Against the placebo effect : A personal point of view

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Availableonlineatwww.sciencedirect.com

j o ur n a l ho me p ag e : w w w . e l s e v i e r h e a l t h . c o m / j o u r n a l s / c t i m

Against

the

‘‘placebo

effect’’:

A

personal

point

of

view

Daniel

E. Moerman

∗

WilliamEStirtonProfessorEmeritusofAnthropology,UniversityofMichigan-Dearborn,6515CherryHillRoad,Ypsilanti,MI 48198,UnitedStates KEYWORDS Meaning; Meaningresponse; Placebo; Inerttreatment

Summary The author reviews 10 of hisfavorite studies which aresaid to be aboutthe ‘‘placebo effect,’’but which,instead, show thesigniﬁcance ofmeaning inamedical con-text.‘‘Placebos,’’heargues,areinertsubstanceswhichcan’tdoanything.Yetit’sclearthat aftertheadministrationofsuchdrugs,thingsdohappen.Theone(andmaybeonly)clearthing hereisthatwhateverhappensisnotduetotheplacebo(that iswhat ‘‘inert’’means).But placeboscanbeofvariouscolorsandformswhichcanconveycompellingmeaningtopatients. Theyoftenrepresentmedicaltreatmentincompellingways;theycanbemetonymic repre-sentationsoftheentiremedicalexperience(ametonymisarepresentationwhereapartof somethingcomestorepresentitall,asin‘‘countingnoses,’’wherethenoserepresentsthe wholeperson,ora‘‘WhiteHousestatement’’wheretheWhiteHouserepresentstheExecutive BranchoftheUSGovernment;here,thepillrepresentsthewholemedicalexperience).More precisely,theycanbemetonymicsimulacra(asimulacrumisasortofartiﬁcialobject,likea statueratherthanaman,oraplaceboratherthananaspirin).Suchobjectsarewellknown fortheirpowerfulabilitiestocontainandconveymeaning;forexample,aEuropeancathedral ordinarilyisconstructedofthousandsofmetonymicsimulacra,fromtherosewindowtothe altar.Inthiscontext,aplacebocanrepeatedlyremindthepatientofthemedicalencounter,its shadingsandcomforts.Placeboscanconveythephysiciansinnermostfeelingsaboutmedication andtreatment;andthecliniciancanbyhersimplepresenceenhancetheeffectivenessofa medicalprocedure(andaclinicianishardlyaplacebo,hardlyinert).

Inert placebos can help us see thehuman dimensions of medicaltreatment; but calling thesethings‘‘placeboeffects’’dramaticallydistortsourunderstandingofsuchtreatments,by focusingontheinert,andavoidingthemeaningful.Think‘‘meaningresponse,’’not‘‘placebo effect.’’

Ithoughtthiswouldbeeasy.Iwouldpickoutmy10favorite studies,theonesI’velearnedthemostfromovertheyears, andgothruthemfrom10to1.Thisturnsouttohavebeen

∗_Tel.:₊₁₇₃₄₄₈₃_3283;_fax:₊₁₇₃₄₄₈₀_1908.

E-mailaddress:[email protected]

moredifﬁcultthanIhadimagineditwouldbe.But

nonethe-less, interesting, and, Iwill argue that in most of these,

theresultsusuallymakemoresenseifwetrytodetermine

howameaningfulinteractionoccurred,ratherthantryingto

understandtheeffectivenessof... ‘‘nothing.’’Iwillargue

that thereis never nothing goingon here. Here’s a good

example:

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Number

10

1

In an important study, 835 women who reported that

they regularly treated headaches with over the counter

analgesics were randomly placed in 4 groups: one group

receivedunlabeled placebo,onereceivedplacebomarked

witha widely advertised brand name, ‘‘one of the most

popular...analgesicsintheUnitedKingdomwidelyavailable

for many years and supported by extensive advertising’’,

onereceivedunbrandedaspirin,andonereceivedbranded

aspirin.

They noted the amount of headache pain relief an

houraftertakingthepills.Results:First,aspirinwasmore

effectivethan placebo. Butbrandname aspirinwasmore

effectivethangenericaspirin,andbrandnameplacebowas

moreeffectivethangenericplacebo.

In particular, 55% of headaches reported by branded

placebousers improved after an hour(rated 2, 3 or 4 on

thescale)whileonly45%of410headacheswerereportedto

bethatmuchbetterbyunbrandedplacebousers(2₌_6.76,

p<.01).Aspirinrelievesheadaches.Butsodoesthe

knowl-edgethatthepillsyouaretakingaregoodones,whichyou

learnedonTV.Thedifferencehereistobeattributednotto

theplacebo(whichis,afterall,inert)buttothebrandname

whichclearlyis not,enhancingtheeffectofbothplacebo

andaspirin.

Notethatsayingthatthisis‘‘Smith’sAspirin’’isnotalie

if,indeed,itisSmith’saspirin.

Both aspirin and placebo work better when they have

a highly advertised brand name on them. That’s NOT a

placebo; that’s meaning, somethingadded to the tablets

withWORDS.

Number

9

2

RickGracely hasdescribed a phased experimentin which

dentalpatientsweretoldtheywouldreceiveeitherplacebo

(whichmightreducethepainofthird-molarextraction,or

might do nothing), naloxone (which might increase their

pain, or do nothing), or the synthetic narcotic analgesic

fentanyl(whichmightreducetheirpain,ordonothing).

Sub-jectswereallrecruitedfromthesamepatientstream,with

consistentselectioncriteriabythesamestaff.

Intheﬁrstphaseofthestudy,clinicians(butnotpatients)

weretoldthatbecauseofadministrativeproblemswiththe

study protocol, fentanyl was not yet a possibility,

yield-ingthePN(‘‘PlaceboNaloxone’’)group;itisworthnoting

that fentanyl is well known in medical circles as a very

powerfuldrug, much more potent than morphine. In the

secondphase,cliniciansweretoldthat,nowpatientsmight

indeedreceivefentanyl, yieldingthe PNF(Placebo

Nalox-oneFentanyl) group. Placebo treated patients during the

ﬁrstphaseofthestudyreceivednorelieffromit,and,after

an hour, their pain reports increased signiﬁcantly. In the

secondphaseofthestudy,placebotreatedpatients

experi-encedsigniﬁcantpainreductionfromtheirinerttreatments.

Theonlyapparentdifferencebetweenthetwogroupswas

that the clinicians knew that no one in the ﬁrst group

wouldgetfentanylwhilethepatients inthesecondgroup

might (although no one reported on here actually did;

theyall receivedonly placebo). Itis not at all clear how

physicianselicitedtheseeffectsfromtheirpatientsina

dou-bleblindtrial.Buttheydid;theclinicianswereclearlymore

impressedbyfentanylthanwerethepatients.

Thisstudyclearlyshowshowphysicianknowledgeofthe

contextinwhichplacebosareadministeredcandramatically

changetheoutcome.

Number

8

3

Inalandmarkstudyin1978,Levineandcolleaguesshowed

thatpainreliefbroughtonbyprescribingaplacebocouldbe

reversedbyadministrationofan opiateantagonist,

nalox-oneorNarcan.Theclearimplicationwasthatsomehow,the

brain produced endogenousopiateswhich ledtothe pain

reliefwhichwasextinguishedbythenaloxone.

Inthisstudy,studentswereenrolledwhohadimpacted

third molars. Following third molar extraction, patients

were told (twice) that they might receive morphine,

placebo,ornaloxone,anopiateantagonist.

Twohoursfollowingtheinitialanesthesiapatientswere

toldtheywouldreceiveeithermorphine,placebo,or

nalox-one: 9 responded to the placebo and 14 didn’t. At three

hours(180min)alltheseindividualsweregivennaloxoneas

asecondtreatment.Ithadnoappreciableeffectonthe

non-responders,butdeﬁnitelyeliminatedthepainreliefinthe

placeboresponders.

Thiswasnotaperfectexperiment;alotwentonwhich

Ihaven’tdescribed,andthepaperwasverycontroversial.

But,18yearslater,FabrizioBenedettisaidofthispaperit

markedthedatethat‘‘thebiologyofplacebowasborn.’’4

It is now generally recognizedthat this is the ﬁrst study

toshowconvincingly thatinerttreatment couldstimulate

theproductionofendogenousopiatesinthebrain.Ina

per-sonal communicationabout this study,HowardFields told

me‘‘The ﬁrsttimewe didthisanddidnothavemorphine

asapossibility,therewasnoplaceboeffect.Oncewetruly

blindedit,sothatnobodyreallyknewwhattheywere

get-ting,westartedseeingrobusteffectsfromsalineinfusions.’’

As in the previous study by Gracely, only when clinicians

knew that patients might get morphine did patientshave

signiﬁcantmeaningresponses.

Number

7

4

This studybyFabrizioBenedettiwaslargelydesignedasa

replicationofthepreviousonebyLevine,GordonandFields.

In thisstudy, subjects induced pain by squeezing on a

handexerciserwithatourniquetontheupperarmcreating

intensepain.

When pain reports reach 7 ona scale of 10, an open

injection of saline — presented asa helpful pain reliever

in about 6 or 8 words — is given tothe members of one

group(seelinewithsquaresinFig.1);theoutcomeis

com-paredtoanother groupwhich receivesa hiddeninjection

ofsaline—thesameinjection,butwithnowords—inthe

othergroup(diamonds).That’stheonlydifferencebetween

thetwogroups. Yettheopen salinegroupshows a

persis-tentdeclineinpainreportswhilethehiddeninfusiongroup

showsacontinuedriseinpain.Letmequalifythis:Doesthis

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4 5 6 7 8 9 10 0 5 10 15 20 25 30 35 40 45 45 hidden saline open saline hidden naloxone hidden proglumide

Figure1 Experimentalpainwasreducedbyopensaline injec-tion (presentedas ahelpful pain reducer;squares), butwas notreduced by hiddensaline injection(diamonds). Asecond injectionofhiddennaloxone15minlaterreducedtheanalgesia (triangles);thisisaclearreplicationoftheLevine,Gordonand Fieldstudy(Number7).Asecondinjectionofhiddenproglumide (an opiate enhancer; ridged circles) increases the analgesic effectofopensaline.

RedrawnfromRef.4.

gotplacebos.Thedifferencebetweenthetwogroupswas

words,language,meaningfulutterances.

Anothergroup,givenopensaline,is,after15min,given

aninjectionofhiddennaloxone(triangles);thepainreturns;

thisisthereplicationofLevine,GordonandFields.

ThenBenedettiaddsanothertrick:after15min,hegives

ahiddeninjectionofproglumide,anopiateenhancer,and

thepaindropsevenmore(ridgedcircles).Benedetti

manip-ulatesplacebolikeamagician.

Number

6

5,6

Itisalsoimportanttonotethatthesematters,where

mean-inghasaninﬂuenceonhealthandevenmortality,canoccur

welloutsidetheordinaryboundsoftheclinic.

Dr.P.D.Phillipsandcolleagueshave shownthat,in the

presenceofabroadrangeofdiseasesinChineseAmericans

inCalifornia,thosewhoareunderstoodbyChinesetraditions

of astrologytobeparticularly susceptibletothese

condi-tions—byvirtueoftheyearoftheirbirth—diesigniﬁcantly

earlierthan thosewiththesame conditionsborn inother

years.Herearethreeexamplesfrom6or8 whichPhillips

described: Chinese born in ‘‘earth years,’’ that is, years

ending with8 or 9 like 1958 or 1969 — andconsequently

deemedbyChinesemedicaltheorytobeespecially

suscep-tibletodiseasesinvolvinglumps,nodules,ortumors—and

whohavelymphaticcancer,die,onaverage,4yearssooner

thanChinesewithlymphaticcancerborninotheryears.

Those withlungdiseases born in‘‘metalyears’’,years

endingin0or1— inChinesetheory,‘‘thelungistheorgan

ofmetal’’— dieonaverage5yearsyounger(roughly7%of

lengthoflife!)thanthoseborninotheryears.Therewere

nosuchdifferences found ina similarexamination of the

mortalityof thousands ofnon-ChineseCalifornians. These

areverycompellingexamplesofmeaningresponses.

Inanotherstudy,PhillipsshowedthatChinese-Americans

andJapanese-Americansweremorelikelytodieonthe4th

dayof themonth than any other because4is an unlucky

number;InChinese,thewordfor‘‘four’’is(approximately)

‘‘sì’’(withafallingtone)whilethewordfor‘‘death’’is‘‘s˘ı

(withafalling-risingtone).

InFig.2youcansee theenhancementofdeathdueto

chronicheartdiseaseinChineseandJapaneseCalifornians

from1989—1998onthe4thdayofthemonth.Thevertical

lineindicatesthe95%conﬁdenceinterval.Thelowergraph

representsnon-AsianCalifornians.

If13isanunluckynumberforCaliforniansingeneral,it’s

notunluckyenoughtoincreasethemortalityrate.Itisworth

notingthatthesemeanings— ofmetalandthelung,orof

earthandlumps,orofdeathlyfours− arenotnotions

con-coctedbyindividualpatientsortherapists;theyareiconsof

asortwhichpermeatethelanguageandcultureof,inthis

case, immigrantChineseor Japanese peopleand/or their

American born children, to some degree or other. These

relationshipshave nothing todowithhaving Asiangenes,

butwithhavingAsianwaysofliving,thinking,behavingand

beingwhichcanhavesigniﬁcanteffectonmortality.

Number

5

7

15 newly admitted ‘‘neurotic’’ outpatients at the Johns

Hopkinspsychology clinic wereinvited toparticipatein a

study.Theypresentedanarrayofsymptoms;allwerepretty

unhappypeople.Theyweretoldthatduringtheirworkup,

theyweregoingtobeprescribed‘‘sugarpills;’’thatis,pills

‘‘with nomedicine in them at all.’’ They were toldsuch

pillshadhelpedmanypeopleinthepast,andthatthe

doc-torthoughtthatitwouldhelpthem.Theyweretoldtotake

3adayatmealtimes.Fourteenofthepatientsreturnedina

week;onanarrayofmeasures,physicianandpatientscores,

13weremarkedlybetter thanaweekearlier(onewoman

wasworse;herhusbandhadattemptedsuicideduringthe

week).Placeboscanhelp,canbedeeplymeaningful,even

ifyouknowthattheyareinert.

Number

5.1

8

TedKaptchuk dida replication ofthis trial 45 yearslater

with 80 patients with severe irritable bowel syndrome.

Patientswere randomized to open label placebo tablets;

they were presented as ‘‘placebo pills made of an inert

substance,likesugarpills,thathavebeenshowninclinical

studiestoproducesigniﬁcantimprovementinIBSsymptoms

through mind-body self-healing processes.’’ The control

groupsreceivedthesametreatment astheplacebogroup

butdidn’tgettheplacebopills.Theplacebogroupwas

bet-terat midpoint andendpoint onall measures. ‘‘Placebos

administeredwithoutdeceptionmaybeaneffective

treat-mentforIBS.’’

Number

4

9

IrvingKirschandhiscolleaguestooktheunprecedentedstep

ofmakinga‘‘FreedomofInformationAct’’(FOIA)requestof

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Figure 2 Upper graph shows mortality by day of month from chronic heart disease for Chinese and Japanese Californians hospitalizedpatients.Lowergraphshowsthesamemortalityfor‘‘white’’Californians.

ReprintedwithpermissionfromRef.6.

fordepression.Theyanalyzeddataon6drugsfrom38

stud-ies with a total of 6944 patients randomized to drug or

placebotreatment.

Table1showstheresultsofthosestudies.Mean

improve-mentwithdrugtreatmentwasadropintheHamiltonscale

Table1 MeanimprovementonHamiltonscorefor6SSRIs approvedforusebytheFDA.Overallaverageimprovement forDruggroups10.01;forcontrolgroups7.82.

Drug Druggroup

improvement Placebogroup improvement Fluoxetine 8.3 7.3 Paroxitene 9.88 6.67 Sertraline 9.96 7.93 Venlafaxine 11.54 8.38 Nefazodone 10.71 8.87 Citalopram 9.69 7.71

scoreof10points;meanimprovementwithplacebo treat-mentwasadropof8points.

Nearly 80% of the improvement from the drug was replicated by the placebo treatment, and the difference betweendrugandplacebowasabout2pointsonthe Hamil-tonScale.So:PlaceboscanimproveaLOTofdepression.

Number

3

10

Walshand colleagues reviewed75 published trialsof

var-ious antidepressants: tricyclics, and SSRIs compared with

placebo. The results of his study show that the

effec-tiveness ofdrug treatment for depression has trendedup

substantially between 1981and 2000, sothatthe

propor-tionofpatientsrespondingtotricyclicantidepressantsand

toSSRIshadincreasedfromabout 40%toabout 55%.Over

thesameperiod,theproportionofpatients respondingto

placebo increasedfromabout 20%toabout 35%.The

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publicationof the studyfor both drugand placebo

treat-ment.The authors concludethat ‘‘Somefactor or factors

associatedwiththelevelofplaceboresponsemusttherefore

havechangedsigniﬁcantlyduringthisperiod.Unfortunately,

wewerenotabletoidentifythesefactors’’.

However, thematter doesn’tseem toocomplicated to

me.Overthepastgeneration,therehasbeenaclearshiftin

consciousnessamongdoctors,patients,friends,and,

gener-ally,everyone,totheeffectthatdepressioncanbetreated

withdrugs. This wassimplynot the case (or at least not

broadlyshared)20or25yearsago.

Asrecentlyas1970,forexample,GoodmanandGilman’s

PharmacologicalBasisofTherapeutics,oneofthestandard

reference sources, was clearly more enthusiastic about

electro-convulsive therapy (ECT) than it wasabout

treat-ment with imipramine or amitriptyline, which were said

nevertobemoreeffectivethanECT.11

Today, while we practically never hear of ECT, we all

‘‘know’’ thatdrugs are effective for depression; we read

itinthenewspapers,inthescientiﬁcjournals;weseeiton

TVdramas,and,intheUSatleast,weseeitindrugcompany

advertisementseverywhere,bothinprofessionalmediaand

onTVcommercials,blogs,TwitterandFacebook.

Antidepressantdrugsareavailableinthedrugstore,and,

intheformofSt.John’sWort,atthedrugsectionofyour

local supermarket. As we change our views of the

effec-tivenessofdrugs, theireffectiveness changes,asdotheir

placebomimicsintrials.Meaningschangeandsodomeaning

responses.Placebosstaythesame,alwaysinert.

Number

2

12,13

Brainimaginghashadasigniﬁcanteffectinplacebo

stud-ies,makingclearertopeoplejustwhatisgoingon;I’mnot

convinced thattheimagingstudies showedusawholelot

wedidn’t knowbefore,butIbelievetheyconvertedalot

ofpeoplepreviouslyskeptical.Suchimagesareindeedvery

compelling:Iwillconsideronlytwoofmanythathavebeen

published,mostlysinceabout2000.

Parkinson’s disease has long been known by clinicians

tobesusceptibletoinﬂuencebyinerttreatments.Imaging

studiesbyagroupfromBritishColumbiahaveshowna

neuro-logicalbasisforthiscommonclinicalobservation.UsingPET

scanning,theauthorsshowedsubstantialincreasein

occu-pancyofD2receptorswithdopamineinthestriatumafter

aninjectionofsalinesolutiontoaParkinson’spatient

pre-sentedashisstandardmedication;theincreaseddopamine

crowdsouttheradioactivedye.12

In a somewhat more complex study, regional glucose

metabolisminPETscansofﬂuoxetine(ProzacintheUS)has

beenshowntooverlapthemetabolicpatternofplaceboin

depressedpatients.Theactiveregionsinﬂuoxetine

respon-dersoverlaptheareawhereactivitywasevidentinplacebo

responders.13

Although the clinical response of drug and placebo

patientswasverysimilarinthisstudy,drugresponseinbrain

activitywassomewhatmoregeneralthanplaceboresponse.

Thismayhelptoaccountforwhyitisthat,whileplacebo

treatmentofdepressionisoftenverynearlyaseffectiveas

istreatmentwithSSRIs,thereisoftensubstantiallyless

evi-denceofunwantedsideeffectswithplacebo.9_These_studies

Figure 3 When the clinician is present for the injection, patientsreportlesspain.Noteinparticularthatthereareno placebosanywhereinthisstudy,henceno‘‘placeboeffects.’’. ReprintedwithpermissionfromRef.14.

underscorethevitalrealityofmeaningfultreatmentin

seri-ousillnesses.

Number

1

14

Finally,Benedetti andhis grouphave reported ona

clini-calexperiment where surgerypatients were treated with

fourdifferentdrugs appropriate totheirconditions;

how-ever,halfthepatientsreceivedtheirdrugsopenly,withan

injectionbyaclinician,whilehalfreceivedequivalentdoses

ofthesamedrugsbyhiddeninfusionthroughanintravenous

line.

One of the four groups was given tramadol. Patients

receivingthemedicationopenly,whoweretoldtheywere

abouttoreceiveit(thelowerlineinFig.3),reportedmore

painreliefthanthosewhoreceivedequivalentamountsof

drugssecretly(upperline).

PainresearcherDonPrice,inanaccompanyingeditorial,

describedthisstudy as‘‘assessingplaceboeffectswithout

placebogroups.’’15_As_much_as_I_respect_Don_Price,_this_is_an

unfortunateuseoflanguage.Therewerenoplaceboshere;

bothgroupsgottramadol. Soobviously,thereweren’tany

‘‘placeboeffects.’’Whatdifferentiatedtheseparategroups

inthisstudywerehumaninteractionandwords.

Benedetti has replicated his open/hidden drug

exper-iment in three other areas: diazepam in anxiety state,

stimulation of the subthalmic nucleus in Parkinson’s

patients,andadministrationof beta-blocker(propranalol)

ormuscarinicantagonists(atropine)inhealthyvolunteers.

Inallthesecases,whenthetreatmentwasgivenopenly,it

wasmoreeffectivethanwhengivensecretly.16

In hisdiscussionof these cases,Benedetti andhis

col-leagues write this: ‘‘It is probably wrongto call placebo

effectthedifferencebetweenopenandhiddentreatments,

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more appropriate,17,18 _in _order _to _make _it _clear _that _the

crucialfactorisnotsomuchtheinerttreatmentpersebut

ratherthemeaningaroundthemedicaltreatment...

There-fore,itmightbetimetolimittheuseofthetermplacebo

effecttothosesituations inwhich inert(dummy)medical

treatmentsaregiven.However,itisworthnotingthatevenif

aplaceboisgiven,thereisnosuchthingasaplaceboeffect,

sincethistermdeﬂectsourgazefromwhatisreally

impor-tant(themeaningandthemeaning-inducedexpectations)

andaimsit atwhatis not(theinertpillsand,ingeneral,

theinertmedicaltreatments).’’16

Conclusions

I,of course,agreefullywithBenedetti.Aplacebo,unless

madebyanincompetent pharmacist,isinert.Thatmeans

it doesn’t do anything. But we often ﬁnd that things do

happen to people after placebos are administered. The

one thing we can know for sure is that these effects

are NOT due to the placebo. But as these long time

favorite studies of mine (plus others) show, the

mean-ings of drugs or other treatments to patients, clinicians,

families, friends, community, are supremely important

here.

It islong past timeto giveupona ﬂawednotion, the

‘‘placeboeffect’’orthe‘‘placeboresponse.’’Peopledon’t

respondtoplacebos.Theyrespondtowhatplacebos,drugs,

clinicians,andothersmeanandwhentherearenoplacebos

inthe study,they respondtothe person whobrings it to

them.

Peoplerespondtowhatweknow,think,andfeel...

People respond to what we are told, believe and

know...

People respond to their various cultural

backgrounds...

They respondto language,to caring,to culture, to

community,tohistory.Inaword,theyrespondto

mean-ingfulphenomena.

Conﬂictofintereststatement:nonedeclared.

Acknowledgements

SpecialthankstoDr.Prof.RobertJütteandtheRobertBosch

Stiftungfor supporting the fascinatingconference at Villa

LaCollina, at Lake Como,in May 2012; thanks toall the

participantswhovigorouslydiscussedtheideaspresentedin

thispaper.AlsospecialthankstoIrvingKirschfordiscussion

andsupport;andtoHowardFieldsforhisreminiscencesof

hisparticipationinoneofthelandmarkstudiesconsidered

here.ForJasonGold,mybeekeeper.

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