13

MEASURING PLACEBO
EFFECTS
Jeremy Howick

1. Introduction
medical research and practice, a placebo~ a
The term placebo is Latin for "I shall please." In
ve it is, or could be, the real treatment whtn
treatment that is capable of making people belie
is indistinguishable to a patient fromreal
in fact it is not that treatment. A sugar pill that
in clinical trials, placebo controls arc often
vitamin C, for example, could be a placebo. With
ents are compared. For example, when
used as a standard against which experimental treatm
patients a placebo ,md other patien ts the
evaluating a new drug, investigators can give some
rforms the placebo by a sufficient margin,
experimental drug. If the experimental drug outpe
le, doctors, outcome assessors, and daca
it is said to be effective. Patients (as well as, if feasib
means they don't know which treatment is
analysts) in these trials are often masked, which
Placebo use in clinical practice and clinical
the experimental drug and which is the placebo.
2009, Howick et al., 2013a). A great deal of
trials is both common and controversial (Howick,
are (G(lltzsche, 1994, Nunn, 2009), as well
philosophical controversy surrounds what placebos
ick, 2009). Ther e is also a dispute-the one
as whether placebos are ethical (Foddy, 2009, How
corre ct methodology that should be used to
I will concern myself in this chap ter-a bout the
measure placebo response.
ed that one-third of the benefit of all
Henry Knowles Beecher's early ( 1955) study claim
). This is still the most widely cited paper
treatments was due to placebo effects (Beecher, 1955
rful persist because of it. Yet more recent
in the field, and the beliefs that placebos are powe
Peter G(lltzsche in Denmark conclude that
studies conducted by Asbjom Hr6bjartsson and
bjartsson and G(lltzsche, 2001, Hr6bjartsSOn
placebos do not have important effects at all (Hr6
and O(1ltzsche, 2004a, Hr6bjartsson and O(1ltzsche,
2010). In this chapter I will review the
odological problems with these attempts.
attempts to quantify placebo effects and list the meth st
estimate is likely to be an overe imate,
To anticipate, I will argue that while Beecher's 1955 shows th3 t
more recen t studies unde restim ate place bo effects. A large body of evidence
the
ailments, especially pain.
placebo effects are very powerful for treating some
and the problems with it. The
I will proceed by first describing Beecher's 1955 study
rectly infers from the fact that someone
main objection to Beecher's study is that he incor
the recovery was due to the placebo (sec-
recovers after taking a placebo to the claim that
recen t studies conducted by Hrobj arrss,on
tion 2 ). I will then proceed to describe the more
ems with them. The main issue with Hrobd
~nd G¢tzsche and list the methodological probl
includes heterogeneous placebos an
Jartsson and G¢tzsche's analysis is that their study I I ebo
k· · ate compatible with powerfu Pac
cond.. tttons, ma mg their average placebo effect estim

134
 MEASURING PLACEBO EFFECTS

f for certain conditions such as pain (section 3). Before concluding (in section 5), I
ef ect_s the evidence and mechanisms that explain why, despite the methodological dif-
descn 6e . . .
. I . . in estimatmg placebo effects, tt 1s reasonable to believe that placebos are effective
ftcu ues .
for creating pain (sec non 4) •

2. Beecher's Powerful Placebos

Although placebos have been used knowingly and unknowingly by physicians for ;:it least
several centuries (Kaptchuk, 1998), Henry Knowles Beecher was the first person we know of
who rigorously attempted to quantify placebo effects. Beecher was a Harvard Medical School
graduate and a doctor in North Africa, France, and Italy during World War II. Morphine was
sometimes in short supply, and he noticed that some soldiers did not require any painkillers.
Many of these patients had very serious wounds; for example, they had been shot. Beecher
chus came to suspect that their mental states and attitudes, as much as their physical wounds,
affected how much pain they experienced.
After the war was over, he investigated placebo effects by doing one of the first systematic
reviews (a study that includes all available studies) with meta-analysis (statistical pooling of
results of the studies within the systematic review). Beecher's review contained 15 placebo-
controlled studies measuring the effects of painkillers for treating conditions ranging from
postoperative pain to angina pectoris, headaches, and cough. The studies contained a com-
bined total of 1,082 patients. He found that one-third of the patients who had received only
placebos got better and concludes: "It is evident that placebos have a high degree of therapeu-
tic effectiveness in treating subjective responses, decided improvement ... being produced in
35.2 ± 2.2% of cases" (Beecher, 1955, p. 1696). Beecher's study is still the most widely cited in
the field, and it was immortalized in his famous article "The Powerful Placebo."
However, in the 1990s, researchers began to formally question Beecher's results. In a provoc-
atively titled article, "The powerful placebo effect: fact or fiction?" Kienle and Kiene (1997)
accused Beecher of failing to "consider that many patients with a mild common cold improve
spontaneously" (Kienle and Kiene, 1997, p. 1312). In this regard, Kienle and Kiene are correct:
Beecher's attribution of change in the placebo control group to the placebo control treatment
is a fallacy. Many ailments, including the common cold and postoperative pain, usually go
away quite quickly without any treatment at all. The so-called natural history of the disease,
and spontaneous remission, are all potential causes of apparent recovery that have nothing to
do with placebo effects. Claiming that one thing (giving a patient a placebo) causes another
thing (reduction in pain) simply because the former comes first is what philosophers call the
Post hoc ergo procter hoc (after, therefore because of) fallacy.
There are at least two additional problems with Beecher's method. First, polite patients
taking the placebo could report improvement to please investigators, although no benefit was
actually felt (Hr6bjartsson et al., 2011 ). Noting that their doctors were trying to help them,
the~e patients could exaggerate how much benefit they felt after being
treated simply to please
their friendly doctors. In addition, caregiver
and doctor attention given to patients could lead
to clinical improvement. Many systematic reviews have demonstrated that empathetic and
encou
. · caregivers improve outcomes in patients sunenng
ragmg a · from pam,
· anxtety,
· and d epres-
sion (Crow et al., 1999, Di Blasi et al., 2001 , Griffin et al., 2004, Derksen et al., 2013, Kelley
it al., 2014, Kelm et al., 2014 ). Hence, the effects observed in the placebo groups within
eecher's studies could be the effects of caregiver empathy and encouragement rather than the
effects of administering say a sugar pill. One could, of course, classify practitioner empathy
and encouragement as types' 'of placebo effects. At the same time, empathy and
encouragement
appear to be distinct from the administration of a sugar pill. If the effects of caregiver empathy

135
-. •-lorA •-• ~- ~ -- - - -- -
•. .>

JEREMY HOWICK

·fferent from the effects of administer ing a sugar pill th h

d uragement are dl I
en t e er
an enco ,' d ' . . ,·ght not be placebo effects. eneqs
. B cher s stu tes m
m ~e II f' I . thodological problems wit I1 Beec her 's stuuy, J
Kienle and Kie I
Given a o ne me . ·I b
cttcl y Beec• h er
" .
f I _ o ric,imil mals . gave
, gro d ne t 1Us
elude 1fo-1t none o t ,e o un s to assume th . con.
1316) e extste
rr t ·"(Kienlcll ndKiene, 1997,p. · nee
of p Iace bo enec s

3, Hr6bjartsson and G~tzsche' s Powerless Placebos

..,. k. ti challenge of estimating placebo effects more accurately, Peter o tzsch
·mg up 1e
1.-1 . . d 0
Asbjorn Hr6bjartsson conducted a systematic review an meta-ana lysts
. . e and
of trials that had three
groups of patients:

l. patients not treated at all (often people in these groups were placed on waiting lists)
2. patients given a placebo
J. patients given a "real" treatment

They identified 114 trials. Typical pill placebos were lactose pills, typical physical placebos were
procedures performed with the machine turned off (e.g., sham transcutane ous electrical nerve
stimulation), and typical psychological placebos were theoreticall y neutral discussion between
participant and dispenser. They then compared what happened to patients who received the
placebo with patients in the untreated groups. This method avoided the post hoc ergo procter hoc
fallacy because it included a comparison of patients whose ailment would have followed its natu-
ral history: the untreated group. They found that on average placebos only have small effects:

[There is] little evidence that placebos in general have powerful clinical effects. Pla-
cebos had no significant pooled effect on subjective or objective binary or continuous
objective outcomes. We found significant effects of placebo on continuous subjective
outcomes and for the treatment of pain but also bias related to larger effects in small
trials. The use of placebo outside the aegis of a controlled, properly designed clinical
trial cannot be recommend ed.
(Hr6bjartss on and G¢tzsche, 2001, p. 1599)

Even in cases where they found a significant placebo effect-not ably for treating pain-
Hr6bjartsson and G¢tzsche question whether the observed effects were actually placebo
effects. They raise a similar concern to Kienle and Kiene, noting that the outcomes in the pla-
cebo groups could have been due to a form of reporting bias, such as patients politely reporting
th ey had recovered when in
fact they did not actually experience any recovery. In their wo rd s:

~atients in an untreated group would know they were not being treated, and patients
tn a placebo group would think they were being treated. It is difficult to distinguish
between reporting bias d
. a
an a true enect o f placebo on subjective outcomes, smc · ea
pattent may tend to try to I h • .
h as occurred. The fact th P ease t e mvesttgato r and report improveme nt wh en none
l
at P ace bos h a d no significant effects on objective conttn· u·
ous outcomes suggests th t . b . l
. .
su6Jecttve outcomes. a reporting ias may have been a factor in the trta s wt.th

(Hr6bjartss on and G0tzsche, 2001, P· 15 9?)

If we accept their results Hrob· turned
Beecher's estimate. Yet while Hr~:.tsson and G¢tzsche seem to have completely ove~oc ergo
Jansson and G¢tzsche's method overcomes the po5t

136
>
MEASURING PLACEBO EFFECTS

ter hoc fallacy, their conclusio ns nre questiom,ble becA use of scvern l problems with their
/JT'~ ., The mc1 in problems :u e: (I) tht' ir rev iew i11cluded heLcrogeneu us s l udi es that argur1 bly
~~ '
I Id not have been lumped together so their HVcrage rcsulLs fa il to rule out powerful placebo
.

:-ideciuatcly put strictures on wha t cou11ts a

sff: tsfor some condi ti~ns; (2) they f'.1ilcd to untrea sa
ed to recognize that ted uroups wiLhin clinic.ii tri als Are no t
• (3 ) they fo il
el:,ce bo·, nnJ . o
11 I intrer1ted. I will go over each of these problems in turn.
trll Yl

3.1. Problem with the Heterogeneity of the Studies within

Hrobjartsson and Gett:sche's Review
neity.
Perhaps the most serious problem with Hr6bjarts son and G¢tzsche 's review is heteroge
but the meta-ana lysis can be misleadin g
It is often acceptable to meta-ana lyze (pool) results,
if researchers include heteroge neous studies-a pples and oranges- within the same analysis.
and
Over 40 clinical conditions were included in the analysis, ranging from hyperten sion
placebo intervent ions were
compulsive nail biting to fecal soiling and marital discord. The
also diverse. Kirsch (2002), for example, notes that Hr6bjartsson and G¢tzsche jumble together
and a
(along with placebo pills and injections) relaxation (described as a placebo in some studies
rs, magazine s,
treatment in others), leisure reading, answering questions about hobbies, newspape
,
eating favorite foods and watching sports teams, talking about daily events, family activities
football, vacation activities, pets, hobbies, books, movies, and television shows as placebos.
In this case it is problematic because it means that although they found a very small average
"real"
placebo effect, some of the placebo treatmen ts within the review had large effects. Just as
medicine is not necessarily effective on average for everythin g, neither are placebos. Instead,
and
like "real" medicine, we might expect placebos to be effective for treating some ailments
not effective for treating others. To illustrate this problem, Howick et al. (20136) reanalyze
d
but instead of just 'mea-
the same three-armed trials from Hr6bjartsson and G!Z)tzsche's review,
also
suring placebo effects (by comparin g outcomes in placebo and no treatmen t groups), they
in treatmen t and placebo groups). They
measured treatment effects (by comparin g outcomes
found that average treatmen t effects in that heterogeneous group of studies were also modest
and not statistically significantly different from placebo effects. Unless we accept that medi-
cine does not have significant effects, the Howick et al. study is arguably a reductio ad absurdum
,
ofHr6bjartsson and G¢tzsche's methodology. If it is legitimate to pool heteroge neous placebos
for diverse conditions, then it is also legitimate to pool similarly heteroge neous treatment
s for
reveals minuscul e treatmen t
the same diverse conditions. Since pooling treatmen ts in this way
effects, and we know some treatmen ts are highly effective, then it follows that pooling hetero-
r
geneous placebos for diverse condition s is not legitimate.
The highly significant heteroge neity of the intervent ions studied calls into question what
conclusions can be drawn from the meta-analysis. An overall finding of insignific ant placebo
effects does not count against the reasonable view that placebos, like treatmen ts, are common
an dpowerful for certain disorders, but not for others. Similarly, certain placebo s-for example,
P1acebo, in1ectton
. . s-cou Id be more effective than oth er pace l bas-for example, placebo pills.
1 large
t sectto.n 4, I will review the evidence supportin g the claim that placebo effects are quite
or treatmg pain.

3.2. Problem with Hr6bjartsson and G~tt:sche's Definition of Placebos

The estimate of th e P1ace bo eff,ect 1s
. b .
the I bo ased on the average difference between outcome in
the
incl~dacde . and no treatmen t groups. This estimate depends on whether the placebos in
e tnals we re "rea l" p1ace b os an d wh et er t e untreated groups were truly untreated . Yet
h h

137
w
r,f

JEREMY HOWIC K

the placebo concep t h:is proven notorio usly difficu lt to define .,d n equate ! I .
. . •
y. t 1s beyond I
of this chapte r to outlm e the definit ional proble ms- see Howic k ' 2016 for a · th1e "'-Oiie
•~
i: · · ns o f p I~ ·
•ce LJOS as mact1v · e or nonspe cific ., . review
t I1e comm on denntt1o . _ . . ,·,re c 1earl • - OI\I
.
can be active, c1t least with respec t to some mlmen ts, and their , I . ~ mistaken: I·acel. ever,
. f. I I . I d rnec 1an1sm f p
uos
. I 4) 'T' 0 actio
as specih c as t 1e actlLln o a p 1armac o og1ca rug (see section · ' 0 avoid h n can
· d G - I d 'd d
jbtzsc 1e ec1 e to adopt a practic al a t e defini . 1.
UI!
proble m, Hr6bJ..irtsson an 0
the~~roa_ch and charat '~af
placeo os "prnc tirn lly as an [any!] interv ention labeled as such in · • tr·,
Su ero, tuf •,' c11nrcal
k ' I ·h '· I · terize,,
· I .11 d
But 1t mm y nee s rcmar mg t 1.it t is approa c 1 1s untena ble.
. . I
. ·11· . , I lJ O ma tna o f some new a _. . . x,1111pfe, th• ppose, for l' . 1,1I.
.
someo ne repartee:I usmg pc111c1 111 ,1s a p ace nt1 6 tot,c as ,it
. Tt ·tt f b " if the d'd a treatrne111
for pneum onia. ne respon se w1 o course c no one would, and I
· 1y. " But t I11s
· I serious · reactio · n seems exact Iy to s h ow that we wy k we . would not takc
the tna
. . or w1t 11 so
ents about what can and canno t count as approp riate . _Ille concept
that involv es Judgm 1
H:!~~11late place.
bos and placeb o contro ls. Since it is unclea r wheth er the placeb os withi~r
effects m b Jansson and
G¢tzsc he's study were actual placeb os, their estima tes of placeb o ust e quest1.0
of ac . ned.
Worse , Hr6bja rtsson and G¢tzsc he go back on their alleged policy cepting a
le the dny treat.
ment labeled as a placeb o in the report of a clinica l trial. For examp I
t n~t assy e~c ud e ~tudies
where "it was very likely that the alleged placeb o had a clinica l benefi ociate with h
ent techni ques for postop erative pain)" (Hrobj artsson and G te
ritual c1lone (e.g., movem
os as the effect f "~_tzsche ,
2001 , p. 1595). Here they seem to sneak in a definit ion of placeb I b so rituals"
. not accept a bl e: ntua
. h 1s . 1 r1eastm . f: .
g or astmg are not p ace os. A similar proble .'
w h 1c
he's study may actual~ a;ises
becaus e the untrea ted groups within Hr6bja rtsson and G¢tzsc
and contac t with health care practit ioners. y ave
benefi ted from observ ation by

3.3. Hawth orne Effects in the No Treatm ent Groups

the phenom enon but after
The Hawth orne effect is named not after the scienti st discov ering
Electri c Company in Chi-
a series of experi ments in the Hawth orne works of the Weste rn
factory remained stable for
cago betwee n 1924 and 1933. In one study, the lightin g in the
the experimental group
the contro l group, wherea s the lights in the part of the factory where
in both groups . In another version
worked were made brighte r. Produc tivity increas ed equally
kept stable in the part of
of the experi ment, the researc hers tried the opposi te: lightin g was
where the experimental
the f:actory where the contro l group worked but was made less bright
ed steadily and equally in
group worked. In the second experi ment, produc tivity also increas
that the workers proteSted
both groups until the lights were so low in the experi menta l groups
Dickso n, 1939). Since the
that they couldn 't see and produc tion fell off (Roeth lisberger and
turned up, turned d?\:11,
produc tivity increas ed in both groups wheth er or not the lights were
the increas e in producttvity.
or remain ed the same, it couldn 't be the lightin g that caused
were being watched .d:'1~
The reason produc tivity increas ed was that the worker s knew they 1
In the case of me ~a
effect of being watche d is called the Hawth orne or observ er effect.
t (or change their behavtor
research, patien ts in clinica l trials could experi ence some benefi
nd
and responses) because they are being investi gated. d . h ' Hr6bjartsson acri-
ld
H aw thorne euects cou have influen ced the untrea te groups wit
a 111 . . I
pants wi th in cl~ica that
G¢tzsche's analysis and confou nded their results. "Untre ated" partici
et al., 2001). Knowingd for
als are typically monito red and observ ed by researc hers (Einar son ' that areII goo duce
· ·
· cond ltlon · emg monito red, the patien ts might do vanou s t h mgs
b · ·
t h e1r ts h.mgs c ould a hat pr0 theY
h · h 1 h h · ier, or drink less. These t
t eir ea t , sue as exercis e more, eat health
virtue of the fact \ioners.
a health benefi t for many condit ions being treated . In additio n, by h I h are practt
. . d " ea t c . · 0 ers are
are bemg momto re , the untrea ted" patien ts have contac t with th
ally if e pracntt o
Conta ct with practit ioners has been shown to have an effect, especi

138
►
MEASURING l'LACEIIO EFI-El ~ S

. rhcric (Di Bl:,si et :ii., 200 1). This prescms a problem with Hro bj:1rrsson ;ind v0t zscl 1e's
enip,i · 'I I Ot1· ' I1 Ievel at Rccchcr. The uut corn cs in the Lm tre·tt cd
. , rh'1t is sltnt nr tll tic I Jccttun L ey
. ,
rev1e11 , .
effrct ~
ups 111 ight not be rhe resL'. t of natural l~istory, but instead be the re.~ulr nf Hawthor ne
grol I e effects of conrnct with empathe tic her1lth care prac titioners.
:in, r 1 b 1· ne
There is good reason to c ievc that the untrcr1ted groups did benefit fro m Hawthor
fou nd that the
a;. cs and the effects of caregiver attention . A recent syste mc1tic review
eceated groups within
cunrr Hr6bjartsson and G~rzsche's review experienc ed ·1 24% improvc-
. . '
wtth baselme (Krogsbo ll et a l. , 2009). There are two nlausible explanati o ns
n1ent Compared t

for the 24% improvem ent from baseline. First, it could be natural history of disease. Second,
rhe improvement is partly due to H awtho rne effects and effects of contact with h ealth care
a large
ractitioners. If it is the second- and this is my preferred explanati on since 24% is
then Hr6bjarts son
~(feet that is not likely to be explainab le solely in terms of natural history-
no t,
and G~tzsche have underesti mated the placebo effect. Because the untreated groups were
's review underesti mated placebo effects. This is
in fact, untreated , Hr6bjartsson and G¢tzsche
by subtracti ng outcome s
due ro simple arithmeti c, noting that the placebo effect is estimated
in the placebo effect with outcomes in the untreated groups.

3.4. Other Biases within Hrobjartsson and Gntzsche's Review

and
Hr6bjartsson and G¢tzsche updated the 2001 meta-ana lysis in 2004 (Hr6bjar tsson
Gotzsche, 20046, Hr6bjarcs son and G¢tzsche , 2010). The 2010 review included 202 studies-
the
almost twice as many as the initial review. The more studies they included, the greater
clinical
placebo effects became, both in terms of statistica l significance and ( in the case of pain)
relevance. Moreover, Hr6bjarts son and G ~tzsche recognized the problem that the untreated
In
participants may have been treated and hence led to an underesti mation of placebo effects.
and the
their words: "Patients in a no-treatm ent group also interact with treatmen t providers ,
respect to receiving a placebo intervent ion"
patients are therefore only truly untrea ted with
problem of heteroge -
(Hr6bjartsson and G¢tzsche , 2004a, p . 97). They also acknowle dge the
trials
neity: "we cannot exclude the possibility that in the process of pooling heterogen eous
a significan t placebo effect] was obscured "
the existence of such a group [of trials that showed
for placebo effects,
(Hr6bjartsson and G¢tzsche , 2004a, p . 97) . Despite the growing evidence
and recognition of at least a few of the problems with their analysis, their conclusio ns remained
t
just as skeptical, concludin g that they "did not find that placebo intervent ions have importan
given that their updated
clinical effects in general" (Hr6bjart sson and G ¢tzsche, 2010). Yet
review found greater placebo effects, one may question whether Hr6bjarts son and G¢tzsche
were justified in maintain ing the same conclusio n.
prac-
Finally, Hr6bjarts son and G¢tzsche 's study may not be applicabl e to routine clinica l
clinica l
tice because placebos are likely to h ave a smaller effect in clinical trials than in
practice. In a clinical trial, patients believe that they might receive the placebo
or the
whether they will receive the
;xperimental treatmen t. There is therefore some doubt as to
real" s
treatment. This could lead to lower expectati ons about recovery and worse outcome ·
com d t and
h pare to the case where they believed they were sure to receive the real treatmen
placebo in clinical practice, how-
t us had higher expectati ons. If a doctor prescribe d a
clinical
ever-and several studies have shown that most doctors h ave prescribe d a placebo in
a
P.ra\~~ce (Fassler, 2009, Howick et al., 2013a)- the patient believes they are receiving
The higher expectati ons, in rum,
c~:~d !treatment, and hence have higher expectati ons.
rev· ead to greater placebo effects in clinical practice. Since Hr6bjarts son and G (lltzsche's
clinical
Pra~etw attempts to measure placebo effects within clinical trials, it may not apply to
ice whe re PIace b o effects could be greater.

139
 JEREMY HOWICK

3.5. Summary of the E"idence for Placebo Effect3

In sum , Beecher's estimate of pl.lcebu effects is problematic for fo iling t , k
. account am J 1.s t·k I . . H owever, Hr6bjartsson c1nd O t ,l C naL I
mLO I e y ,m overest imate. G ura h1~1l,
are likely to underestimate pace I bo e f,ects, most no tably because they f· . ~tzsch c'~ s1uJ1..,
r ' ry
a 11to con5 1"<l -.
t ion in placebo effectiveness and because they fail to acknowledge Hawth . er v,ir 1d·
er
are.l wI1ere t h ere is Ieast controversy ab o ut t h e euectiveness Orne effe
of placebos i . cts. 11,e
sec tion I will rev iew the evidence for both the existence o f .lnd the mechs p~'.11 • lfn the nc:x1
analgesia. .in1s111 or I
P acehu

4 , The Evidence and Mechanisms for Placebo Analgesia

Even Hr6 bjartsson and G¢tzsche's skeptical review acknowledges- albeit with wh
. •c. d sk epuca
were part ly unJustme l b o ana lgesia is effective. A at 1argued
. l caveats- t h at pace
large bod
evidence h.ls demonstrated the effects of placebo analgesia. For example, a rec em : of
a tic review of 198 trials ( involving 16,364 patients) of placebo treatments for ost"o 5yshtc_~-
'- an rit1s
pain found that placebos were effective (Zhang et al., 2008). In one of the more in,,o .
vat1vc
studies that points towards a mechanism for placebo analgesia, Benedetti et al. (2004) uscJ
four common painkillers on a total of 278 patients who had undergone thoracic surgery for
different pathological conditions (Benedetti et al., 2004, p. 680). The patients were then,
of course unbeknownst to them, randomized into "overt" and "covert" groups with sex, ,igc,
weight, and pa in baseline-balanced. The overt group was treated by doctors who "gave the
open drug at the bedside, telling the patient that the injection was a powerful analgesic and
that the pain was going to subside in a few minutes" (Benedetti et al. , 2004, p. 681 ). Then,
one dose of analgesic was administered every 15 minutes until the patients reported a 50%
reductio n of pain. The covert group, on the ocher h and, h ad the analgesic delivered by a pre-
programmed infusion without any doctor or nurse in the room. Boch the covertly ,md overtly
treated patients a lready h ad an intravenous line and machine attached to them because of
their operations. The results were that over 30% more analgesic was required by the patients
who were treated covertly. The P-values reach ed statistical significance, ranging from 0.02 io
0.007 depending on the drug.
H ow come people who expected a positive o utcome- those who were treated ovenl~-
felt less pain? The answer lies in the brain's reward mechanism. The expectation of a po5iuvc
reward (such as decreased pain) excites the body in a way that it produces enough e11d0 g-
enous endorphins to cause a reduction in pain (Benedetti , 2009). Combining the firSl four
letters of the word endogenous with the last letters of the ward morphme . • us the term
gives he
endorphm. . From t h e h uman ce II receptor's pomt . o f view,
. morpl1me. and en dorphins are •sic t
1
same thing. To de mon strate that the body's endorphins are responsi·ble ~or che hana gc chcy
rr
enects o f p1acebos, severa 1 researchers h ave d on e interesting rand omize . d trialsffw ere of opi·
gave some patients a drug called naloxone, which antagonizes (bloc~s) thee ,:~~splacebo
ates such as morphine and endorphins, and didn't give it to other pa_uents. ~ oblocking cht'
analgesia works by act ivating the body's ability to produce endorphms , th en h pened, In
. activity
. . wou Id reduce
en d orph m the placebo effect. In fact, t h 1's .is J·ust what
R. apt al., 1998•
the patients who received na loxone, the placebo effect was diminished (ter ,et e
Sauro and Greenberg, 2005 ). f laccros, ,ind ;ll
In sho rt, dozens of empirical studies demonstrate an an algesic effect O p . oriatcs--h'15
least one mechanism expla ining h ow placebo an algesia works-e n clogenlous •a effect Ji,·~
a lso b een establish ed in rigorous stud ies. The existence o f a PIace bo ana "oes1
. , 1, 1; l
t chat, iit ' '
no t fully exon era te Beecher for his me thodological flaws, but it does sugges

140
111111

MEASURING PLACEBO EFFECTS

for killing pain, Hr6bjartsson And Gy,tzsche are 111istHkcn that placebos have insignificr1nt
effects.

5. Conclusion
What cc1n we conclude about the power of placebos from these studies? The first thing is to
knowledge the fact that placebos won't work for everything. If someone has a leg amputated, '
::l\ing a sugar pill or believing it will grow back is unlikely to h<1ve any effect. In addition, ,I
~:any ailments-especially the most common ones people visit their doctors for, such as mild
to moderate pain, depression, anxiety, flu, colds, and so on-will go away on their own and
without any treatment (placebo or not). Beecher's early and widely cited systematic review of
placebo effects made the methodological error of failing to take natural history into account,
and it led to an overestitnation of placebo effects. However, Hr6bjartsson and G¢tzsche's con.-
clusion that placebos do not have much of an effect at all is equally problematic.Just as "real"
treatments are exceptionally powerful for treating some conditions (for example, antibiotics
for meningitis), so placebo treatments can be effective for treating some conditions, especially
mild to moderate pain and depression, anxiety, and smoking cessation, and they can generally
improve quality of life. By lumping all types of placebos for all conditions together, Hrobjarts ..
son and Gotzsche obscure important placebo effects for conditions like pain. For example,
the effects of placebo analgesia have been demonstrated empirically, and their mechanism
of action-endogenous opiates-has been established in numerous studies. Further focused
research is required to clarify the placebo concept and provide accurate estimates of placebo
effects for specific conditions.