Placebos from St Jerome to functional MRIPlacebos from St Jerome to functional MRIor or ccan we double our gas mileage if we wished for it hard enough?

W Wallis Middlemore Medical Society Millbrook W Wallis Middlemore Medical Society Millbrook 20112011

Placebo DefinitionsPlacebo Definitions A placeboA placebo (L. “ I shall please”) is an (L. “ I shall please”) is an inertinert

substance or substance or shamsham medical intervention, medical intervention, which by which by definition cannot have therapeutic definition cannot have therapeutic effecteffect, but it can, but it can

When it does it is termed the When it does it is termed the placebo effectplacebo effect

Pure placebosPure placebos are sugar or talc pill are sugar or talc pill

Impure placebosImpure placebos are vitamins, antibiotics, are vitamins, antibiotics, physiotherapy, manipulations, physiotherapy, manipulations, acupuncture,etc when ritualistically acupuncture,etc when ritualistically prescribed by a doctor without expectation prescribed by a doctor without expectation of benefit. That is to please patient (and of benefit. That is to please patient (and doctor) doctor)

A nocebo A nocebo ( L.”to harm’)( L.”to harm’) is the unwanted side is the unwanted side effect of a placeboeffect of a placebo

How placebos are UsedHow placebos are Used In In medical researchmedical research, placebos are given as , placebos are given as

control control treatments and depend upon treatments and depend upon deception. These are employed in deception. These are employed in randomisedrandomised controlled medical trials (RCT)controlled medical trials (RCT), where a , where a presumably effective treatment is compared presumably effective treatment is compared against a placebo. That is to see if studied against a placebo. That is to see if studied treatment works better than no treatment. treatment works better than no treatment.

Commonly employed research placebos are Commonly employed research placebos are inert tablets and injectionsinert tablets and injections, and , and sham forms sham forms of: surgery,of: surgery, acupuncture, electrical acupuncture, electrical stimulation, spinal manipulationstimulation, spinal manipulation, and other , and other procedures based on false information. procedures based on false information.

Outside of research trials, doctors (unless they Outside of research trials, doctors (unless they are pathologists) like using placebosare pathologists) like using placebos..

..

Doctors like using placebosDoctors like using placebos

Doctors like using placebosDoctors like using placebos

In one survey In one survey 86%86% of GPs and of GPs and 54%54% of specialists of specialists knowinglyknowingly prescribed prescribed placebos, usually impure ones, such as physiotherapy, antibiotics, placebos, usually impure ones, such as physiotherapy, antibiotics, antidepressants, vitamins and so on, not because they expect them to work antidepressants, vitamins and so on, not because they expect them to work but rather to avoid conflict and give patients what doctors thinks they but rather to avoid conflict and give patients what doctors thinks they want.want.

Placebos Have been with us since prehistoric timesPlacebos Have been with us since prehistoric times

Placebo : Historical AspectsPlacebo : Historical Aspects

St Jerome (c347-420) introduced the term placebo to Christianity when translating the Hebrew Bile to

vulgate but “lost in translation”

Medieval placebo mourners

Chaucer 1386Squire Placebo the sycophant

Many other well-publicized exorcisms with exposures to sham religious objects are recorded. For example, in 1565, King Charles IX arranged to meet a notorious demoniac who testified to Protestant ungodliness. This demoniac had been tested with ordinary wine deceptively mixed with holy water. Her violent reactions to the concealed holy water confirmed to observers that her possession was genuine. Later, however, when other more sceptical investigators repeated the experiment, she could not distinguish genuine from fake exposures.

Placebo Controlled Trials are not New

Used by the early Church To expose fake possession by the devil

(as depicted by Goya)

The first relatively modern use of placebo was by Benjamin Franklin in Paris, in 1784, to discredit the quack and high society hypnotist Mesmer. Mesmer would transform inanimate objects with “animal magnetism” that had extraordinary effects upon his customers. Franklin showed that such people had the same reaction to similar objects not bestowed with these properties

“Well done is better than well said.”

Placebos entered mainstream medicine in the 18Placebos entered mainstream medicine in the 18thth and 19th centuries and were intentionally used to and 19th centuries and were intentionally used to deceive patients into feeling better.deceive patients into feeling better.

There have always been There have always been doubtersdoubters

The great sceptic, HL Menken, on his visit to the shrine The great sceptic, HL Menken, on his visit to the shrine of Lourdes, after contemplating piles of wheelchairs, of Lourdes, after contemplating piles of wheelchairs, crutches, and walking sticks - observed: crutches, and walking sticks - observed: “The one thing “The one thing I did not see were glass eyes, wooden legs, and wigs.”I did not see were glass eyes, wooden legs, and wigs.”

.

Wall Street uses placebosWall Street uses placebos

Politicians use of PlacebosPoliticians use of PlacebosThe Republicans’ view of Obama’s economic stimulus The Republicans’ view of Obama’s economic stimulus

packagepackage

Placebos in Modern MedicinePlacebos in Modern Medicine After the Second World War, the placebo gained wide recognition After the Second World War, the placebo gained wide recognition

because because of of randomised controlled trials (RCTrandomised controlled trials (RCT).).

RCTs are a way of testing a therapy in which, in addition to a group of subjects that RCTs are a way of testing a therapy in which, in addition to a group of subjects that receive the treatment to be evaluated, a separate receive the treatment to be evaluated, a separate control group receives a "placebo" treatment which is specifically designed to have no real effect. Placebos are mosttreatment which is specifically designed to have no real effect. Placebos are mostcommonly used in commonly used in blinded trials, where subjects do not know whether they are receivingreal or placebo treatment.real or placebo treatment.

Placebos in Modern MedicinePlacebos in Modern MedicineDesign of single-blind or double-blind randomised placebo-controlled trialsDesign of single-blind or double-blind randomised placebo-controlled trials

Treatment arm

˅

Placebo arm

˅

Placebo

˂ and nocebo

effects

Treatment Effects and ˃side effects

People with post dental surgery pain >

Randomly assigned to either morphine or placebo. Both patient and

doctor > unaware (both “blind”) of which was used.

Outcome judged by observers unaware of

which treatment used > effects and side effects of: morphine ˄ vs. ˄ placebo Note that both the morphine and the placebo effects are reversed by a morphine antidote

(naloxone)

Example of double-blind controlled trial of a drug vs. a placebo

People with low back pain >

Randomly assigned to either traditional ChineseAcupuncture (L) or “sham”

>Acupuncture (R) . Patients unaware of which was used.Single-blind because only patient is unaware, not the acupuncturist.

Outcome judged by observers unaware ofwhich treatment used

> effects and side effects of “real” ^ acupuncture vs. “sham”

^acupuncture

Example of single-blind controlled trial of a procedure vs. a sham procedure

Not all Placebo controlled Trials are with “inert” Not all Placebo controlled Trials are with “inert” substancessubstances

Sham surgery for Parkinson’s and Comparing leeches to Voltaren

What is the “true” placebo effect?What is the “true” placebo effect?First we need to First we need to removeremove confounding confounding factors factors

natural course of the diseasenatural course of the disease fluctuations in symptomsfluctuations in symptoms regression towards the meanregression towards the mean The effect of other medications.The effect of other medications. Reporting bias by doctor or patientReporting bias by doctor or patient

The placebo effect minus confounding factors = “true” The placebo effect minus confounding factors = “true” placebo effectplacebo effect

The confounding factors do not explain all the The confounding factors do not explain all the phenomenology phenomenology

of the placebo effect.of the placebo effect.

They do not take into account the psychobiological They do not take into account the psychobiological effect of therapeutic milieu (doctor-patient effect of therapeutic milieu (doctor-patient relationship) and the placebo’s capacity to produce relationship) and the placebo’s capacity to produce genuine physiological changes. A placebo may be inert genuine physiological changes. A placebo may be inert but the surrounding psychosocial circumstances are but the surrounding psychosocial circumstances are notnot

How does placebo effect work ?How does placebo effect work ?The psychobiological effects and how to remove The psychobiological effects and how to remove

themthem

Expectation and conditioning drive the “true” Expectation and conditioning drive the “true” placebo effectplacebo effect

ExpectationExpectation means what the patient is expecting. An analgesic means what the patient is expecting. An analgesic cream, described as the most powerful available, is more cream, described as the most powerful available, is more effective than an ordinary one, when in fact both are placebos. effective than an ordinary one, when in fact both are placebos. Colour helps.Colour helps.

ExpectationExpectation is increased by ritualis increased by ritual. That is, the placebo . That is, the placebo becomes more effective if the ritual surrounding the procedure becomes more effective if the ritual surrounding the procedure (such as elaborate sham acupuncture) and supportive-(such as elaborate sham acupuncture) and supportive-practitioner relationships intensify. practitioner relationships intensify.

ExpectationExpectation can be can be incrementally incrementally addedadded in a manner in a manner resembling a graded drug dose escalationresembling a graded drug dose escalation

Doctors’ appearance and behaviour enhance Doctors’ appearance and behaviour enhance both the placebo and nocebo effects both the placebo and nocebo effects

expectationexpectation

good

BAD

Pavlovian Pavlovian Conditioning Conditioning (dog, ring bell, feed, (dog, ring bell, feed, salivate and so on) amplifies the placebo salivate and so on) amplifies the placebo

effecteffect

When placebos are alternated with effective When placebos are alternated with effective medicationsmedications

bothboth the placebos and the medications work better. the placebos and the medications work better.

i.e. morphine i.e. morphine – placebo– placebo – morphine – – morphine – placeboplacebo- morphine- morphine

ConditioningConditioning works in works in both mice and men.both mice and men.

Conditioning put to good useConditioning put to good usetreatment of psoriasis with steroid creamtreatment of psoriasis with steroid cream

full daily dose, alternate placebo-steroid, and gradually full daily dose, alternate placebo-steroid, and gradually reducing steroid dose vs. relapse ratereducing steroid dose vs. relapse rate

Objective placebo effects on Objective placebo effects on brain imagingbrain imaging

Placebos have powerful objective Placebos have powerful objective effects on brain function as seen effects on brain function as seen on brain imaging. on brain imaging.

Placebos analgesia has the same Placebos analgesia has the same effect on sophisticated brain effect on sophisticated brain imaging as opioid drugsimaging as opioid drugs..

Placebo analgesia is reversed by Placebo analgesia is reversed by the opioid antidote naloxone.the opioid antidote naloxone.

Objective placebo effects on brain Objective placebo effects on brain imagingimaging

Placebo analgesic produces identical response to opioid. Reversed by naloxone

˂

Placebo produces identical response In Parkinson's diseaseTo levodopa

˂

Placebos “work” even when Placebos “work” even when patients in RCTs are told that they patients in RCTs are told that they

are receiving themare receiving themWelcome to the home of the

original Obecalp®The first consumer placebo

utilizing pharmaceutical grade

ingredientsavailable for sale at retail

locations around the country.

How does one tell if placebos work How does one tell if placebos work ??

˂ 4. Covert use of placebo

First remove expectation conditioning, and confounding factors . How does one remove expectation ?By 4 strategies :

2. Using cross over trial design

3. Using an untreated control to compare to the placebo

1. Use objective outcomes

Example of good trial design meeting criteria Example of good trial design meeting criteria 1-31-3

objective outcome (FEVobjective outcome (FEV11), cross-over design, and ), cross-over design, and untreated controluntreated control

Double-blind, Double-blind, crossovercrossover pilot study, 46 patients with asthma assigned to active pilot study, 46 patients with asthma assigned to active treatment with an albuterol inhaler, a placebo inhaler, sham acupuncture, and no treatment with an albuterol inhaler, a placebo inhaler, sham acupuncture, and no treatment. treatment. Objective outcome was FEV1Objective outcome was FEV1. . Subjective outcome is what patients Subjective outcome is what patients reportedreported..

Wechsler,M et.al.Active Albuterol or Placebo, Sham Acupuncture, or No Intervention in AsthmaWechsler,M et.al.Active Albuterol or Placebo, Sham Acupuncture, or No Intervention in AsthmaMichael E. N Engl J Med 2011;365:119-26Michael E. N Engl J Med 2011;365:119-26

How well would this chap respond to a How well would this chap respond to a placebo when he wakes up ?placebo when he wakes up ?

Thoracotomy

Covert PlaceboCovert Placebo

Post thoracotomy patients given basal iv saline infusion (placebo) for 3 days. Post thoracotomy patients given basal iv saline infusion (placebo) for 3 days.

1/3 told iv was a “powerful pain reliever’ (1/3 told iv was a “powerful pain reliever’ (placeboplacebo))1/3 told it 1/3 told it mightmight be a” placebo or a powerful pain reliever” ( be a” placebo or a powerful pain reliever” (double-blind groupdouble-blind group))1/3 told nothing (1/3 told nothing (covert placebocovert placebo) )

That is all received the same placebo but 2 were given expectation, 1 told nothingThat is all received the same placebo but 2 were given expectation, 1 told nothing

All patients given access to buprenorphine as requested (prn)All patients given access to buprenorphine as requested (prn)

Record of total mg of buprenorphine used in each of 3 groups recorded Record of total mg of buprenorphine used in each of 3 groups recorded

mg buprenorphinemg buprenorphine

““powerful pain reliever’ (powerful pain reliever’ (placeboplacebo) 7.5 mg) 7.5 mg

mightmight be a” placebo ( be a” placebo (double-blind group) double-blind group) 9.15 mg9.15 mg

Told nothing (Told nothing (covert placebocovert placebo) 11.55 mg) 11.55 mg

Covert administration of placebo eliminates it the placebo effectCovert administration of placebo eliminates it the placebo effect

Pollo A,et al Response expectancies in placebo analgesia and their clinical relevance. Pain. 2001:9377-84. Ju

SummarySummaryDo placebos work?Do placebos work?Well, Well, yesyes and and nono..

YesYes,, if there is if there is conditioningconditioning, , expectationexpectation, and , and the outcome is the outcome is subjectivesubjective..

No,No, if one if one removesremoves conditioning, expectation, conditioning, expectation, and uses and uses objective objective outcomes; particularly, when a outcomes; particularly, when a placebo is compared to an placebo is compared to an untreated cohortuntreated cohort

So you cannot So you cannot double your gas mileage if you wish for it hard enough or find glass eyes, artificial legs, and wigs in Lourdes.