6
THE BULLETIN
concluded that the two were equivalent, but
that either one was more effective in treating
low back pain than no treatment. It is known,
however, that acupuncture gives pain relief
in animals. Brain imaging in humans shows
typical areas of activation with real acupunc-
ture but not with sham acupuncture. Perhaps
the explanation for this discrepancy is that pain
response is a subjective measure.
16
Patient expectations are not the only expecta-
tions involved in the placebo effect. Provider
expectations are also influential. Patients with
post-op dental pain were divided into two
groups, and individuals within each group were randomized to
receive one of three medications: a drug that would increase pain,
one that would decrease pain, and one that would have no effect.
Providers, however, were told that one group would get no anal-
gesia whatsoever. This latter group showed a decreased placebo
effect.
17
The provider’s manner is thought to be one of the most—
or perhaps
the
most—important factors in the placebo effect.
18
Problems exist with a number of these studies. Many rely on
some degree of deception. This raises serious ethical issues for
researchers. In some instances, participants are euphemistically
advised that they will receive a medication that has been “demon-
strated to be effective.”
Early work on placebos demonstrated that the placebo benefit
for pain relief could be partly or completely reversed by naloxone,
an opioid antagonist. It is now known that the µ-opioid system
mediates placebo analgesic effect. In addition, µ-opioid activa-
tion has been localized to the brain, not the spinal cord. Greater
activation of opioid receptors correlates with greater analgesia.
Placebo-activated opioids relieve pain and also modulate heart
rate and respiration.
Specific areas of the brain are involved in different aspects of
the placebo reaction. Several areas of the cerebral cortex are
important. Activation of the prefrontal cortex on functional MRI
or PET is correlated with how effective pain relief is anticipated to
be. Increased activity of the anterior insular cortex and anterior
cingulate cortex correlates with the severity of the pain or with
the emotional state of the individual.
19
Recognizing that the prefrontal cortex was involved, Fabrizio
Benedetti et al, author of
Placebo Effects: Understanding the mech-
anisms in health and disease
, found that patients suffering from
Alzheimer’s Disease have less pain relief from analgesics than
normal individuals. Because they lack input from the prefrontal
cortex, the patients require larger doses of analgesic to control
their pain adequately. In other words, these are patients with
reduced expectation or absent placebo effect. The degree of their
remaining cognitive ability correlated with their placebo effect.
20
Learning is another activity that must be factored into the placebo
equation. Two brain regions interact to correct one’s expectations
based on current experience: the nucleus accumbens, a basal
structure that lies in front of the hypothalamus, and the amygdala,
located medially in each temporal lobe. The nucleus accumbens
is also central to assessing potential gains and losses. Higher
placebo effect revealed greater dopaminergic activation in the
nucleus accumbens.
21
The evil twin of the placebo effect is the nocebo effect, an antici-
patory anxiety or expectation of noxious side effects. In clinical
trials, between 4 and 26 percent of patients in the placebo arm
discontinue the (placebo) drug due to adverse side effects. In
studies described by Damien G. Finniss, of the University of
Sydney Pain Management and Research Institute, 30 percent of
each placebo group had side effects. This, too, has real find-
ings on brain scans. When anticipatory anxiety is prominent, the
hippocampus lights up.
22
The same brain areas activated in the
placebo effect are involved in the nocebo effect, but the neuro-
transmission is different—the µ-opioid and dopamine systems are
actually deactivated.
23
CCK also plays a role in the nocebo effect.
What are the reasons behind the more powerful placebo effect
in the last 20 years? One factor is direct-to-consumer adver-
tising by pharmaceutical companies. This started in 1997 with a
change in FDA regulations and is believed to have generally raised
16. Berman B et al, “Acupuncture for Chronic Low Back Pain.”
NEJM
, 2010; 363:
454–61.
17. “Biological, clinical, and ethical advances of placebo effects.”
18.“Placebos are getting more effective.”
19. “Pain Studies Illuminate the Placebo Effect.”
20.“Biological, clinical, and ethical advances of placebo effects.”
21. Scott D et al, “Placebo and Nocebo Effects Are Defined by Opposite Opioid
and Dopaminergic Responses.”
Arch Gen Psychiatry
, 2008; 65: 220–231.
22.“Biological, clinical, and ethical advances of placebo effects.”
23.“Placebo and Nocebo Effects Are Defined by Opposite Opioid and
Dopaminergic Responses.”
Clinical Research*
Phase
Test Subjects
Purpose
Size
Preclinical
Animal studies
Phase 0
Humans
Learn half-life, bioavailability
10 people
Phase I
Healthy volunteers Learn dose range, establish safety
20–100
Phase II
Patients
Efficacy and safety, therapeutic dose 100–300
Phase III
Patients
Efficacy, effectiveness, safety,
Therapeutic dose, RCT, multicenter
1000–2000
*after “Clinical Trial, Phases of Clinical Research” in Wikipedia.org
PLACEBO EFFECTS, CONT.
