Recent years have seen a huge increase in knowledge about the phenomenon of placebo
analgesia. As such, we are able to state with confidence that placebo analgesia exists
and exhibits clinically relevant effects,1–4 even though the relative sizes of these
effects display a large variation.
The underlying mechanism has been described in a seminal definition by Brody: “a change
in a patient’s illness attributable to the symbolic import of a treatment rather than
a specific pharmacologic or physiologic property”.5 This definition highlights the
importance of the mind–body interaction in the placebo effect, as well as the powerful
influence of meaningful symbols in the healing ritual that goes beyond a merely positivistic
approach. Currently, the underlying psychological and neurobiological mechanisms are
recognizable in outline, with expectation and conditioning believed to lie at the
heart of placebo response.6 High levels of endogenous opioids and cannabinoids, and
low levels of cholecystokinin, are implicated as the principal pharmacologic mediators
of placebo analgesia.4 The dorsolateral prefrontal cortex initiates the placebo analgesic
response7 leading to increased activity within the descending pain-modulatory pathway.8,9
The activity of regions such as the dorsal horn of the spinal cord, the thalamus,
the insula, and the somatosensory cortex is decreased by the placebo, indicating a
reduction in nociceptive transmission in the pain pathways.7–9
Against the background of these groundbreaking findings, it is surprising that the
conscious promotion of the use of placebo analgesia for medical training and in clinical
practice remains uncommon. In my view, there are several reasons for this, as follows.
The first such reason is historical. One of the earliest usages of the word “placebo”
refers to 14th century funeral hymns conveying the message “De mortuis nihil nisi
bene”.4 This explains the close association of the word placebo to hypocrisy, and
when the term was introduced into medicine in the 18th century, placebo treatment
became a synonym for pseudo-healing. Even though alternative terms such as meaning-response10
have been proposed, modern medicine retains this term and its derogatory connotations.
Secondly, the medical use of placebos has always entailed significant ethical concerns.11
Placebo interventions have been equated with the deliberate deception of the patient,
which is incompatible with a doctor–patient relationship based on trust and honesty.
However, at this point of the scientific debate, this argument requires some reexamination.
Since the beginning of modern medicine, the Hippocratic Oath has been seen as the
basis of a salutary doctor–patient relationship: “I will use treatment to help the
sick according to my ability and judgment, but never with a view to injury and wrong-doing”.12
Simply stated, the doctors should do everything in their power to cure the patients
and not bring them any harm. A deception with the sole intention to heal the patients
hence does not contradict this medical commandment, and may even be compatible to
the highest ethical standards, as defined by Kant’s categorical imperative: “act only
in such a way that you can will that the maxim of your actions should become a universal
law”.13
The question then arises: what is the patients’ perspective? In a survey of the attitudes
toward the use of placebos involving 853 US patients with chronic health problems,
76% of respondents deemed that it was acceptable for a doctor to recommend a placebo
if he thought that it would benefit and not harm the patient, while 50% considered
it acceptable in instances where the doctor is uncertain of its benefit.14 Another
ethical question may equally be posed: is a placebo intervention necessarily deceptive?
Clearly, this is a matter of formulation. If a doctor suggests to his patient that
a drug is likely to be beneficial, even though it has no pharmacological activity,
this would be only deceptive if the doctor himself does not believe in the drug’s
effectiveness. If the doctor is convinced of the effectiveness of placebo analgesia,
he may even explicitly recommend it to patients. Thus, Kaptchuk et al15 were able
to prove the effectiveness of placebos in patients with chronic pain due to irritable
bowel syndrome when such placebos were given transparently and accompanied by information
about the placebo effect.
The third argument is associated with the development of modern medicine. In Western
industrialized countries, this development is based on a tradition that can be traced
back to Descartes and the Age of Enlightenment. Descartes’ conception of the existence
of two mutually differentiated substances – res extensa and res cogitans, mind and
matter – has been the basis of the progressive fragmentation of medicine into smaller
and smaller areas of expertise.4,6 However, the incredible growth of knowledge resulting
from this specialization has seen a resultant difficulty in maintaining the balance
between analysis and synthesis in medical treatment, a consequence of which may be
that pain-plagued individuals become lost in a mire of sophisticated medical findings.
Increasing specialization goes hand in hand with the appreciation of specific healing
mechanisms and a disregard of more general healing principles, such as the placebo
response. It may be assumed that this notion played a crucial role when William Cullen
introduced the negatively connoted term “placebo” into medicine in the 18th century.4
This assessment also lies at the heart of randomized placebo-controlled design – the
core methodology of evidence-based medicine. And here we come full circle. Against
this background, the doctor is under the impression that he deceives the patient,
as only the medical intervention proven to be more effective than the placebo is considered
the true remedy.
A fourth and final argument is the increasing economization of medicine in general,
and pain medicine in particular, driven by the sole concern of cost containment and
profitability.16,17 The empathic and time-consuming doctor–patient communication so
essential to the symbolic import of treatment is no longer a fundamental part of the
art of medical healing; rather, it is reduced to the status of a problematic cost
factor. In both Germany and the US, for instance, there is an overutilization of interventional
procedures and spine surgery, which is at least partially attributable to dubious
incentives from industry and the health care system.16–18 Complete transparency is
a necessary requirement to disclose these entangled relationships.19,20 While somewhat
controversial, the Physician Payment Sunshine Act in the US is a first step in this
direction.21 However, German legislation still lags behind. In 2013, the Association
of Voluntary Self-Control of the Pharmaceutical Industry (FSA) in Germany adopted
a code of transparency for interaction with health care professionals, according to
which all future payments in kind by the pharmaceutical industry to health care professionals
and organizations in this field shall be made public. However, only about 30% of doctors
agreed to be named personally as beneficiaries of pharmaceutical industries represented
by the FSA in 2015.22 It remains to be seen whether these are merely clandestine attempts
to avoid strict legal action, or whether they will lead to real transparency. Nevertheless,
the mechanisms of capitalism pose a severe ethical threat to pain medicine if the
patient is no longer treated as an end in itself but as a means to maximize profits.13
Against this background, pain medicine should seek to question how the untapped potential
of placebo analgesia may be better utilized in the future. The following healing ritual
factors can be drawn from an analysis of the psychosocial context: the setting, the
doctor’s personality, the patient’s personality, the type of intervention, and the
interaction between these factors.23 Each of these factors presents specific challenges
for pain medicine and research, which are examined in more detail as follows.
The first question to consider is: what is the best therapeutic setting for placebo
analgesia in terms of time and place? Healing rituals require sufficient time for
a doctor–patient relationship to instill positive expectations in the patient.4 The
location should be somewhere that makes it possible to perceive positively charged
symbols and their meaning. In ancient Greek medicine, healing temples dedicated to
Asklepios provided carefully designed spaces for spiritual and physical healing. A
comparison of the Asklepion in Epidauros and the contemporary design of an aseptic
hospital room makes evident the wide range of places of healing and their possible
potency. In a seminal study, Ulrich24 showed that a hospital window view of trees
could influence surgical patients’ use of analgesics and recovery. Compared with a
wall-view group, these patients had shorter postoperative hospital stays, took fewer
moderate and strong analgesic doses, and had slightly lower scores for minor postsurgical
complications. A more recent study showed that the postoperative exposure of patients
who had undergone spinal surgery to increased amounts of natural sunlight during their
hospital recovery period resulted in decreased stress, pain, and analgesic medication
use.25 Health care architecture should be aware of the healing impact of (natural)
symbols – an area in which research and architectural implementation is still in its
infancy.
Second is the question of the medical self-image. The relationship between doctor
and patient is at the center of the healing ritual. Shapiro and Shapiro26 have emphasized
the relevance of the placebo response to the doctor’s authenticity, empathy, and unconditionally
positive regard for the patient. Equally, several studies have showed a positive effect
on pain reduction in situations where the doctor is perceived as warm and empathetic.27–29
Medical communication is both verbal and nonverbal, with nonverbal communication having
a much greater potency as its influence is less deliberate.30 The credibility of the
medical message depends on the authenticity of the doctor, which is derived from the
congruence of verbal and nonverbal signals.30 This relationship is insufficiently
emphasized in medical training, and as a result, there is a lack of awareness surrounding
it. A brief example may illustrate the problem. If a chronic pain patient undergoing
long and frustrating therapy triggers anger in the doctor, but the doctor himself
is not aware of the feeling, this can severely complicate treatment. The patient senses
the nonverbal signals and feels rejected, resulting in a possible loss of faith in
the treatment and its ultimate discontinuation. Conversely, if the doctor is in a
position to reflect this feeling professionally and incorporate it productively in
the doctor–patient communication, this may lead to positive expectations being developed.
Thus, the doctor’s voice, facial expressions, and gestures become positively or negatively
charged symbols for the patient, turning the healing ritual into a placebo or nocebo.
However, few components in formal medical training – in either direct curricular instruction
or physician role modeling – focus on the emotional lives of students or junior doctors.31
There is currently still a focus on the requirement for doctors to ignore, distance,
and detach themselves from emotions as a means to retain professional control. Obviously,
this runs contrary to genuine expression and authentic communication. There is hence
a need to increase doctors’ self-awareness and convince them to consider their own
emotions as an important tool in medical treatment in general, and in pain medicine
in particular. Medical training should include appropriate opportunities to learn
about and manage the emotional impact of illness experiences and the healing process.32
It may even be that painful experiences and emotions experienced by doctors themselves
may pave the path toward a healing understanding of patients’ pain.
Third, we need a deeper insight into state and trait variables that underlie the substantial
variability of placebo analgesia across individuals. For instance, optimism and resilience
have a positive influence on the magnitude of pain reduction,33,34 whereas emotional
lability35 and anxiety36–38 weaken the effect. One might say that an individual prone
to positive expectations, who is likely to anticipate pain relief in a placebo treatment,
shows a greater profit. In keeping with this finding, Wager et al39 were able to show
that brain activity during the anticipation of pain with increased activity in the
dorsolateral prefrontal cortex, orbitofrontal cortex, parietal cortex, and cerebellum
best predicted individual differences in placebo analgesia, whereas reductions in
pain-processing regions during the application of a placebo skin cream were not correlated
with individual differences in analgesia. However, a majority of these studies relate
to healthy populations, and their findings are not easily transferred to chronic pain
patients characterized by personality traits such as harm avoidance, which predisposes
them to anxiety.40,41 To be able to personalize placebo analgesia, a greater understanding
is required of the subtle influence of situational and personal variables on the creation
of positive expectations in the pre-frontal cortex in different pain populations.
Fourth, the placebo analgesic interventions that work best must be identified. There
is growing evidence that the more impressive interventions are more powerful than
their less impressive equivalents.4 Thus, sham acupuncture and sham surgery are more
effective than oral placebos.42 Recent findings even lend support to the notion that
pain reduction due to acupuncture is mainly explained by the placebo response, as
sham acupuncture and acupuncture are equally effective in the treatment of lower back
pain and osteoarthritis of the knee.43 Placebo analgesia is effective because of the
treatment’s symbolic import: “a symbol is an energy evoking, and directing agent”.44
The more the color, sound, odor, taste, and haptics of a placebo evoke an expectation
of pain relief, the more likely it is to reduce pain. This may also apply to the placebo
response initiated by a verum. A systematic review found that placebo responses could
account for 62% of the benefit of drugs used to treat peripheral neuropathic pain.45
If the placebo effect is mediated and modulated by different neurotransmitters such
as opioids and cannabinoids, the complex interplay between, for example, an opioid
analgesic and the opioidergic neurotransmission of placebo response is unclear. Do
these analgesic effects combine in an additive or an interfering manner?4 An initial
study found a relevant additive effect on clinical outcome, including expectancy modulated
activity in the frontal cortex, with a separable time course from drug effects.46
However, it is important not to use placebo analgesia as a means to justify any and
every bizarre healing ritual.6 Placebo analgesia walks a constant tightrope between
initiating pain relief via healing expectations and the corresponding physiologic
response, and initiating pain via counterproductive expectations.6
The earlier questions indicate that more research is urgently needed to fully explore
the potential of placebo analgesia. For reasons previously discussed, the volume of
funding provided for research into specific analgesics is not comparable with the
funding for placebo analgesia. But perhaps, the time has come to start thinking in
new terms. “Value should always be defined around the customer, and in a well-functioning
health care system, the creation of value for patients should determine the rewards
for all other actors in the system”.47 An important step in this direction would be
the substantial funding of placebo analgesia research by the pharmaceutical industry.
Ultimately, placebo analgesia reminds us of the sometimes forgotten lesson that the
doctor–patient relationship is at the center of all pain medicine: “Sometimes simply
being silently present with a patient may be the most meaningful kind of care”.48