcement with sweetened condensed milk. After control group, while the 9-trials group was significantly
4 months training, the schedule of reinforcement had different from the 3-trials group. These data suggested
established a characteristic pattern of responding, one that the intensity of the placebo response is related to
whose primary feature is that, at the beginning of each the number of pairings between the active drug and the
cycle, there is little or no pressing of the lever, whereas, circumstances under which the drug is presented. Mean-
as the time for reinforcement approaches, the rate of while, a recent study also demonstrated that the number
lever-pressing increases continuously but quite gradu- of trials increases the magnitude of placebo responses in
ally. The effect of scopolamine on this behavior is to humans.24
depress the overall frequency of response and to abolish Regarding immunomodulatory placebo effects, it has
the orderly progression of the rat. At this time, there was been reported that peripheral antigenic stimulation can
no detectable effect on behavior of the saline administra- work as a US, and thus can be associated with a spe-
tions. The results showed that physiologic saline could cific external stimulus (CS = placebo). Metalnikov and
mimic the effect of scopolamine hydrobromide to some Chorine are generally credited with having conducted
extent when the two substances were alternately admin- the first studies on behaviorally conditioned immune
istered in a series of injections. This might be the first effects.25 However, the famous study on conditioned
study to mention the placebo effect in animals using the immunosuppression was published by Ader and Cohe.26
Pavlovian conditioning procedure. In their experiment, an illness-induced taste aversion
The research of Sherman and Schnitzer22 further sup- was conditioned in rats by pairing saccharin with cyclo-
ported a placebo effect in the rat. In their study, rats were phosphamide, an immunosuppressive agent. Three
assigned randomly to a drug-run (DR), drug-not-run days after conditioning, all animals were injected with
(DNR), or untreated-run (UR) group. Both the DR and sheep erythrocytes. Hemagglutinating antibody titers
DNR groups were given d-amphetamine sulfate in the measured 6 days after antigen administration were high
first week of testing. The DR group was placed in the in placebo-treated rats. High titers were also observed
apparatus and activity was measured for 45 minutes in nonconditioned animals and in conditioned animals
immediately after drug injection. The DNR group was that were not subsequently exposed to saccharin. No
returned to the home cages after drug injection. The UR agglutinating antibody was detected in conditioned
PLACEBO ANALGESIA IN RODENTS 17
animals treated with cyclophosphamide at the time of transferable from pain to depression and could produce
antigen administration. Conditioned animals exposed a significant antidepressant effect in a test on depression
to saccharin at the time of, or following, the injection in mice. With this animal model of the placebo response
of antigen were significantly immunosuppressed. An after morphine preconditioning, the opioid placebo
illness-induced taste aversion was also conditioned analgesia was found to be mediated exclusively through
using lithium chloride (LiCl), a nonimmunosuppressive a μ-opioid receptor in the rat.
agent. In this instance, however, there was no attenua-
tion of hemagglutinating antibody titers in response to
injection with antigen. This was formally the beginning DISSECTION OF PLACEBO ANALGESIA
of psychoneuroimmunology as a modern discipline. To IN MICE
date, a number of innate and adaptive immune responses
have been shown to be modulated by behavioral condi- Amanzio and Benedetti11 have investigated the mech-
tioning protocols, in which conditioned immunomodu- anisms underlying the activation of endogenous opioids
lating responses could be conceptualized as placebo in placebo analgesia. Their findings show that the cog-
effects.27–30 nitive factors and conditioning are balanced in different
Many CRs can be learned with a single trial, as in ways in placebo analgesia, and this balance is crucial for
fear conditioning and taste-aversion learning, which the activation of opioid or nonopioid systems. Expecta-
is another kind of placebo effect (nocebo effect) such tion triggers endogenous opioids, whereas conditioning
as Pavlovian fear conditioning. Pavlovian fear con- activates specific subsystems. In fact, if conditioning is
ditioning has become part of the standard arsenal of performed with opioids, placebo analgesia is medi-
behavioral tasks used to interrogate the mnemonic ated via opioid receptors; if conditioning is performed
capacities of rats and mice.31 In fear conditioning, with nonopioid drugs, other nonopioid mechanisms
neutral stimuli (conditional stimuli or CSs) such as are found to be involved. On the basis of Amanzio and
tones, lights, or places (contexts) are arranged to pre- Benedetti’s experiments11 and previous animal work on
dict aversive outcomes such as footshock (an uncondi- placebo responses, the animal model of placebo analge-
tional stimulus or US). After conditioning, CSs come sia was established in these studies. This animal model
to evoke learned fear responses (conditional responses might also help to discover whether placebo analgesia is
or CRs) such as conditioned suppression, freezing and divided into opioid and nonopioid components in mice,
tachycardia.32 Rodent models of aversive conditioning in an attempt to clarify the mechanism of activation of
would become one of the most ubiquitous behavioral opioid and nonopioid responses.37
paradigms to explore the neural substrates of learn- Figure 3.1 shows the animal training procedure of Guo
ing and memory.33 This placebo effect is beyond the et al37 that was performed with 4 days of drug condition-
focus of the present topic, therefore we just mention ing. Female imprinting control region (ICR) mice weigh-
it briefly. ing 18–22 g at the start of the experiment were used. The
hot-plate test was used to measure response latencies
according to the method described by Hargraves and
STUDYING PLACEBO ANALGESIA IN Hentall.38 The reason for using the hot plate test was
ANIMAL MODELS that the supraspinal mechanism was considered to be
involved in this pain model.39 By contrast, some nocicep-
Study of the placebo effect has yielded its most fruit- tive tests, such as the tail-flick test, are spinal reflexes, as
ful results in the field of pain research. An opioid neu- they persist after section or cold block of upper parts of
ronal network in the cerebral cortex and the brainstem the spinal cord.40,41
was found to mediate placebo-induced analgesia.34,35 As animals received saline treatment and a 30-minute
This opioid network belongs to a descending pain- exposure to the cue compartment after morphine condi-
modulating pathway that, either directly or indirectly, tioning, pain tolerance was significantly elevated com-
connects the cerebral cortex to the brainstem.36 However, pared with the control level, indicating that the previous
to date, there have been few studies of placebo analge- morphine conditioning was sufficient to evoke a placebo
sia in animal models. Guo et al37 first evoked opioid and effect. However, if naloxone was administered after mor-
nonopioid placebo responses in mice that were either phine conditioning, paw latency was not increased. The
naloxone-reversible or naloxone-insensitive, depend- same procedures described above were repeated with
ing on the drug used in the conditioning procedure. the nonopioid aspirin conditioning. Interestingly, similar
This procedure in mice may serve as a model for fur- placebo responses were acquired, except that pretreat-
ther understanding of the opioid and nonopioid mecha- ment with naloxone cannot block the conditioned anal-
nisms underlying placebo responses. Furthermore, the gesic response established by prior conditioning with
established placebo analgesia was considered to be the nonopioid aspirin.
18 PLACEBO AND PAIN
FIGURE 3.1 Experimental paradigm used in the study to identify the opioid and nonopioid components of placebo analgesia in mice. Below
each group the experimental condition is specified. Abbreviations: NO, no treatments; Sa, saline; Na, naloxone; AS, aspirin; MO, morphine.
Modified from Guo et al.37
This research suggested that mice can learn to asso- PLACEBO ANALGESIA AFFECTS THE
ciate the context cue with elevated pain tolerance via a BEHAVIORAL DESPAIR TESTS IN MICE
set of procedures. After mice were given 4 days of drug
conditioning with the conditioned cue stimulus (i.e. the An abundance of neuroimaging studies has revealed
chamber) and the unconditioned drug stimulus (mor- the brain basis of placebo effects on pain and emotion
phine or aspirin), saline injection with the contextual cue regulation.42–44 However, in these studies the investiga-
could produce placebo analgesia at day 5. Moreover, as tors focused only on the placebo effect obtained within
a placebo response can be subdivided into opioid and a single domain. That is, they either studied the anal-
nonopioid components in humans, it is also divided into gesic effect of a pain-alleviating expectation45–47 or the
opioid and nonopioid components in mice, depending ataractic effect of an anxiety-reducing expectation.42
on the analgesics used during the training procedure; For a given placebo effect such as the analgesic effect,
morphine conditioning produced a placebo response however, its effective scope might be more general than
that was completely antagonized by naloxone. By con- pain-alleviating. Recent studies in Luo’s laboratory48,49
trast, aspirin conditioning elicited a placebo effect that showed that the placebo effect in humans can be trans-
was not blocked by naloxone. This indicates that placebo ferred from one domain to the other, namely from pain to
analgesia can also be dissected into opioid and nonopi- emotion. A significant transferable placebo effect that alle-
oid components in mice. viated negative feelings was observed. EEG recordings
FIGURE 3.2 Morphine- or aspirin-induced placebo effect and its modulation with naloxone. (A) After the procedure of morphine condition-
ing on days 1–4, mice were injected with saline and put into the conditioned cue box for 30 minutes on day 5 at 8 AM. Paw withdrawal latency
was significantly elevated, which mimics the morphine analgesic response. (B) When an injection of naloxone was delivered before exposure to
the cue environment after morphine conditioning, the morphine-mimicking effect was completely abolished. (C) After the procedure of aspirin
conditioning on days 1–4, mice received a saline injection and stayed in the cue chamber on day 5 at 8 AM for 30 minutes. Paw withdrawal latency
was significantly increased, which mimics the aspirin analgesic response. (D) When an injection of naloxone was employed, instead of saline, the
placebo effect was not affected. ** p < 0.01, * p < 0.05, compared with day 1 AM (control condition). Modified from Guo et al.37
showed that the transferable placebo treatment which included a group of animals that received treatment
was induced decreased P2 amplitude and increased N2 with clomipramine hydrochloride (1, 5 or 50 mg.kg−1).
amplitude, with source location near the posterior cin- Placebo analgesia induced a decrease in immobility (i.e.
gulate, and fMRI results indicated that this transferable antidepressant-like effect) that was significantly differ-
placebo treatment, relative to the control condition, was ent from that shown by the control group. Moreover, the
associated with reduced activity in the amygdala and placebo analgesia produced a more pronounced antide-
insula and increased activity in the subgenual anterior pressant-like effect than that achieved with 1 mg.kg−1
cingulate cortex known to be important in emotional clomipramine, but comparable to that produced by the
regulation. Therefore, this study was performed to test 5 mg.kg−1 dose of clomipramine. Similar results were
whether placebo effect could be transferred from pain also obtained in the FST; placebo analgesia significantly
(placebo analgesia) to the other domain (e.g. depressive- decreased the FST-induced immobility time in mice.
like behaviors) in placebo-analgesic mice.50 Comparison of the antidepressant-like actions of placebo
The tail suspension test (TST) and the forced swim- analgesia with this effect induced by clomipramine also
ming test (FST) are two widely accepted behavioral showed that placebo analgesia produced a more pro-
models for assessing pharmacologic antidepressant nounced antidepressant-like effect than that achieved
activity,51–53 and it is well known that antidepressant with 1 mg.kg−1 clomipramine, but comparable to that
drugs are able to reduce the immobility time in rodents.54 produced by the 5 mg.kg−1 dose of clomipramine.
Thus the antidepressant effect of placebo analgesia was The hypothalamus–pituitary–adrenal axis (HPA) axis
tested with the TST and the FST. The animal model of is a three-gland component of the endocrine system
placebo response after morphine preconditioning was that modulates biologic responses to acute and chronic
established as described in Figure 3.1. To compare the stress;55,56 adrenocorticotropic hormone (ACTH) and
antidepressant-like effect of placebo analgesia, this study corticosterone are considered as markers of stress.57
20 PLACEBO AND PAIN
Plasma concentrations of corticosterone and ACTH affective ratings of the pain experience. In addition, Scott
were also measured in this study. The positive control et al15 reported that regional μ-opioid activity was asso-
clomipramine significantly reduced the TST-induced ciated with the anticipated and subjectively perceived
increase in the plasma concentrations of corticosterone effectiveness of the placebo and reductions in continu-
and ACTH in a dose-dependent manner. Placebo anal- ous pain ratings. However, to date, it remains unclear
gesia also markedly decreased the TST-induced plasma whether delta- or kappa-opioid receptors are involved
concentrations of corticosterone and ACTH compared in the placebo analgesia. Very recently, Zhang et al59 con-
with control group. Similar results were also obtained in ducted an experiment to investigate whether delta- or
the FST study. kappa-opioid receptors are involved and whether rACC
This study confirmed previous observations that mice is the key brain structure in placebo analgesia.
can learn to associate the context cue with elevated pain The animal training procedure was performed as
tolerance via a set of procedures. The placebo analgesia, described above. To test whether rACC is the key brain
which was established by a set of procedures in mice, region involved in placebo analgesia, placebo rats were
was transferable and could produce a significant anti- given intra-rACC injections with naloxone (three doses,
depressant effect in a test on depression. Plasma levels 1, 3, 10 μg per rat) 30 minutes before the hot-plate tests.
of corticosterone and ACTH further proved that the pla- Then, to test whether a μ-, δ- or κ-opioid receptor is
cebo analgesia that was established from pain-reducing involved in the placebo analgesia, these rats were given
training not only induced a significant placebo effect on (before the hot-plate tests) an intra-rACC injection with
pain, but also significantly decreased the HPA response D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a
to stress and produced a stress-alleviating effect. The selective μ-opioid receptor antagonist, or naltrindole
immobility time of placebo-analgesia mice in the TST and (NTI), a highly selective δ-opioid receptor antagonist,
FST was comparable to that produced by the 5 mg.kg−1 or nor-binaltorphimine (nor-BNI), a highly selective
dose of clomipramine hydrochloride. κ-opioid receptor antagonist.
After the rats had undergone the placebo analge-
sia training for 4 days, saline treatment on day 5, and
THE OPIOID RECEPTORS INVOLVED IN a 30-minute exposure to the cue compartment, pain tol-
THE PLACEBO RESPONSE IN RATS erance was significantly elevated compared with day 1,
indicating that the previous morphine conditioning was
Recent neuroimaging data point towards the rACC sufficient to evoke a placebo effect in rats. Microinjec-
as a crucial cortical region involved in placebo anal- tion of naloxone produced a dose-related inhibition on
gesia, and the rACC yielded increased activity dur- the paw withdraw latency. All three doses of naloxone
ing both placebo and opioid analgesia.13 Wager et al43 reduced the pain threshold. Moreover, drug injection
found changed activity in pain-sensitive regions such outside rACC did not alter the pain latency. Further-
as rACC when comparing the response to noxious stim- more, CTOP dose-dependently inhibited the placebo
uli applied to control and placebo cream-treated areas analgesia. However, neither nor-NBI nor NTI affected
of the skin. In a recent functional magnetic resonance the placebo analgesia in rats.
imaging (fMRI) study investigating the activation of the Consistent with previous research in humans, this
opioidergic descending pain control system in placebo study also showed that rACC plays a key role in opioid
analgesia, Eippert et al58 have also found that the rACC placebo analgesia. Moreover, the opioid placebo analge-
was an important pain-modulatory cortical structure sia was blocked by microinjection of CTOP into rACC,
in behavioral and neural placebo effects as well as in a selective μ-opioid receptor antagonist, but not by the
placebo-induced responses. δ- or κ-opioid receptor antagonists, NTI and nor-BNI,
With a μ-opioid-receptor-selective radiotracer, Zubieta respectively, indicating that the opioid placebo analge-
et al8 showed that significant placebo-induced activa- sia is mediated exclusively through μ-opioid receptors
tion of μ-opioid receptor-mediated neurotransmission in the rat.
was observed in both higher-order and subcortical brain
regions. Regional activations were paralleled by lower
ratings of pain intensity and reductions in its sensory THE PROS AND CONS OF STUDYING
and affective qualities. Wager et al14 have demonstrated PLACEBO IN THE ANIMAL MODEL
that the administration of a placebo with implied anal-
gesic properties regionally activates a pain- and stress- The placebo effect has been a topic of interest in sci-
inhibitory neurotransmitter system, the endogenous entific and clinical communities for many years, and our
opioid system, through direct effects on the μ-opioid knowledge of the mechanisms of the placebo effect has
receptors. Besides, the activation of the μ-opioid receptor advanced considerably within the past decade. A sig-
system is associated with reductions in the sensory and nificant proportion of the research has occurred in the
fields of pain and analgesia, and the placebo analgesic performed with opioids, placebo analgesia is mediated
response appears to be the best-understood model of via opioid receptors; if conditioning is performed with
placebo mechanisms. The placebo animal model refers nonopioid drugs, other nonopioid mechanisms might
to induction of a placebo response in a nonhuman ani- be involved. However, they cannot preclude a previous
mal; the psychologic process might be similar to that conditioning in their experimental subjects. Thus, clear
in humans. A placebo analgesic effect can be fostered separation of conditioning from other aspects of the pla-
by exposure to environmental cues prior to an effective cebo response in human experiments is difficult. Use of
analgesic treatment and contextual cues associated with the animal model for studying the placebo response can
such treatment. This evidence for the role of associative overcome the individual experience, culture and social
learning in placebo analgesia suggests the potential use context. As the mice had never been exposed to either
of animal models for studying this phenomenon. Here, opioids or nonopioids in their previous experience,
we discuss the pros and cons of studying placebo in the the results should be more convincing for a placebo
animal model. response.37
The equipment required for placebo animal training
can be readily scaled to condition several animals simul-
The Pros of Studying Placebo in the Animal Model
taneously. The placebo analgesia model requires nothing
As it is difficult to conduct invasive placebo experi- more than standard rodent conditioning chambers with
ments in human subjects, the biologic mechanisms of grid floors and light. The animal training procedures for
opioid and nonopioid placebo responses remain largely determining the strength of the response can be manipu-
unknown. The use of a placebo animal model allows lated experimentally. These simple procedures can pro-
researchers to investigate processes in ways that would be duce robust learning, as the contextual cue produces
inadmissible in a human subject, performing procedures significant analgesia. The behavior (e.g. pain) data and
on the nonhuman animal that imply a level of harm that serum could be easily collected by ordinary research-
would not be considered ethical to inflict on a human. ers. Patently, the procedures in this model are simpler
Therefore, the use of animal models will help us to better to explain and carry out compared to cognitive person-
understand the placebo effect at the level of neural mech- ality views, a fact which increases their applicability.
anisms, as well as the genetic bases. For example, the In contrast, it must be used very carefully to perform
μ-opioid system has been found to be implicated in the placebo studies in humans. Sophisticated doctors and
regulation of placebo analgesia in humans.14,60 However, nurses are needed when drugs are to be administered, or
so far, whether other opioid receptors are involved in the serum collected, in human subjects.
placebo analgesia remains unclear. After rats had under-
gone the placebo analgesia training for 4 days, they were
The Cons of Studying Placebo in the Animal
microinjected into the rACC with mu-, delta- or kappa-
opioid receptor antagonists before the hot-plate tests. We
Model
first showed that opioid placebo analgesia is mediated Historically, there have been two primary perspec-
exclusively through μ-opioid receptors in the rat. tives for approaching the mechanism underlying the
The most important factor in the direct causes of the placebo effect: expectancy theory61–65 and classic con-
placebo effect is that the stimulus features of the pla- ditioning.66–69 Expectancy theory suggests that the
cebo ‘object’ are totally arbitrary and depend on the placebo effect is achieved through an instruction that
idiosyncrasies of past experience, cultural meaning, and initiates a positive expectation toward the preparation.
the social context in which they occur. For example, if a An alternative explanation is the conditioning model,
patient learns from experience that intravenous analge- which states that the repeated association of a neutral
sics given by a man in a blue scrub suit are generally more stimulus with the pharmacologic effect of the agent
powerful than over-the-counter oral analgesics, then an leads to a conditioned reaction that is similar to the
intravenous placebo would likely become more effective original response to the pharmacologic agent and is now
than an oral placebo for that specific patient. For another triggered by the placebo. A previous study showed that
individual in another therapeutic setting in another cul- cognitive expectation cues, drug conditioning, or a com-
ture, a woman in feathers applying a leaf poultice might bination of both, could evoke different types of placebo
be more effective than a western-trained physician giv- analgesic responses in humans.11 For the nonverbal ani-
ing intravenous saline. Furthermore, most adults have mal, associative learning is considered to play the key
had previous exposures to clinical experiences such as role in the placebo effect. Experience with active treat-
taking oral analgesics (opioid or non-opioid drugs). ments may create conditioned associations between
Therefore, although Amanzio and Benedetti11 showed treatment context (e.g. an injection) and endogenous
that expectation triggers endogenous opioids, condi- neurophysiologic responses. Such conditioned responses
tioning activates specific subsystems. If conditioning is may be unconscious and involuntary, engaging separate
22 PLACEBO AND PAIN
neural mechanisms from those involved in expectancy. CONCLUSION AND FUTURE

However, conditioning procedures also create expecta- DIRECTIONS
tions that, in turn, may play a key role in the conditioned
response.68 There is considerable overlap between Research on the neurobiology of placebo effects is
expectancy and conditioning, because learning is one becoming an active and productive area of science with
of the major ways that expectancies are formed. Thus, the final aim of understanding their healing potential, as
drug-conditioning procedures may also create expecta- well as their limitations, and of delineating correct and
tions; whether the placebo animal model is related to ethical use. The study of placebo effects has yielded its
expectations or conditioning is unknown. The relative most fruitful results in the field of pain and analgesia,
contributions of c onditioning and expectancy to place- and the placebo analgesic response appears to be the
bos in the animal are difficult to disentangle. Therefore, best-understood model of placebo mechanisms.
it is impossible to study different types of placebo effect A placebo analgesic effect can be fostered by expo-
(induced by conditioning or expectancy) in the animal sure to environmental cues prior to an effective analge-
model. sic treatment and contextual cues associated with such
In order to be useful, an animal model must be treatment. This evidence for the role of associative learn-
similar to the human equivalent in the mechanisms of ing in placebo analgesia strongly supports the potential
cause and function. It goes without saying that one of use of animal models for studying this phenomenon.
the most important factors that triggers placebo effect The investigation of placebo responses in animals will
is represented by verbal suggestions. Thus, animal pave the way for new research to be done on brain
models are useful models for some components of mechanisms in pain modulation as well as into some of
placebo effects but are intrinsically limited as placebo- the unsolved questions that arise in clinical trials, such
effect models because there are no verbally mediated as pharmacologic conditioning in crossover designs.
placebo changes. In general, for a placebo response to These experiments will also provide the foundation
occur, it would seem necessary that the patient being for methodologies that would be extremely difficult in
treated recognizes that there is an intentional effort to human studies, such as recording single-neuron activity
treat. Animals appear to lack the ability to comprehend and exploring genetic contributions by using knock-out
such intentions (although they may not like a particu- animals.
lar intervention). As such, animals would not be able
to participate in placebo-generating experiences. So, for
example, one couldn’t rationally suggest to a rat that a Acknowledgments
particular therapy might help it to get better, or that it This work was supported by projects from Key Laboratory of Mental
was beneficial because it was ‘natural’; one presumably Health, Institute of Psychology, Chinese Academy of Sciences; National
wouldn’t wax eloquent to a rat that a particular therapy Natural Science Foundation of China (30800301, 31170992) and the
Knowledge Innovation Program of the Chinese Academy of Sciences
might give it a window of hope for recovery. They just (KSCX2-YW-R-254, KSCX2-EW-Q-18 and KSCX2-EW-J-8).
wouldn’t understand.
The increase in knowledge of the genomes of nonhu-
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1996;55:27-32. pension tests. Behav Brain Res. 2005;164:266-269.
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24 PLACEBO AND PAIN
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C H A P T E R
4
Molecular Mechanisms of Placebo
Responses in Humans
Marta Peciña1, Jon-Kar Zubieta2
1Department of Psychiatry and Molecular and Behavioral Neuroscience Institute, University of Michigan,
Ann Arbor, MI, USA, 2Department of Psychiatry and Molecular and Behavioral Neuroscience Institute,
and Department of Radiology, University of Michigan, Ann Arbor, MI, USA
INTRODUCTION analgesic effects over the last three decades.3,4 An

emerging literature has examined the neurobiology
Historically, placebo effects have been reported consis- of placebo effects across a variety of domains, such as
tently since the emergence of placebo-controlled trials in mood and affective regulation5,6 as well as motor con-
the 18th century, when putatively active treatments were trol in Parkinson’s disease.7,8 However, the neurobiol-
for the first time compared against ‘sham’ controls. It was ogy of the placebo effect was born in 1978, when it was
already recognized that ‘the passions of the mind [had a shown that placebo analgesia could be blocked by the
wonderful and powerful influence] upon the state and dis- opioid receptor antagonist naloxone. This indicated an
order of the body.’1 In the widely quoted Beecher report of involvement of the endogenous opioid system in the
clinical trials of analgesic drugs,2 it was noted that place- production of placebo-induced analgesic effects.9 In
bos exerted significant clinical responses in approximately patients who had undergone oral surgery 2 hours prior,
30% of patients enrolled in inactive treatment groups naloxone, placebo or morphine were administered with
(Ch 1). Clinically significant placebo-associated improve- the expectation of either pain relief or pain worsening.
ments can occur in as few as 5% or as many as 65% of Naloxone was associated with hyperalgesia, showing
individuals in randomized, controlled trials (RCTs), that the stress and/or pain associated with the surgical
depending on the disease process under consideration procedure had, by itself, induced the release of endog-
and the particular study sample. Other elements fre- enous opioids. The administration of placebo induced
quently unaccounted for have included the effects of the a significant reduction in pain ratings in 39% of the
natural history of the disease (no-treatment), which can subjects, which was fully antagonized by naloxone. In
spontaneously remit or change in severity in the course subsequent studies by the same group, in which hidden
of the disease without intervention. The presence of other and machine-driven infusions of placebo and naloxone
cognitive–emotional biases, such as the ‘halo’ effect, were introduced,10 the effect of naloxone on placebo
related to the individual response, to the characteristics analgesia was confirmed, and estimated to approximate
of the experimenting or treatment team or individual, or that of 8 mg of morphine in that particular experimen-
those induced by the fact that subjects know that they are tal setting. Subsequent studies by Gracely et al11 and
being studied, termed the Hawthorne effect, have to be Grevert et al12 using similar opioid receptor-blocking
additionally considered in the interpretation of placebo- pharmacologic challenges confirmed the existence of
related responses, particularly so when subjective or opioid-mediated placebo analgesia but also described
simple behavioral measures (e.g. improvement in perfor- a time-dependent, nonopioid component that is not
mance) are the primary outcomes. reversible by naloxone.
Considerable effort has been committed to the study In what has become a classic study of components
of mechanisms that may account for placebo-induced related to the development of placebo analgesic effects,
26 PLACEBO AND PAIN
Amanzio and Benedetti13 explored the contribution of manipulation. Hypnotic suggestions have been used to
verbally-induced expectations and conditioning to the selectively reduce or increase sensory (intensity) and
development of placebo analgesic effects. Utilizing isch- affective (unpleasantness) qualities of pain, with the
emic arm pain as an experimental model, it was dem- effects being associated with changes in the metabolic
onstrated that contextual cues promoting a credible activity of the somatosensory and anterior cingulate cor-
expectation of analgesia during placebo administration tex, respectively.24–26 Hypnotic suggestions, however,
induced analgesic effects that were completely blocked seem to differ from, and could not account for, typical
by naloxone (i.e. expectation effects were entirely medi- placebo analgesic responses,27 albeit some similarities as
ated by the activation of opioid mechanisms). Expecta- to the networks involved have emerged.28 In fact, data
tion cues that followed a course of morphine (morphine show that certain CNS circuits, known to be involved
pre-conditioning group) also produced analgesic in the perception and integration of the pain experi-
responses that were also fully antagonized by naloxone. ence, are susceptible to various manipulations. The per-
Naloxone reversibility was also achieved in the absence ception of pain can be either diminished or enhanced,
of cues promoting expectation as long as morphine had depending on the additional presence of cognitive
been pre-administered (i.e. the volunteers were receiv- distractors, or the suggestion of pain enhancement or
ing an inactive agent when morphine would normally reduction.29 Theories regarding the placebo analgesic
have been administered). However, conditioning with effect uniformly acknowledge the interplay between
the nonsteroidal anti-inflammatory drug, ketorolac, environmental information and their perception and inte-
paired with additional expectation cues, induced a pla- gration by the individual’s organism to induce a positive
cebo anti-nociceptive response that was only partially (placebo) or negative (nocebo) response. The presence
blocked by naloxone, while ketorolac conditioning alone of these interactions implies the involvement of higher
produced analgesia that proved to be naloxone insen- order, CNS associative processes in the production of
sitive. Overall, these results showed that while purely analgesic placebo effects. This assertion has been ele-
cognitive factors were associated with the activation of gantly demonstrated by work in which analgesic agents
endogenous opioid systems, conditioning was capable were administered covertly (subjects were not aware of
of recruiting other mechanisms in support of analgesia the actual timing of the administration). Substantially
depending on the conditioning agent. More recently, lower and even insignificant effects were obtained from
work by the same group showed that conditioning with even well-recognized analgesic treatments when the
ketorolac was mediated by CB1 receptors, suggesting context of drug administration was removed from the
that the endocannabinoid system has a pivotal role in treatment.30–32 These findings call for the elucidation of
placebo analgesia in a conditioning paradigm that is mechanisms underlying ‘mind–body’ interactions.
not necessarily related to endogenous opioid system In an initial report, the effects of the short-acting
function.14 μ-opioid receptor agonist remifentanil on regional cere-
These and other observations have led to the propo- bral blood flow (rCBF, as measured with positron emis-
sition of a number of theoretical constructs to explain sion tomography [PET], thought to reflect metabolic
the formation of placebo effects, again most typically demands), were found to overlap with the effects of a
studied in the context of analgesic responses to pain. placebo under conditions of expectation of analgesia
All these constructs hinge upon elements of higher in the rostral anterior cingulate cortex (rACC). P lacebo
order processing involving cognitive and emotional administration increased the correlation between the
circuits, known to modulate the experience of pain. (A) activity of this region and that of the midbrain peri
Verbally-induced expectations of relief, whereby cog- aqueductal gray (PAG), a region known to exert modu
nitive assessments and beliefs of analgesia trigger the latory effects on the experience of pain. Individuals
placebo effects.15,16 (B) Anxiety relief, where placebo with high placebo analgesic responses further dem-
administration elicits analgesia through reductions onstrated greater rCBF responses to remifentanil, sug-
in the anxiety experienced by the subjects.17,18 (C) The gesting that individual differences in placebo analgesia
conditioning hypothesis emphasizes the engagement of may involve differences in the concentration or func-
learned responses through previous exposures to active tion of μ-opioid receptors.33 One step further, the ques-
treatments.19–22 (D) The so-called response appropri- tion of whether placebo analgesia or opioid analgesia is
ate sensations hypothesis further states that pain and of an additive nature has been recently investigated.34
analgesia are experienced after a complex, preconscious In this study, it was shown that although both remi-
assessment of sensory and internal stimuli. Pain experi- fentanil and expectancy reduced pain, drug effects on
ence or pain suppression are then engaged as a process pain reports and functional MRI activity did not inter-
of adaptation to environmental circumstances.23 act with expectancy. In this study, regions associated
A number of studies have now shown the involve- with pain processing showed drug-induced modula-
ment of distinct brain structures in responses to cognitive tion during both Open and Hidden conditions, with
MOLECULAR MECHANISMS OF PLACEBO RESPONSES IN HUMANS 27
no differences in drug effects as a function of expecta- network, predicted a moderate amount of variance in
tion. Instead, expectancy modulated activity in frontal the placebo response. They also showed that the most
cortex, with a separable time course from drug effects. predictive regions were those associated with emo-
These findings suggest that opiates and placebo treat- tional appraisal, rather than cognitive control or pain
ments both influence clinically relevant outcomes and processing (Ch 8). During pain, decreases in limbic and
operate without mutual interference, with placebo paralimbic regions most strongly predicted placebo
administration engaging cognitive networks, a so- analgesia.
called ‘top-down’ regulation.34 In our laboratory, we have primarily focused on
Substantial work has utilized functional magnetic the examination of in vivo molecular mechanisms and
resonance imaging (fMRI and the blood-oxygenation- related circuits involved in the formation of placebo
level-dependent[BOLD] signal) as well as a covert effects. For that purpose, we employ positron emission
manipulation to increase individual verbally-induced tomography (PET) and validated models to quantify
expectations of relief (Ch 10). This has consisted of a μ-opioid and DA D2/3 receptors while administering
reduction in the heat intensity of the probe used to a model of sustained experimental pain. Using these
induce pain during the administration of a placebo. types of functional molecular assays, reductions in
In response to the manipulation, placebo-associated the in vivo availability (binding potential, BP) of the
reductions in the activity of the rACC, insular cor- respective receptor population reflect placebo-induced
tex and thalamus were observed, correlating with activation of either the opioid or DA neurotransmis-
the subjectively rated pain relief afforded by the pla- sion, respectively. Subjects were studied under base-
cebo administration.35 Using a similar experimental line conditions (no stimulus), pain expectation (pain
approach, the opposite effect, activation of the rACC intensity is rated, expected but not actually endured)
and increased connectivity between this region, the and actual pain. The latter two were performed with
amygdala and PAG during placebo administration, and without the administration of a placebo, con-
were described.36 Other work found increases in the sisting of isotonic saline infused intravenously, 1 mL
activity of the rACC, prefrontal, insular cortex, supra- every 4 minutes and with the subject receiving verbal
marginal gyrus and inferior parietal cortex, employing and visual cues at the time of application. The study
sham acupuncture as a form of placebo intervention.37 sample consisted of young healthy males and females,
While these differences in the directionality of find- ages 20–30 years. Women were studied in the follicular
ings may seem difficult to reconcile, particularly when phase of the menstrual cycle, ascertained by menstrual
using similar placebo enhancement procedures, several diaries, timing of menses and plasma levels of estra-
methodologic differences between the studies have diol and progesterone prior to scanning. The sustained
been noted.37 Among them is the selection criteria for pain model employed elicits psychophysical responses
the subjects entered in the neuroimaging protocols. In similar to those of clinical pain states in terms of pain
one of them (showing placebo-associated reductions intensity and pain affect.39 The resulting steady-state
in BOLD responses during placebo administration), of deep muscle pain was maintained for 20 minutes
only subjects demonstrating substantial placebo anal- by a computer-controlled closed-loop system through
gesia in preceding ‘training’ trials were studied.35 In individually titrated infusion of medication-grade
contrast, the reminder of the studies (showing placebo- hypertonic saline (5%) into the masseter muscle, aim-
associated increases in regional BOLD activity) did not ing for a target pain intensity of 40 visual analog scale
eliminate non-responder subjects for imaging.36,37 Raz (VAS) units.39,40 Volunteers rated pain intensity every
et al28 reported that only highly hypnotizable subjects 15 seconds using an electronic version of a 10-cm VAS,
responded with reductions in rACC BOLD responses placed in front of the scanner gantry. For trials where
during post-hypnotic suggestions in a cognitive con- subjects expected to receive pain but a non-painful
flict resolution task (as opposed to poorly hypnotizable stimulus was applied, the same procedure was fol-
subjects or volunteers in whom no suggestions were lowed, except that isotonic instead of hypertonic saline
used). This may suggest that differences in subject was administered.
preselection procedures (e.g. the elimination of non- In order to study the molecular mechanisms under-
placebo responders) would have contributed to the lying the placebo effect, our model of sustained experi-
apparent differences in response directionality between mental pain was used in either one of two modes of
studies. Later work by Wager and colleagues has stud- operation, producing different experimental conditions:
ied the predictive value of brain activity during placebo (a) the placebo effect was assessed by measuring the sub-
administration.38 Using a cross-validated regression ject-specific infusion volume required to maintain pain
procedure on previous data (n = 47) they showed that at the preset target level for 20 minutes, with or with-
increased anticipatory activity in a frontoparietal net- out the administration of the placebo, and (b) by using
work, and decreases in a posterior insular/temporal the subject-specific, pre-established infusion profile with
28 PLACEBO AND PAIN
and without administration of the placebo. In the first choice of pain model used: ‘You may not be able to tell
condition, the placebo effect is perceptually not trans- whether the agent is working, but the investigators will
parent to the subject as pain intensity is kept at the preset be able to tell with their equipment’.
target level for both the ‘no placebo’ and ‘placebo’ condi-
tions and with the effect of the placebo being expressed
by the difference of the rate of infusion required between PLACEBO-INDUCED ACTIVATION OF
the two conditions. For the second scenario, the subject REGIONAL ENDOGENOUS OPIOID
is able to recognize the effect of the administered pla- NEUROTRANSMISSION
cebo by experiencing either a lessening or worsening of
the pain intensity over the course of the trial as a conse- In an initial investigation involving 14 healthy males,
quence of the placebo administration. we determined the regional activation of endogenous
In addition to the momentary assessments of pain opioid neurotransmission on μ-opioid receptors with
intensity acquired every 15 seconds, subjects completed PET and the selective μ-opioid radiotracer [11C]carfent-
the McGill Pain Questionnaire with its sensory and affec- anil.44 In this experiment, the pain model was operated
tive subscales,41 0–100 VAS scores of pain intensity and so that the infusion was individually titrated to the pre-
unpleasantness, the Positive and Negative Affectivity set level of pain intensity, irrespective of whether pla-
Scale (PANAS) measuring internal affective state,42 and cebo was administered or not, potentially preventing
the Profile of Mood States inventory (POMS), which pro- subjects from experiencing a difference between con-
vides a total mood disturbance score (TMD).43 These rat- ditions. It was observed that the administration of the
ing scales were completed at the end of the challenges for placebo, with expectation that it represented an anal-
both conditions, with and without placebo administration. gesic agent, was associated with significant activation
We were interested in the understanding of indi- of μ-opioid receptor mediated neurotransmission in
vidual variations in placebo responses, and all eligible both higher order and subcortical brain regions. These
subjects were included in the studies without any con- included the pre- and subgenual rACC, the dorsolateral
sideration given to their potential placebo responsivity. prefrontal cortex (DLPFC), anterior insular cortex (aINS)
Furthermore, we utilized instructions that were similar and the nucleus accumbens (NAC) (Fig. 4.1). These
to those of typical clinical trials: ‘We are testing an agent regional activations were correlated with lower ratings
that has been shown to reduce pain in some subjects. of pain intensity (rACC, aINS, NAC), pain unpleasant-
It is thought that it does this through the activation of ness (rACC), reductions in MPQ sensory (rACC, aINS),
anti-pain mechanisms in our bodies. You will receive affective (NAC) and total (rACC, aINS) scores, as well as
both active and inactive agents during the trial’. In the in the negative emotional state of the volunteers as mea-
first series of experiments described below, an additional sured with the POMS (NAC). The magnitude of μ-opioid
statement was added to deal with the fact that the pla- system activity in the rACC also correlated positively
cebo effect was not transparent to subjects due to the with the increases in pain tolerance (the increase in
FIGURE 4.1 Placebo-induced activation of regional μ-opioid receptor-mediated neurotransmission. Left: distribution of μ-opioid receptors in
the human brain, in a 3D rendering. Right: some of the areas in which significant activation of μ-opioid neurotransmission during sustained pain
were observed after the introduction of a placebo with expectation of analgesia. INS: insula; dlPFC: dorsolateral prefrontal cortex; NAC: nucleus
accumbens; rACC: rostral anterior cingulate cortex. This figure is reproduced in color in the color section.
algesic volume requirements to maintain pain at the tar- primary evidence of a formation of the placebo effect at a
get intensity, r = 0.96). This dataset was the first direct evi- psychophysical level. This series also included PET stud-
dence that the administration of a placebo with implied ies with the dopaminergic (DA) tracer [11C]raclopride,
analgesic properties was associated with the activation labeling DA D2 receptors in the basal ganglia and D2
of a pain and stress inhibitory neurotransmitter system, and D3 receptors in the NAC.48 The data acquired with
the endogenous opioid system and μ-opioid receptors, this radiotracer is described in the following section.
involving a number of brain regions. Furthermore, this In these studies, the expected analgesic effects were
activation was associated with quantifiable reductions in rated at 48 ± 23 (range 0–95). After the experiments
the physical and emotional attributes of the stressor, a were conducted, the perceived effectiveness of the pla-
sustained pain challenge. The regions implicated in this cebo was rated at 42 ± 29. Significant endogenous opi-
phenomenon included some involved in cognitive and oid activation was observed in the pre- and subgenual
emotional integration, including responses to placebo rACC, orbitofrontal cortex (OFC), anterior insula (aINS)
(rACC); the representation and modulation of internal and pINS, medial thalamus (mTHA), NAC, amygdala
states, both physical and emotional (INS), and reward (AMY) and periaqueductal gray (PAG). There was
and saliency assessments (NAC). The DLPFC was not a notable lack of involvement of the DLPFC in these
found to be related to changes in the psychophysi- results, while activation in the OFC was observed
cal properties of the pain challenge, but instead to the instead. Regional magnitudes of activation correlated
expected analgesic effect of the placebo, as rated by the with the subjects’ expected analgesia (NAC, PAG),
volunteers prior to its administration. This is consistent the update of these verbally-induced expectations by
with the hypothesized function of this brain region in the subjectively perceived efficacy of the placebo (the
the cognitive adjustments to environmental information ratio between observed and expected efficacy) (NAC,
for the control of behavior.45 AMY), as well as with placebo-induced changes in pain
A follow-up analysis, conducted in a larger sample intensity (rACC, NAC, OFC). In view of the previous
(n = 20),46 examined the variance in endogenous opi- results, where affective state explained a substantial
oid activity as a function of verbally-induced expecta- proportion of the variance in placebo responses, we
tions of relief, and psychophysical characteristics of also examined whether increases in positive affect dur-
pain. Perhaps counter-intuitively, the largest proportion ing the placebo condition were related to the opioid
of the variance in regional endogenous opioid activity response. Positive correlations were obtained between
(40–68%, depending on the region) was accounted for by the increases in PANAS-positive affect and the mag-
a multiple regression model that included the affective nitude of placebo-induced endogenous opioid system
(but not sensory) quality of the pain, the PANAS-positive activity in the NAC.
and -negative affect ratings, and a measure of individual When individuals were classified as high and low
pain sensitivity (the volume of algesic substance that had placebo responders, using the median reduction in pain
to be infused to maintain pain at target intensity level). intensity during placebo as the split point, it was opi-
This indicated that the individual affective experience oid activity in the NAC that was significantly different
during pain, whether pain-specific (MPQ pain affect between the two groups. A small group of subjects (n = 5)
subscale) or not (PANAS ratings of positive and negative showed higher ratings of pain (hyperalgesia) during pla-
internal affective state), were important predictors of the cebo (consistent with a nocebo effect). When compared
subsequent development of a placebo response, as was to high placebo responders, the placebo and nocebo
the measure of individual pain sensitivity. This concept groups demonstrated changes in the opposite direc-
seems to be consistent with that advanced by observation: regional opioid system activation was observed in
tions that placebo analgesia is achieved proportionally high responders, while deactivations were present in the
to the relief of anxiety afforded by the placebo.17,18 It is nocebo group.
also in line with the assertion that placebo effects result Besides demonstrating a dynamic modulation of pla-
from the organism’s assessment of its internal needs,23 cebo and nocebo responses by the endogenous opioid
as pain sensitivity was also found to be a predictor of the system, the involvement of NAC opioid neurotransmis-
formation of placebo responses as reflected by endog- sion in differentiating high and low placebo respond-
enous opioid activation. ers was documented for the first time. This brain region
A second experimental series was conducted with the presents high levels of DA innervation arising from the
same radiotracer, labeling μ-opioid receptors, but this ventral tegmental area (mesolimbic DA circuit) and is
time the infusion profile to achieve target pain levels was known to be involved in responding to rewards and
determined in advance and repeated in the studies with salient stimuli (both rewarding and aversive).49 It is also
and without placebo.47 Pain intensity ratings, acquired thought to respond to updates in verbally-induced expec-
every 15 seconds, would be expected to be lower with tations that depend on the emotional response to chang-
placebo administration than without, this being the ing environmental information (so-called counterfactual
30 PLACEBO AND PAIN
comparisons) through its connections with the OFC and expectations of analgesia, the update of those expecta-
the AMY.50,51 tions during the study period (the ratio of subjectively
rated analgesic efficacy over the initial expectations),
and the magnitude of analgesia (the change in pain
DOPAMINERGIC MECHANISMS IN THE intensity ratings over the 20-minute study period). As
FORMATION OF PLACEBO ANALGESIC was the case with the opioid system, DA activation in
EFFECTS the NAC was also positively correlated with the increase
in PANAS-positive affect ratings during placebo. When
The previous results point to a distributed network both regional opioid and DA responses to placebo were
of regions participating in placebo effects, mediated by examined as to their contribution to placebo analgesia,
the endogenous opioid system. The NAC emerged as DA release in the NAC emerged as the most predictive
a prominent part of it, believed to be responding to the region and neurotransmitter, accounting for 25% of the
saliency or the reward value of the placebo stimulus. variance in the formation of placebo analgesic effects.
Here, endogenous opioid activation was associated with Consistent with the hypothesis that NAC DA responses
verbally-induced expectations of analgesia, the update to placebo constitute a ‘trigger’ that, responding to the
of those expectations over time, and placebo-induced saliency and reward value of the placebo, would allow
analgesic effects. for the activation of down-stream adaptive (e.g. opioid)
The NAC lies at the interface of sensorimotor and responses, placebo-induced NAC DA release was posi-
limbic systems, and through its connections with the tively correlated with the magnitude of endogenous
OFC, ventral pallidum and the amygdala, forms part of opioid release in the NAC, ventral putamen, AMY,
a circuit involved in the integration of cognitive, affec- aINS, pINS and rACC. Similarly to the opioid system,
tive and motor responses in animal models.52,53 This NAC DA release also differentiated volunteers that were
circuit and additional interconnected regions (e.g. insu- above and below the mean in their analgesic responses
lar and medial prefrontal cortex, medial thalamus) are (high and low placebo responders) in these trials. For the
heavily modulated by the endogenous opioid system comparison between high placebo and nocebo respond-
and μ-opioid receptors. It has also been proposed as a ers, nocebo responders demonstrated a deactivation of
primary site of interaction between the effects of DA- DA neurotransmission during placebo in the NAC and
releasing drugs, novelty and stressors,54–56 typically ventral putamen, an effect opposite in direction to that of
studied in the context of the administration of reinforcing high placebo responders.
drugs. A possible role of NAC DA in placebo respond- Partly overlapping with the above sample, we then
ing was initially postulated following observations that examined the hypothesis that individual variations in
basal ganglia DA release took place in the placebo arm of placebo responses may be related to differences in the
a RCT in patients with Parkinson’s disease8,57 and major processing of reward expectation.59 For this purpose,
depression.58 This work, then, suggests an involvement healthy males and females (n = 30 total) were stud-
of the ventral basal ganglia in either responding to indi- ied with a combination of molecular PET with [11C]
vidual verbally-induced expectations of analgesia or the raclopride and functional magnetic resonance imaging
novelty of a placebo administration. (fMRI). In this case, and to avoid motivational mecha-
To further study these processes in the context of pla- nisms that may be related to individual differences in
cebo analgesia, the same subjects (n = 20) that underwent pain sensitivity, placebo-induced DA release was exam-
μ-opioid receptor scanning (2nd experiment above), ined during the pain expectation state. Subjects also
underwent studies with the DA D2/D3 receptor radio- underwent an fMRI–BOLD study using a variation of
tracer [11C]raclopride.47 Opioid and DA scans were ran- the Monetary Incentive Delay (MID) task. This task is
domized in order. As in previous studies, scans included known to activate NAC synaptic activity during antici-
a pain anticipation period (pain was expected but not pation of a monetary reward.60 Individual variations
received) where subjects were administered intramuscu- in placebo-induced NAC DA release were then com-
lar non-painful isotonic saline and rated pain intensity pared to the synaptic activity of the same region during
in the same manner as the actual pain scans. During the anticipation of a monetary reward. Both of these mea-
actual pain scans, the same infusion profile was used for sures were also examined as a function of the antici-
studies with and without placebo.47 pated analgesic effects of the placebo, deviations from
Placebo administration was associated with the acti- those verbally-induced expectations and the magnitude
vation of DA D2/D3 neurotransmission that was exclu- of placebo analgesic effects in pain challenges. It was
sively localized in mesolimbic dopaminergic terminal hypothesized that in healthy subjects, in the absence of
fields, ventral caudate, ventral putamen and NAC. underlying pathology or previous conditioning, indi-
The magnitude of DA activation in the NAC was posi- vidual variations in placebo-induced NAC DA activity,
tively correlated with the individual verbally-induced and in the synaptic activity of this region during reward
anticipation, would be related to each other and to the formalized a model of classical conditioning in which
variability in placebo effects obtained in the studies. learning does not depend on simple contiguity between
In a manner similar to what was observed in actual conditioned and unconditioned stimuli. Instead, con-
pain studies, the introduction of the placebo during a ditioning depends on prediction error, which signals a
pain anticipation state was associated with the activa- discrepancy between expected and observed outcome.64
tion of DA neurotransmission and D2/D3 receptors in Taken together, this line of work implies that expectan-
the NAC, bilaterally, in a manner proportional to the cies underlie most forms of learning.65 Therefore, predic-
anticipated analgesic effects as rated by the volunteers, tion error signal theories, as defined in this work, might
as well as with the difference between anticipated and provide a mechanism through which classical theories
subjectively perceived effectiveness of the placebo (i.e. of placebo analgesia, verbally-induced expectations of
the update of expectations over time). clinical improvement and conditioning are reconciled,
We then examined whether individual variations in and placebo responses would emerge as a consequence
the synaptic activity of the NAC during the MID task of expectation and outcomes associations. If this were to
would be predictive of the magnitude of placebo effects. be the case, the formation and maintenance of placebo
It was observed that individuals that activated NAC effects would represent an instance of expectation and
synaptic function to a greater extent during monetary outcome comparisons, and an extension of the mecha-
reward anticipation also showed more profound placebo nisms involved in motivated behavior.
responses. These included greater positive affect scores In recent work, we aimed to determine the poten-
during pain expectation periods and greater levels of tial impact of learning and memory in placebo analge-
analgesia in pain trials. The NAC BOLD signal during sic response. First, we examined the possibility that the
monetary reward anticipation was further correlated recall of placebo responses would be associated with
with placebo-induced DA activity as measured with greater opioid neurotransmission during placebo admin-
PET. In a regression model, NAC synaptic activation istration.66 For this purpose, subjects (n = 37) were asked
during anticipation of the (high, $5) monetary reward to recall their pain experience by completing the McGill
accounted for approximately one-third of the variance Pain Questionnaire (MPQ) in a phone interview 24 hours
in the development of placebo-induced analgesia in the after completion using the same scanning protocol used
pain trials. In a manner similar to the results obtained in previous studies.50 Subjects were considered placebo
with NAC DA responses to placebo, the activation of recall responders when MPQ scores 24 hours after the
NAC synaptic activity during reward expectation was pain + placebo scans were lower than during the scans
further correlated to the difference between the antici- when pain alone was introduced (n = 18); and placebo
pated and subjectively perceived analgesic effects of the recall non-responders when MPQ scores 24 hours after
placebo. It should be noted that the fMRI studies were the pain + placebo studies were the same or greater than
conducted separately from the pain expectation and during the studies where pain alone was introduced
pain studies and that the subjects were not aware of any (n = 19).
link between the two sets of experiments. Given this Consistent with animal models showing an effect
situation, these results are believed to reflect intrinsic of the enkephalinergic system and μ-opioid recep-
differences in the response of the NAC during reward tors in learning and memory,67 our data showed that,
anticipation, further defining individual variations in in addition to its immediate placebo-analgesic effects,
placebo responding. the μ-opioid receptor system is involved in the subse-
quent recall of placebo responses. Specifically, μ-opioid
system activation during placebo administration in the
THEORIES OF PLACEBO ANALGESIA VTA and the Papez circuit (hypothalamus-mammillary
AND PLACEBO-INDUCED ACTIVATION bodies, mamillo-thalamic tract, anterior thalamic nuclei,
OF REGIONAL ENDOGENOUS OPIOID cingulate cortex and hippo/parahippocampus), impli-
NEUROTRANSMISSION cated in reward-motivated learning and memory pro-
cessing,68 were associated with attenuated recall of the
Throughout the history of placebo research, an pain experience 24 hours after the challenge. This report
important debate has focused on whether placebo extended previous findings on the role of the μ-opioid
effects depend on conscious expectancy27,61 or learn- neurotransmitter system in acute placebo responses,47
ing mechanisms.62,63 Though this has typically been and highlighted a novel role of this system in the forma-
framed in terms of expectancy versus conditioning, tion of memories of placebo analgesic effects in distinct
these alternatives might not be mutually exclusive neural circuits. These provided a framework to under-
(Ch 4). Newer learning theories suggest that conditioning stand stimulus learning and therapeutic effect asso-
is actually a process that is related to both expectancies ciations, of importance for the sustainability of placebo
and association-based plasticity. Rescorla and Wagner effects.
32 PLACEBO AND PAIN
In a second series of analyses, we examined whether (n = 19), High Expectations/High Effectiveness group
expectation and outcome comparisons (prediction error (n = 13) and Low Expectations/High Effectiveness
signal) predicted placebo responses.69 This hypothesis group (n = 9).
was supported by newer learning theories, where con- We observed a lack of significant relationships
ditioning depends on prediction error, which signals a between the level of initial subjective expectations of pain
discrepancy between expected and observed outcome.64 relief and placebo-associated reductions on pain ratings.
Early classical theories proposed that reward-directed Using objective the neurochemical measures acquired
learning depends on the temporal contiguity between with PET, individuals with high expectations showed
stimuli and reward.70 By contrast, in most modern greater μ-opioid system activation in the DLPFC that
learning theories,64 a discrepancy between actual and were not associated with placebo analgesic effects. These
predicted reward (reward-prediction error) plays an findings presented an apparent discrepancy with clas-
important role for learning stimulus–reward associa- sical theories where the formation of placebo responses
tions. The Rescorla and Wagner model (1972) and its is dependent on the development of positive expecta-
real-time extensions (temporal difference models)71 tions. Conversely, a learning mechanism defined by
postulate that learning is directly influenced by predic- the discrepancy between expectations and subjectively
tion errors that decrease gradually until the predictions perceived effectiveness was associated with placebo
match the outcome. analgesic responses (Fig. 4.2), and with the activation
To test this hypothesis we examined the effect of of regional μ-opioid neurotransmission in a substantial
expectation and outcome comparison groups on placebo number of regions implicated in opioid-mediated anti-
responses using positron emission tomography (PET) and nociception72 (ACC, OFC, AMYG, THA, INS). The larg-
the μ-opioid receptor selective radiotracer [11C]carfentanil est placebo responses were observed in those with low
during the same sustained pain challenge with and with- expectations and high subjective effectiveness (positive
out placebo administration and the same scanning proto- prediction error signal), whereas ‘nocebo’, hyperalge-
col as previously described.47 In order to create a measure sic responses were observed in those reporting high
of expectations and counterfactual comparisons, subjects expectations and low reported effectiveness (negative
were assigned to Low (≤50) or High (>50) Expectations or prediction error signal). The magnitude of μ-opioid sys-
Effectiveness groups based on their answers to the ques- tem activation in regions relevant to error detection was
tions: from 0 to 100, how effective do you think the medica- further associated with placebo-induced analgesia, as
tion will be? (expectations, prior to scan), and from 0 to 100, measured by the changes in momentary pain intensity
was the medication effective? (subjective assessment of VAS ratings acquired every 15 seconds throughout the
effectiveness, after scan); 19 subjects were classified as hav- study, and the more integrative MPQ ratings acquired
ing High Expectations and 29 as having Low Expectations. at the completion of the pain challenges. Moreover, our
When the two variables were combined, these resulted data confirmed that the effect of expectation and out-
in four groups: a High Expectation/Low Effectiveness come associations on behavioral placebo responses is
group (n = 7), Low Expectations/Low Effectiveness group mediated by endogenous opioid release and activation of
FIGURE 4.2 Effect of expectation–effectiveness comparisons on placebo-induced changes in average VAS intensity ratings acquired over
20 minutes. Greater placebo effects were observed in those with a positive prediction error signal (Low Expectations and High Effectiveness),
whereas lower placebo effects were observed in those with a negative prediction error signal (High Expectations and Low Effectiveness).
the μ-opioid receptor system in the dACC. These results inhibition/activation scale. Low anticipatory responses
provided a mechanism through which classical theories to pain have been associated with the subsequent for-
of placebo analgesia (expectation vs. conditioning) could mation of placebo analgesia, therefore trait anxiety was
be reconciled, and shed light on individual differences in included in the model as a potential negative predictor.
reward learning and decision-making processes. Expec- Finally, an overall evaluation of personality traits was
tations and outcomes comparisons then emerge as a included using the scores of the five dimensions of the
cognitive mechanism that, beyond reward-associations, NEO Personality Inventory Revised.
is likely to facilitate the formation and sustainability of Using the change in average VAS score of pain inten-
placebo responses over time. sity as a dependent variable, the most predictive traits
of placebo analgesia in a univariate model were Ego-
Resiliency, NEO Agreeableness, and NEO Neuroticism,
PERSONALITY PREDICTORS OF which respectively explained 16%, 14%, and 12% of the
PLACEBO-INDUCED ACTIVATION OF variance in placebo response (Fig. 4.3). The former two
REGIONAL ENDOGENOUS OPIOID were positive predictors, while the latter was a negative
NEUROTRANSMISSION predictor. A multivariate model with Ego-Resiliency,
and the NEO facets Altruism, Straightforwardness and
Substantial interest exists in the development of Angry Hostility (negative predictor) accounted for 25%
simple measures, such as personality traits, that may of the variation in placebo analgesic responses and had a
provide predictive value for the formation of placebo predictive ability of 18%.
effects, as they might substantially influence the thera- Molecular imaging showed that subjects scoring
peutic context73 and therefore placebo effects. Recent above the median in a composite of those trait measures
work has studied the effect of the patient–practitioner also presented greater placebo-induced activation of
relationship on placebo acupuncture responses.73 In μ-opioid neurotransmission in the subgenual and dor-
this study, participants were randomized to a waitlist sal ACC, OFC, INS, NAC, AMYG and at a lower thresh-
(observation), limited (placebo acupuncture + n eutral old, the PAG. These regions largely overlap with those
practitioner) or augmented placebo acupuncture treat- identified in previous reports as responsive to placebo
ment (placebo acupuncture + empathic practitioner). It administration and involved in the regulation of the pain
was shown that gender (female) and personality traits experience.44,47,78 As previously observed, activation of
(extraversion, agreeableness and openness to expe- μ-opioid receptor mediated neurotransmission in some of
rience) influenced placebo response, but only in the these regions was associated with reductions in individ-
warm, empathic, augmented group. These results sug- ual pain report (Fig. 4.3). Additionally, we found signifi-
gested that to the degree a placebo effect is evoked by cant reductions in cortisol plasma levels during placebo
the patient–practitioner relationship, personality char- administration, which were correlated with reductions in
acteristics of the patient will be associated with placebo subjective pain report and μ-opioid system activation in
response and highlight the complexity and variabil- the dorsal ACC and PAG. While no significant relation-
ity of placebo effects in the context of a therapeutic ships were observed between the composite scores and
relationship. reductions in cortisol, these were negatively correlated
In line with this work, trait optimism and trait anxiety with NEO Angry Hostility scale scores at trend levels.
were found to be positive and negative, reproducible Previous studies have suggested that dispositional
predictors.74,75 Personality traits thought to be related optimism, as defined by the Life Orientation Test-
to dopaminergic function (novelty seeking, harm avoid- Revised scale, might be a predictor of placebo analge-
ance, behavioral drive, fun seeking and reward respon- sia using experimental models of phasic heat and a
siveness) have also been associated with both placebo preconditioning procedure to increase expectations of
analgesic effects and gray matter density in the basal analgesia,75 or cold pain (cold pressor test) without pre-
ganglia and prefrontal cortex.76 conditioning, where an interaction between Life Orien-
We examined the possibility that personality traits tation Test-Revised scores and experimental condition
would be associated with analgesic placebo responses was reported.74,75 Similarly, placebo effects have been
in a sample of 50 healthy volunteers using the sus- associated with dopaminergic function, such as novelty
tained pain paradigm described above.77 Since our seeking, harm avoidance, behavioral drive, fun seeking
primary hypothesis stated that personality predictors and reward responsiveness, during intramuscular infu-
of placebo responses would be associated with stress sion of hypertonic saline paired with a cream using a
resiliency, we examined the predictive value of scales conditioning-like procedure.76 However, these findings
assessing emotional, psychologic, and social well- were not replicated in the present study using a sus-
being, dispositional optimism, satisfaction with life and tained pain model and no preconditioning procedures.
ego-resiliency. Personality traits related to dopaminer- These results suggested that stable personality traits
gic function were also evaluated using the behavioral related to stress resiliency and interpersonal function
34 PLACEBO AND PAIN
FIGURE 4.3 Personality traits effect on placebo-induced activation of regional μ-opioid receptor mediated neurotransmission. Left: Regions
of greater μ-opioid system activation during placebo administration in subjects with high levels of Ego Resilience, Straightforwardness and
Altruism and low levels of Angry Hostility. Upper right: Simple linear regression representing percent change in Placebo Response associated
with 1 SD increase in Trait Measure (with 95% Confidence Intervals). (** indicates p < 0.01; * indicates p < 0.05). Lower right: Correlations
between Δ μ-opioid BPND in the dACC during pain compared to (pain + placebo) and Δ in pain ratings (MPQ) during placebo administration.
INS: insula; NAC: nucleus accumbens; r/sgACC: rostral and subgenual anterior cingulate cortex; AMYG: amygdala; PAG: periaqueductal
gray. This figure is reproduced in color in the color section.
have a substantial impact on the capacity to develop pla- understand the inter-individual variability that leads to
cebo effects. If replicated in clinical samples, these trait recovery from any illness. A network of regions, includ-
measures could be employed to reduce variability in ing the rostral anterior cingulate, dorsolateral prefrontal
treatment trials for conditions, such as persistent pain, and orbitofrontal cortices, insula, nucleus accumbens,
mood and movement disorders, where placebo effects amygdala, medial thalamus and periaqueductal gray
can be particularly prominent and obscure the effects of appear to be involved. Opioid and dopamine neuro-
potentially active treatments. transmission in these areas modulates various elements
of the placebo effect, which appear to include the repre-
sentation of its subjective value, updates of expectations
CONCLUSIONS over time, the recall of pain and placebo experiences
and changes in affective state and in pain ratings. The
An emerging literature is demonstrating that cogni- circuitry involved in placebo analgesic effects also has
tive and emotional processes that are engaged during the potential to modulate a number of functions beyond
the administration of an otherwise inactive agent, a pla- pain, as the brain regions involved have been implicated
cebo, are capable of activating internal mechanisms that in the regulation of stress responses, neuroendocrine
modify physiology. These processes are of importance to and autonomic functions, mood, reward and integrative
cognitive processes, such as decision-making. Besides 19. Gleidman L, Gantt W, Teitelbaum H. Some implications of con-
the perspective that placebo effects confound RCTs, ditioned reflex studies for placebo research. Am J Psychiatry.
1957;113:1103-1107.
the information so far acquired points to neurobiologic 20. Voudouris NJ, Peck CL, Coleman G. The role of conditioning and
systems that, when activated by positive expectations verbal expectancy in the placebo response. Pain. 1990;43(1):121-128.
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Acknowledgments 24. Rainville P, Duncan G, Price D, et al. Pain affect encoded in
Support was provided by the National Center for Complementary and human anterior cingulate but not somatosensory cortex. Science.
Alternative Medicine grant R01 AT 001415 and R01 DA 016423 to J.K.Z. 1997;277(5328):968-971.
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C H A P T E R
5
How does EEG Contribute to Our
Understanding of the Placebo Response?
Insights from the Perspective of Bayesian Inference
Anthony Jones1, Christopher Brown1, Wael El-Deredy2
1Human Pain Research Group, University of Manchester, Manchester, UK, 2Department of Psychological Sciences,
University of Manchester, Manchester, UK
THEORETICAL MODELS OF PLACEBO the intensity of stimulation, when paired with an inert
ANALGESIA treatment, produce strong placebo responses. However,
Montgomery and Kirsch8 found, using an almost iden-
A scientific understanding of the mechanisms of pla- tical procedure, that when subjects were told that the
cebo analgesia must conform to a theoretical model that treatment was inert, there was no placebo response,
is consistent across multiple domains of knowledge suggesting that cognitive expectations were essential.
(e.g. neurophysiologic, pharmacologic, psychologic, A comprehensive discussion on the theoretical debate
social). In the psychologic domain, it has been argued between cognitive expectancy versus noncognitive
that expectations are largely responsible for placebo conditioning models is offered by Stewart-Williams
effects.1–3 Expectation may be partly related to the and Podd.9 For the purposes of this chapter, it suffices
information provided about the treatment by health- to point out that Montgomery and Kirsch8 argued that
care professionals, and partly to psychologic processes conditioning will produce placebo response expectan-
particular to the patient. Wager1 and Morton et al4 pro- cies rather than actual placebo responses. The idea that
posed overlapping models of the role of expectancy, it is the expectancies that actually elicit the response
positing a role also for a second factor, anxiety reduc- bears close resemblance to assimilation theory, which
tion, in placebo analgesia. Morton et al5 argued that is a framework that predicts the effects of expectations
dispositional optimism, the tendency to expect positive on sensory perception.10 Grounded in ideas around
outcomes, also plays a role in facilitating the reduction cognitive dissonance, it assumes that the discrepancy
in anxiety. between expected and actual experience is undesir-
There are also noncognitive approaches to account able, and therefore the perception is altered to match the
for placebo responding, which may or may not rely expectation. The idea is consistent with the concept of
on expectation, most notably classical conditioning.6 the placebo response being an erroneous non-detection
A true drug or treatment is an unconditioned stimulus of pain signals.11
(US) leading to an unconditioned response (symptom The concept of cognitive dissonance is also consis-
relief). A placebo treatment repeatedly pairs a neutral tent with more complex probabilistic approaches to
stimulus (e.g. sugar pill) with the notion of the US understanding pain perception, such as used within

and thus become conditioned stimuli that can elicit a the framework of Bayesian theory.1 In this conceptual
response similar to that of the active drug, a conditioned approach, which builds on the notion of perception as
response.7 Early experiments showed a role for classi- inference,12 pain perception is thought of as a product of
cal conditioning in the placebo effect, with studies by prior information (informing expectation/anticipation)
Voudouris et al6 showing that surreptitious reduction in and current information (nociceptive processing). In
38 PLACEBO AND PAIN
applying these Bayesian concepts to sensory neuro- (SPN) (Fig. 5.1). The LEPs that are most reliably recorded
science the balance between the influence of prior are an early negative component N1, subsequent N2
expectation over sensory evidence is governed by the component and ensuing positive component P2.18–21

uncertainty in those expectations,13 such that sensory N2/P2 are generally thought to be related to the
evidence has more influence when expectations are conscious experience of pain,19,21 are modulated by

more uncertain, due to processes of attention and learn- attention and mood22,23 and are correlated with antici-
ing that become activated during uncertainty. However, patory p rocessing as measured by the amplitude of the
it has been suggested also that uncertainty necessarily SPN.24
increases pain reports,14 a view that appears to conflict
with a purely Bayesian model of pain. The evidence we
review below favours the Bayesian model, although it PAIN ANTICIPATION AND ITS ROLE IN
is possible that uncertain anticipation may induce anxi- PAIN PERCEPTION
ety and higher pain ratings under a psychologic context
in which uncertainty is associated with greater threat EEG, because of its high temporal resolution, has the
value.15 potential to investigate top-down mechanisms such as
Based on the above theoretical considerations, here expectation, attention, and anxiety in terms of anticipa-
we propose an integrated model. The model argues that tory processes preceding pain. Specifically, EEG pro-
the placebo response is primarily driven by cognitive vides the means to clearly differentiate between neural
processes of expectation and assimilation with expecta- processes during anticipation and experience of pain
tion, processes that are influenced by a range of other and to begin to unpick the somewhat complex relation-
cognitive processes such as confidence in treatment cues, ship between these two aspects of pain processing in the
implicit conditioning based on past treatments, and brain.24 The SPN generated prior to a pain stimulus can
explicit memories of those treatments. Nonspecific psy- be used as a measure of pain anticipation. In this section
chologic processes such as positive emotional responses we review EEG studies of anticipation,24,25 which show
arising from an empathic therapeutic relationship have that anticipatory activity is correlated with the expected
also been shown to be involved in placebo responding,16 intensity of pain and is a predictor of subsequent pain
which may then influence treatment-specific expectancy perception and neural correlates of pain such as laser-
processes by increasing confidence in treatment cues evoked potentials (LEPs).
(i.e. increasing the subject’s perception that those cues Behaviorally, Brown et al,24 have shown that when
are reliable). We also propose that one of the mediators high-, medium- and low-intensity laser stimuli are
of the effects of expectations on pain may be a reduction delivered to the back of the arm in a pseudo-randomized
in anxiety and stress. order, the perception of those stimuli is influenced by
The remainder of this chapter will review in more preceding cues that provide either certain or uncer-
detail the evidence for four key components of this tain information about subsequent stimulus intensity.
model: expectation, conditioning, attention and anxiety In other words, prior expectation generated from the
reduction, and will provide evidence from EEG studies cues significantly influenced pain ratings. Certain
for the involvement of these processes. expectations of high pain increased pain perception,
whereas certain expectations of low pain decreased
pain perception, relative to uncertain conditions in
EEG MEASURES OF PAIN AND ITS which the same intensity of pain was delivered. The
ANTICIPATION probability distribution of stimulus intensity was
roughly centered on the medium intensity stimuli,
Electroencephalography (EEG) allows us to record as high, medium and low stimuli had equal likeli-
changes in cortical neuronal activity using surface hood. The ratings during relative uncertainty were
electrodes on the scalp. Two types of information can more clustered towards the medium intensity and
be analyzed from EEG recordings: (1) the frequency this would favor a probabilistic or B ayesian model of
characteristics of the EEG, either at rest or in response pain perception, rather than the view that uncertainty
(time-locked) to specific events, (2) event-related poten- increases pain via anxiety.
tials (ERPs), which are responses that are consistent When EEG data from the above experiment were
across multiple trials of data, determined by averaged studied,24 it was found that under ‘certain’ conditions,
time and phase-locked responses to stimuli or actions, when the future pain intensity was known, anticipatory
or in anticipation of these. In this chapter we focus processing was a predictor of pain processing, but not
mainly on ERPs to painful or non-painful laser stimuli during ‘uncertain’ conditions. During uncertainty, antic-
(laser-evoked potentials, LEPs) and anticipation-evoked ipation, as measured by the SPN, did not correlate with
potentials known as the stimulus-preceding negativity LEPs, whereas during certain expectation the SPN was
EEG AND OUR UNDERSTANDING OF THE PLACEBO RESPONSE 39
FIGURE 5.1 A model of the core components of the placebo response. An expectation of effect (1) causes ambiguity (2) regarding the intensity
of the pain experience. Sensory ambiguity is further compounded by attentional processes such as distraction from the pain. When faced with
the ambiguity of the perceived pain signal, subjects can either assimilate (3) or contrast their experience to their prior expectation of treatment.
Assimilation results in enhancement of the effects of expectation (1). Expectation then goes on to cause a decrease in anxiety (4), which is known
to cause decreases in perceived pain intensity (5). The reduction in pain from placebo and real analgesics will act as a conditioning stimulus that
enhances memory of analgesic efficacy (6) and subjective confidence (8) in any cues indicating than an analgesic treatment is taking place. Posi-
tive emotional responses arising from an empathic therapeutic relationship may also increase confidence in treatment cues. Confidence acts as a
facilitator of assimilation with expectation (3), thus further enhancing placebo effects. Reproduced from Brown et al.17
indeed correlated with subsequent LEPs. In other words, (compared to uncertain) were associated with anticipa-
not only did certain information about forthcoming pain tion being processed in areas of the brain more associated
bias pain perception, it also caused anticipatory processes with semantic memory, conditioning and emotional/
to better predict subsequent pain processing. To shed autonomic responses such as anterior prefrontal cortex
light on this, further analysis looked at the brain sources (aPFC), inferior frontal and temporal cortices and sub-
of anticipatory activity during certain and uncertain con- genual cingulate cortex.24 This is consistent with greater
ditions, showing that they appeared to be processed in reliance on past information in determining pain experi-
different circuitry in the brain.24 Uncertain anticipation ence (via expectation) when the intensity of forthcoming
was processed in areas of the brain more concerned with pain is known. In sum, these differences in processing
attention, such as dorsolateral prefrontal cortex (DLPF), provide further evidence in favor of a Bayesian model
posterior cingulate cortex (PCC) and inferior parietal cor- of pain perception and placebo analgesia. During more
tex (IPC). This is possibly because uncertainty promotes uncertain expectation the Bayesian model predicts that
mechanisms of learning by directing attention to current more attention will be placed on the incoming sensory
sensory information, as suggested by Bayesian accounts information (nociceptive information presented to the
of sensory perception.13 Conversely, certain conditions brain), with less reliance on any prior information.
40 PLACEBO AND PAIN
According to Bayesian theories of perception, greater way they anticipate pain (less modulation of anticipa-
reliability of a predictor increases its influence on per- tory processing by external cues). Recent work also that
ception and behavior.13,26,27 Consistent with this, there is suggests that patients with FM demonstrate subtle dif-
evidence that subjects who are more certain/confident ferences in experimental placebo response consistent
of their likely response to pain will tend to be more influ- with differences in the way they attend to prior informa-
enced by information about the forthcoming intensity of tion (unpublished data).
pain. Brown et al25 studied the effects of prior beliefs and
confidence in those beliefs as a way of measuring sub-
jects’ perceived reliability of expectations. In an exten- EEG STUDIES OF PLACEBO ANALGESIA
sion of the previously described study by Brown et al,24
the same subjects rated how much emotional distress The above methodology for studying pain anticipa-
they predicted they would experience in response to the tion and perception using EEG has been applied to the
pain stimuli. They also rated their confidence in this pre- study of the mechanisms of placebo analgesia. The model
diction as an index of the extent to which they might rely presented above for placebo analgesia requires placebo
on their expectations when making sensory judgments. to be a true physiologic phenomenon rather than due to
Analysis of the high-intensity laser stimulations revealed increased compliance (i.e. the subject complying with
that confidence in prior beliefs was a predictor of the implicit wishes of the experimenter to observe a pain
extent to which certain anticipation (relative to uncertain reduction). Watson et al34 provided the first clear EEG
anticipation) was able to bias the perception of pain. This evidence of this, showing that placebo analgesia is a real
is consistent with a Bayesian model of pain perception. physiologic phenomenon in which cortical responses
Further evidence for this model came from data from to pain (P2 peak of the LEP) are diminished. Further
the same study25 showing that greater confidence, and a work by Wager et al35 established that the N2 peak of
greater effect of certain vs. uncertain anticipation cues on the LEP does not appear to be affected as a part of the
pain, was positively correlated with activity in the right placebo response, finding only effects on the P2 peak in
anterior insula (a region known to be involved with aver- agreement with the results of Watson et al.34 Of further
sive conditioning and affective responses to pain)28,29 interest to the study by Wager et al was the finding that
and negatively correlated with activity in the inferior variance in P2 peak responses did not entirely account
parietal and midcingulate cortices (regions involved for the changes in reported pain as a result of placebo.
with attentional orientation to pain).30,31 In individuals The authors discussed this as possibly due to later pain
with greater confidence in prior beliefs, there will be less processing (post-LEP) being important in modifying
need for attention to the sensory–discriminatory compo- pain reports. Similarly, Colloca36 did not establish a cor-
nents of pain and therefore less resources given to atten- relational relationship between the neurophysiologic
tional areas of the pain matrix such as inferior parietal response and pain reports. In a study by Fiorio et al of
and mid-cingulate cortices. On the other hand, greater ‘placebo-like’ enhancement of non-noxious stimulus
confidence in prior beliefs may induce processing within perception,37 reported stimulus intensity was also not
areas concerned with conditioned affective responses to correlated with late evoked-potential amplitudes. In this
pain such as anterior insula. case, the authors discussed the possibility that greater
These EEG studies in normal volunteers have some evoked potential amplitudes represented a ‘cortical sen-
potentially important clinical implications. The results sory gain’ that enhanced stimulus salience, possibly via
suggest that patients who attend poorly to the details enhancement of attention, but that this is only one out of
of sensory pain processing may appraise pain in a way many possible processes that may influence perceptual
that is weighted towards prior beliefs. This may mean judgements.37
that such patients are also more prone to manipulation Studies have shown that, in healthy populations, both
of these beliefs, and may therefore be more susceptible to placebo analgesia and physiologic changes as measured
both placebo and nocebo responses. On the other hand, with EEG are reproducible across different experimental
if chronic pain and attentional deficits are associated sessions.4,5,38 For example, it has been clearly demon-
with significant psychologic comorbidity such as anxi- strated that the experimental placebo response is asso-
ety and depression, these may result in less psychologic ciated with reductions in SPN.38 However, the way in
flexibility that may interfere with the ability to induce which this reduction occurred was unexpected. In this
placebo responses. Indeed, recent experiments from study, experimental placebo was induced in a group of
our laboratory32,33 suggest that patients with fibromyal- subjects by providing a sham treatment (a cream) to the
gia (FM), who can often present with such psychologic skin, which was paired to reinforced expectation (condi-
comorbities, have abnormalities of both their ability to tioning) by telling subjects that the cream may have been
allocate attentional resources (less focus on sensory dis- an analgesic. A control group had the same procedure
crimination and more on affective processing) and the but were fully informed that the cream did not contain
an anaesthetic. Unexpectedly, there was no reduction Research has begun to use EEG to differentiate
in SPN in either group in this first session. There was between verbal expectancy and conditioning mecha-
also a lack of correlation between changes in the SPN nisms underlying placebo analgesia. Research by Colloca
and changes in pain as a result of the sham. These nega- et al36 has shown that both conditioning and expectation
tive results may indicate a persistence of fear and/or alone lead to reductions in LEP responses, but only con-
lack in confidence in predictions of reduced pain. How- ditioning leads to an actual reduction in pain consistent
ever, in both groups, the experiment was repeated with with a placebo analgesic response. Colloca et al assessed
a minimum gap of two weeks (range 2–6 weeks). The the effect of verbal suggestion alone in one group and
SPN was substantially reduced in the repeat sham treat- reinforced suggestion (i.e. conditioning) in a second
ment group both before and after application of cream, group, whereby the intensity of the laser stimulus was
although with bigger reductions post-application. This surreptitiously turned down after bland cream applica-
may be because there was greater confidence in the tion. Only significant reduction in pain was produced
belief that the cream would work on the second session by reinforced suggestion. Interestingly, the LEP (N2/P2)
having experienced the beneficial effects of the placebo was significantly reduced in both groups but this was
treatment in the first session. only associated with pain reduction in the group who
These reproducibility findings may be related psycho- were exposed to reinforced suggestion. This provides
logic traits that predispose towards placebo responding. evidence that learning in the context of experience of
For example, in studies by Morton et al,4,5 reproducibility pain reduction is a more powerful mediator of placebo
of placebo analgesia has been positively correlated with analgesia than learning from verbal suggestion alone.
the psychologic trait of optimism with a trend towards a One crucial question is: does attention influence placebo
negative association with generalized anxiety. EEG work responses? ‘Attention’ is a broad concept that includes a
has gone some way towards supporting the role of cog- number of processes and ways of classifying these pro-
nitive factors and anxiety in placebo analgesia and its cesses. A key example is the dual-processing theory of
reproducibility. Morton et al38 showed that reductions in Schneider and Shiffrin43,44 in which a distinction is made
state anxiety preceded the large reductions in anticipa- between automatic and controlled processing. Automatic
tory activity occurring when the experimental placebo processing is fast, parallel, and not limited by short-term
was repeated in the same individuals. It was suggested memory, while controlled processing allows little subjec-
that this reduction in anxiety may be one of the main tive control and requires extensive and consistent train-
mediators of placebo analgesia, although this was not ing to develop. This is an important distinction in relation
correlated with changes in anxiety. However, the cogni- to the model of placebo (Fig. 5.2), as it may be the case
tive trait of dispositional optimism was found to be sig- that only automatic processes of attention interact with
nificantly correlated with changes in anxiety, SPN and pain expectancy. For example, work by Buhle et al45 has
LEP (N2/P2) over the two sessions. usefully established that controlled processes of attention
There are some caveats to using the SPN to make are additive rather than interactive with placebo anal-
inferences about changes in cognitive mediators of pla- gesia, suggesting that controlled attentional processes
cebo analgesia. The SPN is also known to be increased are not required for a placebo response. In their paper,
by reward,39,40 and it is possible that placebo analge- Buhle et al describe using a cognitive distraction task (the
sia (in particular, expectations of reduced pain) may n-back task) that requires working (short-term) memory,
increase reward processing and contribute to larger SPN and is therefore an example of controlled attention.
amplitudes. In other words, the SPN could represent a Going back to the study by Colloca,36 automatic pro-
mixture of anticipatory processes related to both aver- cesses of attention may have been a factor in the results,
sion and reward originating from different regions of the in that the suggestion-alone group were less certain and
brain, but that cannot be differentiated using a simple (according to the Bayesian model) would have allocated
analysis of scalp amplitudes. This may explain why a greater attentional resources to nociceptive process-
reduction in the SPN was not found in the first session of ing to resolve this uncertainty, compared to the group
the above-mentioned reproducibility study.38 Also, the exposed to reinforced suggestion. As such, changes in
results of Morton et al are not entirely consistent with attentional processing may partially explain a degree
recent fMRI experiments41,42 (reviewed in Chapter 10) of variance in the LEPs that was not present under the
that clearly show focal reductions in brain activity dur- more certain conditions induced by reinforcement. This
ing pain anticipation in a single placebo session after hypothesis could be tested using measurement of antic-
changes in reinforced altered expectancy (‘condition- ipatory processing (SPN) and source reconstruction to
ing’). This highlights the importance of identifying the identify whether there were any differences in atten-
different brain sources that give rise to the SPN and tional processing regions, but behavioral experiments
interrogating them individually, as done in the studies that assess automatic attentional processes may also be
by Brown et al24,25 on pain anticipation. required.
42 PLACEBO AND PAIN
FIGURE 5.2 An example of the evoked-potential responses that can be recorded using EEG during the anticipation and experience of acute
laser pain. Early and late phases of the stimulus-preceding negativity (SPN) can be differentiated that may have functionally distinct roles in pain
expectancy.
CONCLUSION However, more work is required to further refine our

current cognitive model of placebo analgesia. In particu-
EEG provides the means to understand some of the lar, research should focus on (1) the role of anticipatory
variability in placebo response, and the mechanisms reward processing, (2) whether anxiety reduction is a
behind this variability. It provides a relatively cost- necessary mediator of expectancy effects, (3) whether
effective way of monitoring some key components of there are distinct neuronal mechanisms related to con-
placebo response and the role of psychologic traits and ditioning effects or whether these simply act to reinforce
phenotypes in modifying these components. So far, we expectations of pain relief, and (4) the possible role of
have learnt that expectations drive pain perception in a attention in explaining physiologic differences between
way that is consistent with a Bayesian model. Within this verbal expectancy and conditioning (reinforcement)
model, more certain expectation (as a result of percep- mechanisms.
tions of pain reduction cues being reliable) weights pain
perception towards prior experience and beliefs, while
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C H A P T E R
6
Spinal Mechanisms of Placebo Analgesia and
Nocebo Hyperalgesia: Descending Inhibitory
and Facilitatory Influences
Serge Marchand
Université de Sherbrooke, Faculté de médecine and Centre de recherche clinique Étienne-Le Bel du
CHUS Sherbrooke, Québec, Canada
INTRODUCTION The reality is a little more complex than that. As

described in the other chapters of this book, the placebo
The outcomes of an inactive treatment that mimics response is clearly triggering cortical changes that sev-
the effect of a real treatment are called placebo or nocebo eral good laboratories are recording. However, this effect
effects. The placebo effect defines the positive response is not restricted to the cortex and will influence the rest
of a subject to a substance or to any procedure that has no of the central nervous system (CNS), from the cortex to
therapeutic effect for the treated condition.1 More specif- the spinal cord.
ically, this effect can be defined by the physiologic and/ In this chapter, I concentrate on how the placebo and
or psychologic changes, such as a reduction of pain asso- nocebo mechanisms are closely linked to endogenous
ciated with the use of an inert medication, a simulated pain modulation mechanisms and how placebo analge-
therapeutic procedure or a meeting with therapeutic sia or nocebo hyperalgesia acts through brainstem and
symbols. The nocebo effect is the appearance of adverse spinal facilitatory and inhibitory mechanisms.
effects accompanying the use of an inert substance. Pla-
cebo and nocebo responses can be present without the
administration of an inert substance, such as when you PAIN AND PLACEBO HAVE DYNAMIC
have just received a diagnosis or when you are warned INTERACTIONS
of an upcoming particularly painful stimulus.2
The least we can say is that these effects are frequently To better appreciate the mechanisms and the clini-
perceived as mysterious or questionable by the care- cal implications of the placebo and nocebo responses in
giver and the patient. The care-giver may interpret these pain, we need to understand the basic neurophysiology
responses to an inactive treatment as the proof of the of the development and persistence of pain.
absence of a real pathology, while the patient may feel Pain is a complex phenomenon playing a major role in
that the caregiver has fooled him/her and perceives his/ protecting us from injury or illness. The pain signal needs
her response as a psychologic weakness. These impres- to be clear and emotionally salient for an individual to
sions about the placebo response are probably based on act rapidly and adequately to get away from the nocicep-
the fact that most people are seeing the placebo effect as tive source and take care of the injury. However, in some
a mere reinterpretation of the patient’s perception, like conditions, the nociceptive signals have to be temporar-
the impression that the pain is now reduced or has just ily silenced to focus on actions required to reduce further
disappeared while, in fact, it is exactly the same. Physi- harm and thus, increasing chances of survival.
ologically, this point of view on the placebo mechanisms The pain perceived following a nociceptive stimulus
will be described as a purely cortical effect. would then be completely different depending on the
46 PLACEBO AND PAIN
context and situation. To avoid an injury, the CNS needs responds at higher frequency when recruited by noci-
to be able to rapidly encode the localization and intensity ceptive (hyperalgesia) and non-nociceptive primary
of a nociceptive stimulus. However, the nervous system input (allodynia). Central sensitization is defined as an
also needs to be able to ignore pain in other situations, increase of excitability and spontaneous discharge of the
such as getting out of a car on fire after an accident, even dorsal horn neurons with an associated increase in the
if you have fractures or lacerations. It is most likely for receptive field of these neurons. This phenomenon will
these reasons that the CNS has developed several com- principally affect the wide dynamic range (WDR) neu-
plex endogenous facilitatory and inhibitory mechanisms rons from the dorsal horn and is dependent on the activ-
that can either emphasize or reduce the perception of ity of the N-methyl-D-aspartate (NMDA) receptors.6,7
pain following a nociceptive stimulus depending on the These neurophysiologic and neurochemical mechanisms
circumstances. involved in central sensitization are responsible for the
Nociceptive afferents can be modulated at all levels modification of the spinal nociceptive circuitry and con-
from periphery to higher CNS centers. Because of the tribute to the maintenance of pain.
dynamic and plastic characteristics of the nervous sys- In the spinal cord, secondary hyperalgesia is a phe-
tem, pain perception is not the sole result of the nocicep- nomenon that refers to sensitization.8 Repeated recruit-
tive activity, but the endpoint of complex facilitatory and ment of C fibers following an injury will produce
inhibitory endogenous pain modulation mechanisms. central sensitization by changing the response proper-
This plasticity speaks to the nervous system’s ability to ties of the membrane of secondary neurons. This will
adapt and change. It is then not surprising that the eti- result in an increase of the firing rate, a phenomenon
ology of pain of two patients suffering from apparently known as windup.9 The high frequency recruitment of
similar clinical conditions may be related to different C fibers, either by increased repetitive stimuli or by a
mechanisms such as increased facilitatory mechanisms in tonic stimulation,10 will then induce an increase in the
one case and a reduction of endogenous pain inhibitory perceived pain, even if the intensity of the stimulation
mechanisms in the other case. As we will see, the placebo remains constant. This central sensitization at the spinal
and nocebo responses modulate the nociceptive activity level can persist for minutes, but can also be present for
and pain responses by acting through these mechanisms. hours and even days.11 The prolonged activation of the
To better understand the link between pain and NMDA receptors will induce the transcription of rapidly
placebo mechanisms, we have to study the nociceptive expressed genes (c-fos, c-jun), resulting in sensitization
signal from the periphery to the higher centers of the of nociceptors. This neuronal plasticity of the secondary
CNS, but we also need to understand the descending neuron will result in a reduced threshold and enlarge-
pain modulation controls arising from the higher centers ment of their receptive field in the spinal cord and pro-
and projecting to the spinal cord. duce hyperalgesic and allodynic responses that may
Based on our knowledge of the neurophysiology of persist even after the injury is healed.
pain, we can conclude that the development, maintenance
and recovery from pain depend on several factors. Persis-
Descending Facilitatory Mechanisms
tent pain can result from the activity of nociceptive affer-
ents, but it can also be related to a reduction of endogenous It is now well documented that several supraspinal
inhibition and/or an increase of endogenous facilitatory facilitatory and inhibitory mechanisms play a major role
mechanisms. Central sensitization supports the impor- in pain perception and most probably in certain chronic
tance of endogenous pain facilitatory circuitry in the devel- pain conditions.12 The work of Fields describing acti-
opment and maintenance of pain. The facilitatory and vation of ‘ON’ cells and inhibition of ‘OFF’ cells in the
inhibitory roles on pain modulation played by different brainstem during nociceptive activity has demonstrated
structures of the brainstem have been well documented.3–5 the importance of facilitatory mechanisms in amplify-
In order to better understand the effects of placebo on ing the nociceptive response.13 Considering that proglu-
descending facilitatory and inhibitory mechanisms and mide, an antagonist of cholecystokinin (CCK), blocked
on the spinal nociceptive activity, we will shortly review nocebo hyperalgesia,14 and that CCK directly activates
some of these pain modulatory mechanisms. ‘ON’ cells,15 it is possible that the hyperalgesia reported
during the nocebo effect depends on these excitatory
bulbospinal circuits that facilitate spinal nociceptive
activity.
FACILITATORY MECHANISMS
Recent studies have also demonstrated that certain
physiologic conditions, such as nociceptive hyperactiv-
Spinal Sensitization
ity, may change the usual neuronal response to specific
Central sensitization refers to a phenomenon whereby neurotransmitters. A particular example is the hyperal-
the second neuron membrane permeability changes and gesic effect that can be observed in some patients using
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We also had to get Garvice’s books, and also Oppenheim’s. But
even at the beginning of our venture, we were by no means limited
in opportunity to authors of any particular class. It was quite
possible that one man in a ward would be reading, say, Nat Gould’s
‘Jockey Jack’—a great favourite—and the man in the next bed would
be reading Shakespeare, or ‘The Pilgrim’s Progress,’ or Shelley, or
Meredith, Conrad, or the Encyclopædia. We found, in fact, so many
different kinds of minds and upbringings, that we could never have
remembered without the aid of a note-book what each man wanted.
So after various experiments, this became our system. We divided
the wards between us, and went round with our note-book to each
bedside, found out if our soldier cared to read, and, if he had no
suggestion to make, found out in a vague sort of way, without
worrying him, of course, what he would be likely to want—if, indeed,
he wanted anything at all. For in some cases the very thought of a
book was apparently worse than a bomb. In instances like this,
matches and cigarettes or tobacco served as a substitute for
literature, and generally speaking as a natural concomitant too! Now
and again we have had men who have never learnt to read at all.
With one exception, these have invariably been miners.
One day our work took on a new phase, the development of which
has been the source of great satisfaction, both to readers and
librarians. We were asked for a book on high explosives. We made
inquiries about the one in question, and found it cost eighteen
shillings. That seemed a good deal to spend on one book for one
person, but on mentioning this matter to our doctor in charge, we
were told to go ahead and buy it, and also anything else that
seemed to be wanted. This one incident fired us with the idea to find
out what subjects the men were interested in, what had been their
occupation before the war, or their plans for the future. And from
that moment the work of the librarians became tenfold more
interesting, and in some degree constructive.
We were asked for books on paper-making, printing, cabinet-
making, engineering, marine engineering, veterinary work, Sheffield
plate, old furniture, organic and inorganic chemistry, fish-curing,
coal-mining, counterpoint, languages, meteorology, electricity,
submarines, aeroplanes, flowers, trees, gardening, forestry, the
Stone Age, painting and drawing, violin making, architecture, and so
on. The fish-curing instance was particularly interesting. The soldier
in question was from Nova Scotia, and his father’s business was fish-
curing. He was anxious to learn the English methods, and gain all
the information he could during his sojourn in England, before he
was invalided out of the army and returned to his home.
We have therefore made it our business to supply these various
needs, and also to provide any weekly papers bearing on the
different subjects in which the men are interested. Our Department
could not, of course, be always buying costly books, but with the aid
of our subscription to Mudie’s, and by the help of friends who have
come to the rescue and lent their valuable books to us for the
special purpose which we have unfolded to them, we have been able
so far to meet all demands; and this part of our work is increasing
all the time. The Sheffield plate book lent us by a generous
antiquary was a perfect godsend to one of our crippled men. His
business was that of a second-hand dealer, and he said it was a rare
chance to get hold of that book and make copious notes from it
which would be invaluable to him afterwards.
Turning aside from technical subjects to literature in general, I
would like to say that although we have not ever attempted to force
good books on our soldiers, we have of course taken great care to
place them within their reach. And it is not an illusion to say that
when the men once begin on a better class of book, they do not as a
rule return to the old stuff which formerly constituted their whole
range of reading. My own impression is that they read rubbish
because they have had no one to tell them what to read. Stevenson,
for instance, has lifted many a young soldier in our hospital on to a
higher plane of reading whence he has looked down with something
like scorn—which is really very funny—on his former favourites. For
that group of readers, ‘Treasure Island’ has been a discovery in more
senses than one, and to the librarians a boon unspeakable.
We have had, however, a large number of men who in any case
care for good literature, and indeed would read nothing else.
Needless to say, we have had special pleasure in trying to find them
some book which they would be sure to like and which was already
in our collection, or else in buying it, and thus adding to our stock.
The publishers, too, have been most generous in sending us any
current book which has aroused public interest and on which we
have set our hearts. For we have tried to acquire not only standard
works, but books of the moment bearing on the war, and other
subjects too.
The following are items from two or three of our order books. The
order books have been chosen at random, but the items are
consecutive; and the list will give some idea of the nature of our
pilgrimages from one bedside to another bedside, and from one
ward to another.
One of Nat Gould’s novels; Regiments at the Front; Burns’s
Poems; A book on bird life; ‘The Last Days of Pompeii’; Strand
Magazine; Strand Magazine; Wide World Magazine; The Spectator; A
scientific book; Review of Reviews; ‘By the Wish of a Woman’
(Marchmont); one of Rider Haggard’s; Marie Corelli; Nat Gould;
Rider Haggard; Nat Gould; Nat Gould; Nat Gould; Good detective
story; Something to make you laugh; Strand Magazine; Adventure
story; ‘Tale of Two Cities’; ‘Gil Blas’; Browning’s Poems; Tolstoy’s
‘Resurrection’; Sexton Blake; ‘Scarlet Pimpernel’; Nat Gould; Wide
World Magazine; Pearson’s Magazine; ‘Arabian Nights’; Jack London;
Shakespeare; Nat Gould; ‘The Encyclopædia’; Rex Beach; Wm. Le
Queux; Strand Magazine; Nat Gould; Something in the murder line;
Country Life; The Story Teller Magazine; one of Oppenheim’s novels;
‘The Crown of Wild Olive’; ‘Kidnapped’; Nat Gould; Shakespeare; Nat
Gould; Silas Hocking; Oppenheim; Le Queux; Nat Gould; Nat Gould;
Jack London; ‘Handy Andy’; ‘Kidnapped’; ‘Treasure Island’; Book
about rose growing; ‘Montezuma’s Daughter’ (Rider Haggard);
‘Prisoner of Zenda’; Macaulay’s Essays; ‘The Magnetic North’
(Elizabeth Robins); Nat Gould; Sexton Blake; Modern High
Explosives; ‘Dawn’ (Rider Haggard); ‘Wild Animals’; Book on horse-
breaking; ‘Radiography’; ‘Freckles’ (by Gene Stratton-Porter); ‘The
Blue Lagoon’; ‘Caged Birds’; ‘The Corsican Brothers’; ‘Sherlock
Holmes’; French Dictionary; Kipling; ‘Mysticism’; Nat Gould; ‘Pilgrim’s
Progress’; ‘Mystery of Cloomber’ (Conan Doyle); and so on.
These are, of course, only a few items. I should say that on the
whole, and leaving out entirely books on technical and special
subjects, the authors most frequently asked for by the average
soldier are: Nat Gould, Charles Garvice, Wm. Le Queux, Rider
Haggard, Guy Boothby, Oppenheim, Rex Beach, Conan Doyle, Marie
Corelli, Joseph and Silas Hocking, Jack London, Dickens, Mrs. Henry
Wood, Kipling (whose ‘Barrack Room Ballads’ they learnt by heart),
Dumas, Ian Hay, Baroness Orczy, and Hornung’s ‘Raffles.’
And very favourite books are those dealing with wild animals and
their habits, with ferrets, rats, and birds, and all stories of adventure
and travel, and of course detective stories.
The New Zealanders and Australians have always asked for books
on England, and also for Bushranger stories, also for their own
poets. And even before we began to pay special attention to
technical subjects, all books on aeroplanes, submarines, electricity,
and wireless telegraphy were much in request. An Encyclopædia was
so much asked for that we wrote to Mr. Dent, who most kindly sent
us the twelve volumes of the ‘Everyman’s Encyclopædia.’ And they
are always ‘out.’ Shakespeare holds his own surprisingly and
encouragingly well.
The Society novel is never read, and we weeded it out to make
room for another class of book which would be in demand. We have
been sometimes astonished by the kind of book asked for by some
man who seemed to us a most unpromising reader. The puzzle has
been solved when we learnt that he had seen it on the
cinematograph. ‘The Last Days of Pompeii’ was one of the books
asked for in these circumstances, and our soldier was literally riveted
to it until he had finished it, when he passed it on to his neighbour
as a sort of ‘real find.’ Similarly, ‘Much Ado about Nothing’ was asked
for, and after that several volumes of Shakespeare were taken to
that bedside. This experience certainly shows that the cinema has a
great possibility of doing good as well as harm.
The magazines most in demand are The Strand, The Windsor,
Pearson’s, The Wide World, The Red, and a few others. But some of
our readers have refused to be interested in any magazines except
their own pet ones. One man, for instance, confined himself entirely
to Blackwood’s. He proudly preferred an old number of Maga to a
current number of any other magazine on earth. A second man
remained loyal to the Review of Reviews, and a third to Land and
Water. Another was never satisfied with anything except The
Nineteenth Century. Others have asked only for wretched little rags
which one would wish to see perish off the face of the earth. But as
time has gone on, these have been less and less asked for, and their
place has been gradually taken by the Sphere, the Graphic, the
Tatler, the Illustrated London News, and the Sketch—another
instance of a better class of literature being welcomed and accepted
if put within easy reach. In our case this has been made
continuously possible by friends who have given subscriptions for
both monthly and weekly numbers, and by others who send in their
back numbers in batches, and by the publishers, who never fail us.
John Bull deserves a paragraph all to himself. The popularity of his
paper is truly remarkable. The average soldier looks upon it as a sort
of gospel; and new arrivals from the trenches are cheered up at
once by the very sight of the well-known cover. Even if they are too
ill to read it, they like to have it near them ready for the moment
when returning strength gives them the incentive to take even a
glance at some of its pages.
We have found that men who have not naturally been readers
have acquired the habit of reading in our Hospital, and there have
been many instances of men who have become out-patients asking
for permission to continue to use the library. It has been one of our
great pleasures to see old friends strolling into the recreation room
and picking out for themselves some book by an author whom they
have learnt to know and appreciate. Another gratifying feature of the
work has been the anxiety of many of our readers to have a book
waiting for them after an operation, so that as soon as possible they
may begin to read it and forget some of their pains and sufferings.
In many instances the author or the subject has been deliberately
chosen beforehand.
Our experiences, in fact, have tended to show that a library
department organised and run by people who have some knowledge
of books might prove to be a useful asset in any hospital, both
military and civil, and be the means of affording not only amusement
and distraction, but even definite education, induced of course, not
insisted on. To obtain satisfactory results it would seem, however,
that even a good and carefully chosen collection of books of all kinds
does not suffice. In addition, an official librarian is needed who will
supply the initiative, which in the circumstances is of necessity
lacking, and whose duty it is to visit the wards, study the
temperaments, inclinations, and possibilities of the patients, and
thus find out by direct personal intercourse what will amuse, help,
stimulate, lift—and heal.
LOST HORSES.
A month or so after the traitor Maritz had made his flamboyant
proclamation in German South-West Africa, a small body of mounted
Union troops was operating in a district which may be described as
‘somewhere near Upington.’ Probably such secrecy of places and
names is not at all necessary, but it lends an appropriate military
flavour to the small events I describe. I may go so far as to say that
the setting I have provided is fictitious, though similar events did, no
doubt, occur in the operations against Maritz and Kemp and their
heroes. The characters of the roan horse and of the boy Frikkie are
true to life, and the small adventures did occur much as described,
but in another country in South Africa and upon a different occasion.
Accept the story as fiction, not as history; it will at any rate serve to
throw a light upon one of the aspects of the fighting in that dry land,
and it illustrates the close relationship between horse and man in
that country of long distances and sparse population and infrequent
water-holes. The conditions are the absolute antithesis of those in
Flanders and the trenches.
The risk of losing his riding or pack animals is constantly present
to the veld traveller. Fortunately it is seldom the cause of anything
more troublesome than a temporary inconvenience, but there are
occasions when serious hardships result, the loss of valuable time or
of your animals, or risk to your own life. In most cases the loss of
your beasts is due merely to the fact that they have strayed. They
have, as a rule, either followed the lead of some restless animal who
is making back for his stable, or else they have wandered away in
search of grass or water.
A horse is less hardy than his hybrid half-brother, and more the
slave of his belly. Thirst and hunger pinch him at once, and he is
quick in search of comfort; he is therefore more likely to stop and
suffer capture at the first patch of good grass he comes to. His
superficial character, moreover, generally affords some indication
both of the reason he has strayed and the direction he has taken.
There are, however, a few horses who are inveterate and
troublesome wanderers; they are generally old animals whose
accumulated experience has developed a cunning foreign to their
normal character. Such animals often possess an irritating facility for
choosing the most inconvenient time to stray and the most unlikely
direction to go.
If horses are the most frequent offenders, their sins in this respect
are seldom serious. In my own experience mules are more liable to
travel back along the road they have come than horses; they are
more creatures of habit, their memory is more retentive, and they
have greater natural intelligence. When a mule has acquired the
habit of absenting himself from duty he is a perpetual trouble. The
most malignant form of this disease occurs when the beast has
developed an insatiable longing for one particular place, a definite
goal from which nothing will turn him. This haven of his constant
desire is generally the place where he was born, or where he passed
the pleasant days of his absurd youth.
There are traits in most horses which, in conjunction with this
foundation of congenital simplicity, go to make ‘character.’ Men who
have dealt with horses in the less frequented parts of the earth
know this well. They will remember one animal who had in a highly
developed degree that instinctive correctness of demeanour which
can best be described as good manners; a second had a heart like a
lion and checked at nothing; another was a prey to an incurable
nervousness; while yet another was just simply mean. These mean
horses are a perpetual menace; you never know when they will let
you down. Sometimes they are clearly actuated by malice;
sometimes, however, there is a subtle quality and timeliness in their
apparent stupidity which gives you a horrid suspicion that you’ve
been had, and that your horse is more of a rogue than a fool. Such
an animal is always an old horse, never a young one.
I am not quite clear as to what a scout should look like. The
typical scout of the North American Indian days, as exemplified in
the person of Natty Bumpo, wore fringed buckskin and moccasins
and coon-skin cap, while Texas Bill and his vivid companions had a
more picturesque costume still, in which great silver-studded saddles
and jingling spurs and monstrous revolvers bore a conspicuous part.
I must confess that my own nine sportsmen were scrubby-looking
fellows compared to their picturesque predecessors at the game.
(The khaki trousers issued by an administration which was always
more practical than picturesque do not lend themselves, in this
generation at any rate, to romance.) But they were a hard and
useful lot, much sunburnt, and with gnarled, scarred hands.
Deerslayer himself probably could not have taught them much about
their own veld craft. Every one was South African born; three of
them were younger sons of loyal Boer farmers. One was a coloured
boy, a quiet, capable fellow. He was with us nominally as a sort of
groom, but his civil manners and extraordinary capacity soon won
him an accepted place in the scouts; though he rode and ate with
us, he always sat a little apart in camp. He had spent three or four
years up country, where I had first come across him in fact, and had
shot some amount of big game; he was excellent on spoor and had
a wonderful eye for country, and I really think he was the quickest
man on and off a horse, and the quickest and most brilliant shot I
ever saw. He stood on the roster as Frederick Collins, but was never
known by any other name than Frikkie.
The commandant of the rather nondescript commando, which was
officially described, I believe, as a composite regiment, had a sound
idea of the value of a few competent and well-mounted scouts, and
had done us very well in the matter of horse. We had been ‘on
commando’ now for nearly five weeks, and had got to know our
animals pretty well. During the confusion and changes of the first
fortnight I had got rid of a dozen horses I saw would be of no use
for our work, though suitable, no doubt, for slower troop duty, and
by a cunning process of selection had got together a very
serviceable lot, with four spare animals to carry kit and water on the
longer trips away from the main body. Your spirited young things,
though well enough to go courting on, are apt to get leg-weary and
drop condition too soon on steady work, and all my mob were aged
and as hard as nails. I will describe one or two of them presently.
Things were getting a little exciting about that time. Three rebel
commandos, or rather bands, were known to be in the
neighbourhood, and it was essential to find out what their strength
was and who their leaders were. There was not much reason to fear
attack, for they were not well found in either guns or ammunition,
and their ragamuffin cavalry were concerned to avoid and not invite
a stand-up engagement. Rapidity of action was essential to the loyal
troops, for the longer the rebellion dragged on the more risk there
was of it spreading. It was necessary to find out at once the actual
movements of these bands, and the best way of doing so was to
keep tally of the water-holes. Men can, if necessary, carry water for
themselves, but horses, especially those from the moist high veld of
the Transvaal, must have water regularly or they go to pieces very
quickly in that dry, hot land. And so the remote and forgotten pit at
Ramib had suddenly become of importance, and I had been told to
send two men to examine it at once.
It lay within the rocky belt which came down south of the Orange
River somewhat to our right; it was supposed to be twenty miles
away, but it might prove five miles less or ten miles more. It was
known to have held water fifteen months before, and our business
was to find out if it still held water, how long that water would be
likely to last, and if any of the rebels had been to it recently. No one
in the column was aware of its exact location, but I myself knew
enough of those parts to guess roughly where it must lie. I decided
to take one man and a pack-horse, and to take the patrol myself. No
native guide was available, and the Colonel did not, for obvious
reasons, care to make use of any of the few local Boers who carried
on a wretched existence as farmers in that barren country.
My own horse was a big bay, an uncomfortable beast, but capable
of covering much ground; like many big men, he had little mental
elasticity and no vices. Frikkie had an unassuming bay of ordinary
manners and capacity, and with a natural aptitude for routine and a
military life. The third horse was a king of his class. He did not
belong to the scouts, but I had borrowed him to carry the pack on
that patrol. He was mean all through; in colour a sort of skewbald
roan, and in character an irreclaimable criminal. He had a narrow
chest, weedy white legs, and a pale shifty eye; he was very free with
his heels, and an inveterate malingerer. He had never carried a pack
before and we were prepared for trouble, for his malevolent spirit
had already acquired a wide reputation.
The patrol left the column a little before sunset, after a windless,
baking day. The horses were in excellent fettle. The roan had given
some trouble with the pack, but before he could throw himself down
or buck through the lines he was hustled out of camp to an
accompaniment of oaths and cheers in two languages. Once away
and alone he went quietly, but doubtless with hate in his heart, for
his beastly eye was full of gall.
Dawn found us hidden on the top of a low stony kopje, the horses
tied together among the brown boulders below. It was bitter cold as
the light grew, and the sun came up into an empty world. I waited
there for half an hour, partly to find any signs of white men, and
partly to work out the lay of the land and the probable direction of
the pit. Nothing was moving in the whole world. It was clear where
the water must be. On the right was the usual barren desert country
we had come through during the night, low ridges of stone and
shale, and a thin low scrub of milk bush and cactus. On the left the
land grew much rougher towards the river; the rocky valleys
stretched for miles in that direction. Presently we led the horses
down off the kopje, and an hour later saw us looking down at the
chain of small holes, still full of good water. I stayed with the hidden
horses while Frikkie cut a circle round the pools. There was no sign
of life, he reported, only the old sandal spoor of some natives; no
horse had been down to the water for weeks, probably for months.
We off-saddled in a hidden corner some way from the water, and got
a small fire going of thin dry sticks. The horses were given a drink
and turned loose. It was criminal foolishness not to have hobbled or
knee-haltered the roan, for ten minutes after they were let go Frikkie
called out that the horses had completely disappeared.
One realised at once that there was no time to be lost. It was
probable that the roan had led them away, and that he meant
business. The saddles and pack were hurriedly hidden among some
rocks with the billy of half-cooked rice, the fire was put out, and we
took up the spoor.
It was soon evident that the animals were travelling, and were not
straying aimlessly in search of feed. The spoor of the discoloured
strawberry beast was always in front—his footprints were like his
character, narrow and close. Above his tracks came those of Ruby,
the police horse, round ordinary hoof-marks, and well shod; my own
horse’s immense prints were always last, solid and unmistakable.
Mile after mile the tracks led into a rockier and more barren country.
What little stunted and thorny scrub there was had not yet come
into leaf, and there was no shade and no sign of green anywhere.
Ridges of sharp gravel and small kopjes of brown stone alternated
with narrow valleys without sign of green or water. In the softer
ground of these valleys the spoor was plain and could be followed
without any trouble, but on the rocky ridges the tracks became
difficult to hold where the horses had separated and wandered
about. The trail led eastwards, into a rocky, waterless, and
uninhabited country. There was no reason for the roan’s choice but
just native malice, for he had come from the west the previous day.
Doubtless the main camp would be his ultimate destination, but it
seemed apparent that he intended to inflict as deep an injury as he
could before he set his sour face again to the west.
It was within half an hour of sundown before I came up with the
horses, and then only the two bays; the roan’s spoor showed that he
had gone on about an hour before. They were standing under a
bunch of thorn trees, the only shade they had passed since they
were let go that morning. For the last mile or two the tracks, which
had become more aimless as the hot afternoon wore on, had turned
a little to the north. Probably, as the allegiance of his small following
had weakened, the leader’s thoughts had turned to the
companionship of the camp, and when they had finally refused to
follow him any further he had abandoned the rest of his revenge and
had turned frankly for home.
We rounded up the two horses and thought of our camp, probably
eight miles away in a direct line. Though they were tired and empty
they would not be caught, and it was soon evident that they would
not be driven either. I will not ask you to follow the dreadful hour
which ensued. This crowning flicker of rebellion at the end of a
disastrous day nearly broke our hearts. It was well after dark when
we finally abandoned the horses in an area of steep rocky ridges and
narrow valleys covered with cactus; it was quite impossible to cope
with them in the dark in such a country. We reached camp about
ten, but were too tired and disappointed to make a fire. A tin of
bully-beef, and the mass of opaque jelly which had once been good
Patna rice, were the first pleasant incidents of a baking, hungry day.
The second day began before dawn with as large a breakfast as
we could compass: black coffee, the little bread that was left, and a
large quantity of rice. I have seldom eaten a more cheerless meal.
Three or four pounds of rice, some coffee, a tin or two of bully, and
a little sugar were all that remained to us, and there was no chance
of getting more. I must confess that at this stage a tactical error was
committed which cost us the long day’s work for nothing. A golden
rule where lost animals are concerned is to stick to the spoor, but as
I thought it very probable that the horses would turn north and west
again during the night and make for their last place of sojourn, I
tried to save half a dozen hours by cutting the spoor ahead. It was
nearly noon, and a mile or two beyond where the roan had left the
others, before it became a certainty that the horses had done the
unlikely thing, and had gone either south or further east into the
broken country. At that moment they were probably ten miles away.
I then did what one should have done at first, and went to the point
where we had last seen them. That afternoon was hotter and
emptier than the last, and sunset found us on a cold spoor going
north. We had wisely brought rice and coffee and water-bags with
us that morning, and Frikkie had shot a klipspringer—baboons and
klipspringer were the only animals we had seen the last two days. If
you suppose that we had used any of the water for washing you are
making a mistake, though Heaven knows that we both would have
been the better for a bath. We slept on the spoor, and bitter cold it
was without blankets; there was not scrub enough for a decent fire.
Matters were getting serious. We were then twelve miles from the
saddlery and, so far as we knew, the nearest water, and twenty
more from the camp. If the horses were not found and caught that
day they would have to be abandoned, and we would have to pad
the hoof home via the disastrous pools at Ramib.
But fortune does not frown for ever; it is a long worm that has no
turning. Within an hour of sunrise we came into the quite fresh
tracks of the horses crossing their own spoor. Frikkie exclaimed that
there were three horses, and an examination showed the narrow
tracks of the red horse with the other two; they had not found water
and were evidently on their way back to Ramib. We came on to the
animals a few minutes afterwards. Except that they were hollow
from want of water they were none the worse, and apparently they
were not sorry to see us. By the time the sun was in the north they
had had a good drink and were finishing the little grain in the pack.
Midnight saw us riding into the main camp—only to find it deserted,
for the column had marched. The camp was apparently completely
empty, and it felt very desolate under a small moon. I expected I
would discover a message of some sort for me at sunrise; in the
meantime the obvious thing was to keep out of the way, so I went
half a mile off into the veld, and the boy and I kept watch by turn
until dawn.
Nothing moved in or round the camp till near sunrise, when three
men rode out of some shale ridges about a mile away on the
opposite side, and came down to the water. By the white bands
round the left arm—the sign of loyal troops—I knew them for our
own men; indeed we had recognised the horse one of them was
riding. They gave me the message they had stayed behind to deliver.
We were to stay and watch the camp site for three or four days, and
to patrol daily some distance to the south-east. The water was
important, for it was quite probable that one or other of the rebel
commandos would come to it. The men had hidden provisions for us
and some grain for the horses; they themselves were to hurry on to
the column with our report of the Ramib pits. We rode a few miles
along the column spoor with them, and then turned off on some
gravelly ground and fetched a compass round back to the place in
the shale ridges where the men had slept and where the provisions
were. We took no more chances with the strawberry horse; he was
closely hobbled.
The loss of the animals had been a serious thing, and we were
extremely fortunate to have got out of it so easily. It did not lessen
the annoyance to realise that it was my own fault for not hobbling
the roan, but only a rogue by constitution and habit would have
carried his hostility to so dangerous a length. But within a week he
was to provide another taste of his quality. This time nothing more
serious was involved than the risk of his own loss, for we were never
led far from water in so menacing and barren a country as that
beyond Ramib.
Most of that day was spent in the stony krantz, from which a view
could be obtained over the whole dry, grey landscape, and the pools
a mile away. In normal times the laagte was frequently used for
sheep grazing, but in these days of mobile and ever-hungry
commandos the few farmers in the vicinity were grazing their
meagre flocks nearer their homesteads. Except for a few wandering
Griquas, and possibly a band of ragged rebels on tired horses, it was
not likely that our watch would be interrupted. A rough shelter made
of the stunted spiny scrub served as a sentry box; the saddles were
hidden in a narrow cleft on the lee side of the ridge, and the horses
were kept down in the valleys.
In the afternoon we saddled up and rode south and east, keeping
for the most part to the rough ridges, and overlooking the level
country along which our column had come, and which was the
natural approach from that side for any body of men having wheeled
transport with them. We did not ride for more than an hour, but my
glasses showed an empty, treeless world for miles beyond. If the
commandos did come our way they would probably trek by night;
we should hear them arrive and laager about dawn, and sunrise
would have seen us well on our way to our own men.
Just at dusk that evening we rode along the lee of the ridge upon
which our poor home was. Frikkie was riding the roan. He was
leading his own animal, for a single horse could not be left grazing
alone, to be picked up, perhaps, by any wandering rebel, or to stray
off in search of companionship. When we passed under the highest
point of the ridge I stopped and sent Frikkie to the top, for he could
spy in both directions from there. I took the led horse from him, and
he threw the roan’s reins over the neck to trail on the ground—the
accepted instruction to every trained veld horse to stand still. I
watched the boy’s slim figure against the sunset sky in the west as
he turned about, searching the veld through his binoculars, though it
was really getting too dark for prism glasses. He called out that
nothing was moving, and presently came lightly down the steep
slope in the gathering dusk. As he reached his horse the beast
turned his quarters to him and walked away; the boy walked round,
but again the horse turned away; and when I put my horse across to
check him he lifted his head and trotted off. We knew that we
couldn’t catch the beast if his views on the matter did not coincide
with ours, so we walked on the half-mile to where the skerm was,
thinking the horse would follow up his mates at his leisure.
This was a new, but not unexpected, trait in an already depraved
character. Some horses, though they are inveterate strayers, are
easy to catch when you do come up with them; others are very
difficult to catch, though they seldom go more than a mile from the
camp; this hectic degenerate apparently combined both these bad
habits.
An hour after dark the horse had not turned up, though our own
reliable animals were knee-haltered and turned loose for a time with
their nosebags on as decoys. At dawn he was not visible in any of
the shallow valleys we could see to the east of the ridge; and to our
surprise and concern he was not in the valley where the water was
and where the camp had been.
Our own horses were knee-haltered short and let go, and we
spent a careful hour examining the margin of the pool, but there
was no narrow spoor to show that the roan had been down to drink
during the night. I spent the morning with our horses and on the
look-out, while the boy cut a wide semicircle round to the south and
west of the water. He came in at mid-day, certain that the truant had
not gone out in those directions. Then Frikkie took over the sentry
work, and I set out to cover the remainder of the circle. I worked
methodically along the soft ground of the valleys outside the range
of the area already fouled by the spoor of our own animals, and
where I would find the roan’s tracks at once. From time to time I
climbed one of the low ridges, for the boy was to spread a light-
coloured saddle blanket over a prominent rock on the side away
from the water as a signal if he saw either the lost horse or anyone
approaching from the south, or in case of other danger. Nothing
occurred during the long, hot afternoon.
That evening, when I got back to camp, I found two Griquas
sitting over the coals with Frikkie. They said they were shepherds,
and they may have done a little of that congenial work recently, but
they looked to me more like sheep-stealers. They were wild people
from the Orange River, and I was sure they had never been any sort
of farm labourers. However, they were friendly enough and promised
help in the morning. The horse had then been without water since
the morning of the previous day. He had not strayed away, for at
sunset he must have been still within four or five miles of the camp;
if he had intended business we would have cut his outgoing spoor
during the day. Horses were too valuable in that country and at that
time for the loss of even such a three-cornered abomination as the
pink horse to be taken lightly.
Morning showed that the horse had not been to the water during
the night. He had then been forty-eight hours without water. The
only thing was to take up the spoor where the animal had last been
seen, and so stick to it till he was found. The Kalahari bushmen have
the reputation of being the finest trackers in South Africa, but these
two cross-bred Griqua bushmen gave us an incomparable exhibition
of skill. I have had some experience of that game, and Frikkie was a
master, but these savages astonished us.
Inch by inch the spoor was picked out from that of the other
animals. No proved mark was abandoned until the next was
certified, often only an inch or two away. The only slight help they
had was the rare and very faint mark where the trailing reins had
touched the ground. The first hundred yards took probably an hour
to cover, but when the spoor reached comparatively clean ground
the work was easier. At this point Frikkie got the water-bags and
some food and joined the bushmen, for it was possible that the
horse, driven by thirst, had taken it into his head to travel far during
the previous night.
Late that evening the trackers returned with the horse. He was
emaciated and weak, but otherwise quite well, though for some days
his back was tender from the continual ‘sweating’ of the saddle
blanket. His spoor showed that he had spent the first night and day
wandering about the low ridges and hollows not far from our camp,
and that the night before he had commenced to journey away into
the empty country to the east. Somewhere about dawn of that third
day his trailing reins had hooked up on one of the few bushes in that
country strong enough to hold him, and there he was found by the
bushmen, the picture of a natural misery, and too dejected to take
much notice of his rescuers. Nothing but his own gloomy thoughts
had prevented him from going down to the water at any time, or to
the companionship of our camp.
Thirty-six hours after this we were back with the main column. It
is not necessary to add that we were glad to get a bath and a
generous meal, and that I took the first opportunity of handing over
the parti-coloured strawberry to troop duty.
In the first of these two offences it is clear that the white-legged
roan was animated by spite. Such malevolence is rare enough, but
his second performance is much more remarkable. I offer three
alternative explanations. The first is that it was just stupidity. I have
the poorest opinion of the intelligence of the horse, as distinct from
instinct. It is Professor Lloyd Morgan, I think, who defines instinct as
‘the sum of inherited habits,’ and this may be accepted as a sound
definition. Elementary necessity, to say nothing of instinct or
intelligence, should have driven him to the water soon after he had
obtained his freedom. He could not have forgotten where the water
was. If his normal mental process was so dislocated by the fact of
the saddle on his back without the presence of the masterful human
in it, then he was a fool of the first class.
The second solution I offer is that his action was prompted by
roguery; for even a very limited intelligence would have warned him
that he would be captured if he ventured near either the water or
the camp. It may be that when his reins hooked up he was on his
way to the free water at Ramib. The third explanation is that he was
a little daft. In a long and varied experience of horses I cannot really
remember one so afflicted, though I had a pack-mule once that I am
certain was a harmless lunatic. You may take your choice of these
alternatives; for my part I incline to the second.
John Ridd’s rustic wisdom led him to express the opinion, upon
the memorable occasion when John Fry was bringing him home from
Blundell’s School at Tiverton, that ‘a horse (like a woman) lacks, and
is better without, self-reliance.’
R. T. Coryndon.
‘THE PROGRESS OF PICKERSDYKE.’
Second Lieutenant William Pickersdyke, sometime quarter-master-
sergeant of the ⸺th Battery and now adjutant of a divisional
ammunition column, stared out of the window of his billet and
surveyed the muddy and uninteresting village street with eyes of
gloom. His habitual optimism had for once failed him, and his
confidence in the gospel of efficiency had been shaken. For Fate, in
the portly guise of his fatuous old colonel, had intervened to balk the
fulfilment of his most cherished desire. Pickersdyke had that morning
applied for permission to be transferred to his old battery if a
vacancy occurred, and the colonel had flatly declined to forward the
application.
Now one of the few military axioms which have not so far been
disproved in the course of this war is the one which lays down that
second lieutenants must not argue with colonels. Pickersdyke had
left his commanding officer without betraying the resentment which
he felt, but in the privacy of his own room, however, he allowed
himself the luxury of vituperation.
‘Blooming old woman!’ he said aloud. ‘Incompetent, rusty old dug-
out! Thinks he’s going to keep me here running his bally column for
ever, I suppose. Selfish, that’s what ’e is—and lazy too.’
In spite of the colonel’s pompous reference to ‘the exigencies of
the service,’ that useful phrase which covers a multitude of minor
injustices, Pickersdyke had legitimate cause for grievance. Nine
months previously, when he had been offered a commission, he had
had to choose between Sentiment, which bade him refuse and stay
with the battery to whose well-being he had devoted seven of the
best years of his life, and Ambition, which urged him, as a man of
energy and brains, to accept his just reward with a view to further
advancement. Ambition, backed by his major’s promise to have him
as a subaltern later on, had vanquished. Suppressing the inevitable
feeling of nostalgia which rose in him, he had joined the divisional
ammunition column, prepared to do his best in a position wholly
distasteful to him.
In an army every unit depends for its efficiency upon the system
of discipline inculcated by its commander, aided by the spirit of
individual enthusiasm which pervades its members; the less the
enthusiasm the sterner must the discipline be. Now a D.A.C., as it is
familiarly called, is not, in the inner meaning of the phrase, a
cohesive unit. In peace it exists only on paper; it is formed during
mobilisation by the haphazard collection of a certain number of
officers, mostly ‘dug-outs’; close upon 500 men, nearly all reservists;
and about 700 horses, many of which are rejections from other and,
in a sense, more important units. Its business, as its name indicates,
is to supply a division with ammunition, and its duties in this
connection are relatively simple. Its wagons transport shells,
cartridges, and bullets to the brigade ammunition columns, whence
they return empty and begin again. It is obvious that the men
engaged upon this work need not, in ordinary circumstances, be
heroes; it is also obvious that their rôle, though fundamentally an
important one, does not tend to foster an intense esprit de corps. A
man can be thrilled at the idea of a charge or of saving guns under a
hurricane of fire, but not with the monotonous job of loading
wagons and then driving them a set number of miles daily along the
same straight road. A stevedore or a carter has as much incentive to
enthusiasm for his work.
The commander of a D.A.C., therefore, to ensure efficiency in his
unit, must be a zealous disciplinarian with a strong personality. But
Pickersdyke’s new colonel was neither. The war had dragged him
from a life of slothful ease to one of bustle and discomfort. Being
elderly, stout, and constitutionally idle, he had quickly allowed his
early zeal to cool off, and now, after six months of the campaign, the
state of his command was lamentable. To Pickersdyke, coming from
a battery with proud traditions and a high reputation, whose
members regarded its good name in the way that a son does that of
his mother, it seemed little short of criminal that such laxity should
be permitted. On taking over a section he ‘got down to it,’ as he
said, at once, and became forthwith a most unpopular officer. But
that, though he knew it well, did not deter him. He made the lives of
various sergeants and junior N.C.O.s unbearable until they began to
see that it was wiser ‘to smarten themselves up a bit’ after his
suggestion. In a month the difference between his section and the
others was obvious. The horses were properly groomed and had
begun to improve in their condition—before, they had been poor to a
degree; the sergeant-major no longer grew a weekly beard nor
smoked a pipe during stable hour; the number of the defaulters,
which under the new régime was at first large, had dwindled to a
negligible quantity. In two months that section was for all practical
purposes a model one, and Pickersdyke was able to regard the
results of his unstinted efforts with satisfaction.
The colonel, who was not blind where his own interests were
concerned, sent for Pickersdyke one day and said:
‘You’ve done very well with your section; it’s quite the best in the
column now.’
Pickersdyke was pleased; he was as modest as most men, but he
appreciated recognition of his merits. Moreover, for his own ends, he
was anxious to impress his commanding officer. He was less pleased
when the latter continued:
‘I’m going to post you to No. 3 Section now, and I hope you’ll do
the same with that.’
No. 3 Section was notorious. Pickersdyke, if he had been a man of
Biblical knowledge (which he was not), would have compared
himself to Jacob, who waited seven years for Rachel and then was
tricked into taking Leah. The vision of his four days’ leave—long
overdue—faded away. He foresaw a further and still more difficult
period of uncongenial work in front of him. But, having no choice, he
was obliged to acquiesce.
Once again he began at the beginning, instilling into unruly minds
the elementary notions that orders are given to be obeyed, that the
first duty of a mounted man is to his horses, and that personal
cleanliness and smartness in appearance are military virtues not
beneath notice. This time the drudgery was even worse, and he was
considerably hampered by the touchiness and jealousy of the real
section commander, who was a dug-out captain of conspicuous
inability. There was much unpleasantness, there was at one time
very nearly a mutiny, and there were not a few courts-martial. It was
three months and a half before that section found, so to speak, its
military soul.
And then the colonel, satisfied that the two remaining sections
were well enough commanded to shift for themselves if properly
guided, seized his chance and made Pickersdyke his adjutant. Here
was a man, he felt, endowed with an astonishing energy and
considerable powers of organisation, the very person, in fact, to save
his commanding officer trouble and to relieve him of all real
responsibility.
This occurred about the middle of July. From then until well on
into September, Pickersdyke remained a fixture in a small French
village on the lines of communication, miles from the front, out of all
touch with his old comrades, with no distractions and no outlet for
his energies except work of a purely routine character.
‘It might be peace-time and me a bloomin’ clerk’ was how he
expressed his disgust. But he still hoped, for he believed that to the
efficient the rewards of efficiency come in due course and are never
long delayed. Without being conceited, he was perhaps more aware
of his own possibilities than of his limitations. In the old days in his
battery he had been the major’s right-hand man and the familiar
(but always respectful) friend of the subalterns. In the early days of
the war he had succeeded amazingly where others in his position
had certainly failed. His management of affairs ‘behind the scenes’
had been unsurpassed. Never once, from the moment when his unit
left Havre till a month later it arrived upon the Aisne, had its men
been short of food or its horses of forage. He had replaced
deficiencies from some apparently inexhaustible store of ‘spares’; he
had provided the best billets, the safest wagon lines, the freshest
bread with a consistency that was almost uncanny. In the darkest
days of the retreat he had remained unperturbed, ‘pinching’ freely
when blandishments failed, distributing the comforts as well as the
necessities of life with a lavish hand and an optimistic smile. His wits
and his resource had been tested to the utmost. He had enjoyed the
contest (it was his nature to do that), and he had come through
triumphant and still smiling.
During the stationary period on the Aisne, and later in Flanders,
he had managed the wagon line—that other half of a battery which
consists of almost everything except the guns and their complement
of officers and men—practically unaided. On more than one occasion
he had brought up ammunition along a very dangerous route at
critical moments.
He received his commission late in December, at a time when his
battery was out of action, ‘resting.’ He dined in the officers’ mess,
receiving their congratulations with becoming modesty and their
drink without unnecessary reserve. It was on this occasion that he
had induced his major to promise to get him back. Then he
departed, sorrowful in spite of all his pride in being an officer, to join
the column. There, in the seclusion of his billet, he studied army lists
and watched the name of the senior subaltern of the battery creep
towards the head of the roll. When that officer was promoted
captain there would be a vacancy, and that vacancy would be
Pickersdyke’s chance. Meanwhile, to fit himself for what he hoped to
become, he spent whole evenings poring over manuals of telephony
and gun-drill; he learnt by heart abstruse passages of Field Artillery
Training; he ordered the latest treatises on gunnery, both practical
and theoretical, to be sent out to him from England; and he even
battled valiantly with logarithms and a slide-rule....
From all the foregoing it will be understood how bitter was his
disappointment when his application to be transferred was refused.
His colonel’s attitude astonished him. He had expected recognition of
that industry and usefulness of which he had given unchallengeable
proof. But the colonel, instead of saying:
‘You have done well; I will not stand in your way, much as I
should like to keep you,’ merely observed,
‘I’m sorry, but you cannot be spared.’
And he made it unmistakably plain that what he meant was:
‘Do you think I’m such a fool as to let you go? I’ll see you damned
first!’
Thus it was that Pickersdyke, a disillusioned and a baffled man,
stared out of the window with wrath and bitterness in his heart. For
he wanted to go back to ‘the old troop’; he was obsessed with the
idea almost to the exclusion of everything else. He craved for the old
faces and the old familiar atmosphere as a drug-maniac craves for
morphia. It was his right, he had earned it by nine months of
drudgery—and who the devil, anyway, he felt, was this old fool to
thwart him?
Extravagant plans for vengeance flitted through his mind.
Supposing he were to lose half a dozen wagons or thousands of
rounds of howitzer ammunition, would his colonel get sent home?
Not he—he’d blame his adjutant, and the latter would quite possibly
be court-martialled. Should he hide all the colonel’s clothes and only
reveal their whereabouts when the application had been forwarded?
Should he steal his whisky (without which it was doubtful if he could
exist), put poison in his tea, or write an anonymous letter to
headquarters accusing him of espionage? He sighed—ingenuity, his
valuable ally on many a doubtful occasion, failed him now. Then it
occurred to him to appeal to one Lorrison, who was the captain of
his old battery, and whom he had known for years as one of his
subalterns.
‘Dear Lorrison,’ he wrote, ‘I’ve just had an interview with my

old man and he won’t agree to my transfer. I’m afraid it’s a
wash-out unless something can be done quickly, as I suppose
Jordan will be promoted very soon.’ (Jordan was the senior
subaltern.) ‘You know how much I want to get back in time
for the big show. Can you do anything? Sorry to trouble you,
and now I must close.
‘Yours,
‘W. Pickersdyke.’
Then he summoned his servant. Gunner Scupham was an elderly

individual with grey hair, a dignified deportment, and a countenance
which suggested extreme honesty of soul but no intelligence
whatsoever. Which fact was of great assistance to him in the
perpetration of his more complicated villainies. He had not been
Pickersdyke’s storeman for many years for nothing. His devotion was
a by-word, but his familiarity was sometimes a little startling.
‘’E won’t let us go,’ announced Pickersdyke.
‘Strafe the blighter!’ replied Scupham feelingly. ‘I’m proper fed up
with this ’ere column job.’
‘Get the office bike, take this note to Captain Lorrison, and bring
back an answer. Here’s a pass.’
Scupham departed, grumbling audibly. It meant a fifteen-mile
ride, the day was warm, and he disliked physical exertion. He
returned late that evening with the answer, which was as follows:
‘Dear Pickers,—Curse your fool colonel. Jordan may go any

day, and if we don’t get you we’ll probably be stuck with
some child who knows nothing. Besides, we want you to
come. The preliminary bombardment is well under way, so
there’s not much time. Meet me at the B.A.C.[7] headquarters
to-morrow evening at 8 and we’ll fix up something. In haste,
‘Yours ever,
‘T. Lorrison.’
There are people who do not believe in luck. But if it was not luck
which assisted Pickersdyke by producing the events which followed
his receipt of that note, then it was Providence in a genial and most
considerate mood. He spent a long time trying to think of a
reasonable excuse for going to see Lorrison, but he might have
saved himself the trouble. Some light-hearted fool had sent up
shrapnel instead of high explosive to the very B.A.C. that
Pickersdyke wanted to visit. Angry telephone messages were coming
through, and the colonel at once sent his adjutant up to offer
plausible explanations.
Pickersdyke covered a lot of ground that afternoon. It was
necessary to find an infuriated artillery brigadier and persuade him
that the error was not likely to occur again, and was in any case not
really the fault of the D.A.C. section commander. It was then
necessary to find this latter and make it clear to him that he was
without doubt the most incompetent officer in the allied forces, and
that the error was entirely due to his carelessness. And it was
essential to arrange for forwarding what was required.
Lorrison arrived punctually and evidently rather excited.
‘What price the news?’ he said at once.
Pickersdyke had heard none. He had been far too busy.
‘We’re for it at last—going to bombard all night till 4.30 a.m.—every
bally gun in the army as far as I can see. And we’ve got orders to be
ready to move in close support of the infantry if they get through. To
move! Just think of that after all these months.’
Pickersdyke swore as he had not done since he was a rough-riding
bombardier.
‘And that’s boxed my chances,’ he ended up.
‘Wait a bit,’ said Lorrison. ‘There’s a vacancy waiting for you if
you’ll take it. We got pretty badly “crumped”[8] last night. The
Bosches put some big “hows” and a couple of “pip-squeak” batteries
on to us just when we were replenishing. They smashed up several
wagons and did a lot of damage. Poor old Jordan got the devil of a
shaking—he was thrown about ten yards. Lucky not to be blown to
bits, though. Anyway, he’s been sent to hospital.’
He looked inquiringly at Pickersdyke. The latter’s face portrayed an
unholy joy.
‘Will I take his place?’ he cried. ‘Lummy! I should think I would.
Don’t care what the colonel says afterwards. When can I join? Now?’
‘As soon as I’ve seen about getting some more wagons from the
B.A.C. we’ll go up together,’ answered Lorrison.
Pickersdyke, who had no conscience whatever on occasions such
as this, sent a message to his colonel to say that he was staying up
for the night (he omitted to say precisely where!), as there would be
much to arrange in the morning. To Scupham he wrote:
‘Collect all the kit you can and come up to the battery at
once. Say nothing.’
He was perfectly aware that he was doing a wildly illegal thing. He

felt like an escaped convict breathing the air of freedom and making
for his home and family. Forty colonels would not have stopped him
at that moment.
II.
The major commanding the ⸺th Battery sat in his dug-out
examining a large-scale trench map. His watch, carefully
synchronised with those of the staff, lay on the table in front of him.
Outside, his six guns were firing steadily, each concussion (and there
were twelve a minute) shaking everything that was not a fixture in
the little room. Hundreds of guns along miles of front and miles of
depth were taking part in the most stupendous bombardment yet
attempted by the army. From ‘Granny,’ the enormous howitzer that
fired six times an hour at a range of seventeen thousand yards, to
machine guns in the front line trenches, every available piece of
ordnance was adding its quota to what constituted a veritable hell of
noise.
The major had been ordered to cut the wire entanglements
between two given points and to stop firing at 4.30 a.m. precisely. He
had no certain means of knowing whether he had completed his task
or not. He only knew that his ‘lines of fire,’ his range, and his ‘height
of burst’ as previously registered in daylight were correct, that his
layers could be depended upon, and that he had put about a
thousand rounds of shrapnel into a hundred and fifty yards of front.
At 4.29 he rose and stood, watch in hand, in the doorway of his dug-
out. A man with a megaphone waited at his elbow. The major, war-
worn though he was, was still young enough in spirit to be thrilled
by the mechanical regularity of his battery’s fire. This perfection of
drill was his work, the result of months and months of practice, of
loving care, and of minute attention to detail.
Dawn was beginning to creep into the sky, and he could just
distinguish the silhouettes of the two right-hand guns. The flash as
one of them fired revealed momentarily the figures of the gunners
grouped round the breech like demons round some spectral engine
of destruction. Precisely five seconds afterwards a second flash
denoted that the next gun had fired—and so on in sequence from
right to left until it was the turn of Number One again.
‘Stop,’ said the major when the minute hand of his watch was
exactly over the half-hour.
‘Stop!’ roared the man with the megaphone.
It was as if the order had been heard all along the entire front.
The bombardment ceased almost abruptly, and rifle and machine-
gun fire became audible again. On a colossal scale the effect was
that of the throttling down of a powerful motor-car whose engine
had been allowed to race. Then, not many moments afterwards,
from far away to the eastward there came faint, confused sounds of
shouts and cheering. It was the infantry, the long-suffering,
tenacious, wonderful infantry charging valiantly into the cold grey
dawn along the avenues prepared by the guns....
For Pickersdyke it had been a night of pure joy, unspoilt by any
qualms of conscience. He had been welcomed at the battery as a
kind of returned wanderer and given a section of guns at once. The
major—who feared no man’s wrath, least of all that of a dug-out
D.A.C. commander—had promised to back him up if awkward
questions were asked. Pickersdyke had only one cause for
disappointment—the whole thing had gone too smoothly. He was
bursting with technical knowledge, he could have repaired almost
any breakdown, and had kept a keen look-out for all ordinary
mistakes. But nothing went wrong and no mistakes were made. In
this battery the liability of human error had been reduced to a
negligible minimum. Pickersdyke had had nothing further to do than
to pass orders and see that they were duly received. Nevertheless
he had loved every moment of it, for he had come into his own—he
was back in the old troop, taking part in a ‘big show.’ As he observed
to the major whilst they were drinking hot coffee in the dug-out
afterwards:
‘Even if I do get court-martialled for desertion, sir, that last little
lot was worth it!’
And he grinned as does a man well pleased with the success of his
schemes. To complete his satisfaction, Scupham appeared soon
afterwards bringing up a large bundle of kit and a few luxuries in the
way of food. It transpired that he had presented himself to the last-
joined subaltern of the D.A.C. and had bluffed that perplexed and
inexperienced officer into turning out a cart to drive him as far as
the battery wagon line, whence he had come up on an ammunition
wagon.
It was almost daylight when the battery opened fire again, taking
its orders by telephone now from the F.O.O.,[9] who was in close
touch with the infantry and could see what was happening. The rate

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INTRODUCTION phrase seems to have been mistranslated to ‘I will please

6 Placebo (group PN)

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