May/June 2016
5
in France and Belgium, it remained more effective than placebo. In
contrast, Prozac (fluoxetine) was more effective than placebo in the
United States but not in Western Europe and South Africa.
4
Within a given region, the placebo effect of products for different
conditions can vary. In Germany, ulcer medication has a high
placebo effect, while antihypertensive drugs have a low placebo
effect. So the placebo effect appears to depend on culture and
geography.
5
Expectations are basic to placebo effects. Expectancy connotes
positive beliefs about outcomes.
6
Current theory proposes that
there are multiple ways of producing expectations. These include
conditioning
with repeated medical rituals,
verbal suggestion
on
the part of the provider, and
social observation
(watching someone
else’s response to treatment).
7
If the very first medical encounter
is strongly positive, the placebo effect will subsequently be greater
because of higher expectations.
8
Ted Kaptchuk, a well-known and somewhat controversial placebo
researcher, defines placebo effects as “improvements in patients’
symptoms that are attributable to their participation in the ther-
apeutic encounter, with its rituals, symbols, and interactions.”
Kaptchuk adds that there are well described, reproducible neuro-
biological events that explain the placebo effect—release of
neurotransmitters like endorphins, cannabinoids, and dopamine,
and activation of specific areas of the brain that can be detected
using functional MRI and PET scans.
9
A number of experiments have used an open/hidden technique
to study placebo effects. There is a noticeable difference between
pain relief when morphine is given in an open fashion (“I am
giving you a shot of morphine”) and when morphine is dosed
randomly by a hidden pump. Open administration typically leads
to a rapid reduction in pain, while hidden administration produces
more gradual relief.
When morphine administration is discontinued in an open fashion
(“I am stopping the morphine now”), there is an abrupt increase
in perceived pain. In contrast, when morphine discontinuation
is done in a hidden fashion, the perceived pain only gradually
increases. A similar open/hidden experiment using diazepam for
post-op anxiety had comparable results.
10
Attempts to quantify the placebo effect have also employed the
open/hidden technique. When migraine sufferers were given a
triptan labeled as triptan, they had 50 percent more pain relief
than when they were given the very same triptan labeled as
placebo.
11
Another study used methylphenidate in patients with
a history of cocaine abuse and compared brain glucose metabo-
lism following methylphenidate administration when the individuals
were told it was placebo and when they were told it was active
drug. When told they were receiving active drug, the participants
had a glucose metabolism 15 percent higher than when told the
methylphenidate was placebo.
12
The conclusion from these studies is that the administration of
any drug has a dual effect—an
expectation
effect (which is due
to the knowledge and experience of relief of symptoms) and a
pharmacological
effect.
13
An experiment in 1995 on post-cholecystectomy pain found that
proglumide, a cholecystokinin (CCK) antagonist, gave excellent
pain relief—but
only
if the patient knew he or she was receiving
the drug. Cholecystokinin inhibits the placebo response, and
thus proglumide, which blocks CCK receptors, can reactivate the
placebo effect. Proglumide has no pharmacologic effect, only an
expectation effect.
14
A small study of mild to moderate asthmatics randomized to an
albuterol inhaler, a placebo inhaler, sham acupuncture, and no
treatment adds further insight. Only the albuterol inhaler had a
pharmacological effect and significantly improved FEV1. But subjec-
tive improvement in symptoms between patients in the albuterol
inhaler, placebo inhaler, and sham acupuncture groups was,
respectively, 50 percent, 45 percent, and 46 percent, which did
not differ significantly. The non-intervention controls had subjec-
tive improvement of just 21 percent.
Placebo effect can make a patient feel better even when airflow
is unchanged. Patients’ subjective evaluation of their asthmatic
symptoms must be interpreted with caution.
15
Subjective assessment may explain why sham acupuncture seems
to be as effective as real acupuncture. A metaanalysis in 2008
1. “New drug failure rates rising in Phase II and III clinical trials,”
MedCity News
,
June 2, 2011.
-
rising-in-phase-ii-and-iii-clinical-trials
2. “Placebos are getting more effective. Drugmakers are desperate to know why.”
Wired.com, August 24, 2009.
3. Rutherford B, et al, “Placebo Response in Antipsychotic Clinical Trials.”
JAMA
Psychiatry
2014; 71:1409–1421.
4. “Placebos are getting more effective.”
5. Ibid.
6. Brody H and Miller F, “Lessons From Recent Research About the Placebo
Effect—From Art to Science,”
JAMA
, 2011; 306: 2612–2613.
7. Colloca L, “The Science of the Placebo Effect.”
National Center for
Complementary and Integrative Health
, May 9, 2011.
summary.asp?Live=10192&bhcp=1.
8. Finniss DG, Kaptchuk T, Miller F, Benedetti F, “Biological, clinical, and ethical
advances of placebo effects.”
Lancet
, 2010; 375: 686–695.
9. Kaptchuk T and Miller F, “Placebo Effects in Medicine.”
NEJM
, 2015; 373: 8–9.
10.“The Science of the Placebo Effect.”
11. “Placebo Effects in Medicine.”
12.“The Science of the Placebo Effect.”
13.“Placebo Effects in Medicine.”
14. Kuehn B, “Pain Studies Illuminate the Placebo Effect.”
JAMA
, 2005; 294:
1750–1751.
15. Wechsler M et al, “Active Albuterol or Placebo, Sham Acupuncture, or No
Intervention in Asthma.”
NEJM
, 2011; 365: 119–126.
FEATURE
