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==Placebos in clinical trials==

Placebo simulators are a standard [[Scientific control|control]] component of most [[clinical trial]]s which attempt to make some sort of [[quantitative]] assessment of the efficacy of new medicinal drugs;<ref>It is a view held by many "''that placebo-controlled studies often are designed in such a way that disadvantages the placebo condition''" (Herbert and Gaudino, 2005, pp.788-789).</ref> and, generally speaking, for a drug to be put on the market, it must be significantly more effective than its placebo counterpart.

In recent times, the practice of using an additional, [[natural history group]] as the trial's so-called "''third arm''" has emerged; and trials are conducted using three [[randomized clinical trial|randomly selected]],<ref>David (1949), p.28:
:''…it is necessary to remember the adjective ‘random’ [in the term ‘random sample’] should apply to the method of drawing the sample and not to the sample itself.''</ref> equally matched trial groups:<ref> According to Yoshioka (1998), the first-ever randomized clinical trial was the trial conducted by the [[Medical Research Council]] (1948) into the efficacy of [[streptomycin]] in the treatment of [[pulmonary tuberculosis]].There were two test groups in this trial
:(a) those "''treated by streptomycin and bed-rest''", and
:(b) those "''[treated] by bed-rest alone''" (the control group).
What made this trial exceptional was that the subjects were randomly allocated to their test groups. The up-to-that-time practice was to allocate subjects alternately to each group, based on the order in which they presented for treatment. This practice was considered to be extremely [[Bias (statistics)|biassed]], because those admitting each patient knew to which group that patient would be allocated (and it was considered that the decision to admit or not admit a specific patient might be influenced by the experimenter's knowledge of the nature of their illness, and their knowledge of the group to which the alternate allocation demanded they would occupy).</ref>
:1. The '''Active drug''' group ('''A'''): who receive the active test drug.
:2. The '''Placebo drug''' group ('''P'''): who receive a placebo drug that simulates the active drug.
:3. The '''Natural history''' group ('''NH'''): who receive no treatment of any kind (and whose condition, therefore, is allowed to run its ''natural'' course).

The outcomes within each group are observed, and compared with each other, allowing us to measure:
:1. The efficacy of the active drug's '''treatment''': the difference between '''A''' and '''NH''' (i.e., '''A-NH''').
:2. The efficacy of the entire '''treatment process''' alone: the difference between '''P''' and '''NH''' (i.e., '''P-NH''').
:3. The efficacy of the active drug's '''active ingredient''': the difference between '''A''' and '''P''' (i.e., '''A-P''').
:4. The magnitude of the '''placebo response''': the difference between '''P''' and '''NH''' (i.e., '''P-NH''').<ref>Note that, depending upon the focus of your interest, the value of '''P-NH''' can either indicate the ''efficacy of the entire treatment process'' or the ''magnitude of the "placebo response"''.</ref>

The results of these comparisons then determine whether or not a particular drug is considered efficacious.

In recent times, as the demands for the scientific [[validation]] of the various claims that are made for the efficacy of various so-called "talking therapies" -- such as [[hypnotherapy]], [[psychotherapy]], [[counselling]] and [[psychiatry|non-drug psychiatry]] -- has significantly increased, the issue of what might or might not stand as an appropriate placebo for such therapeutic interventions has become a matter of continuing controversy that has yet to be resolved.<ref>In 2005, the ''Journal of Clinical Psychology'', an eminent peer-reviewed journal (founded in 1945), devoted an entire issue to the question of "''The Placebo Concept in Psychotherapy''", and contained a wide range of articles that made many valuable contributions to this overall discussion.</ref>

===The placebo response as an index===

In certain clinical trials of particular drugs, it may happen that the level of the "placebo responses" manifested by the trial's subjects are either considerably higher or lower (in relation to the "active" drug's effects) than one would expect from other trials of similar drugs.

In these cases, [[Ceteris paribus|with all other things being equal]], it is entirely reasonable to conclude that:
* the degree to which there is a '''considerably higher''' level of "placebo response" than one would expect is an index of the degree to which the drug's ''active ingredient'' is '''not efficacious'''.
* the degree to which there is a '''considerably lower''' level of "placebo response" than one would expect is an index of the degree to which, in some particular way, the ''placebo'' is '''not simulating''' the active drug in an appropriate way.

====The placebo response as a warning signal====

In 1983, [[medical anthropologist]] Daniel Moerman conducted a [[meta-study]] of 31 placebo-controlled trials of the [[gastric acid]] secretion inhibitor drug [[Cimetidine]] in the treatment of [[Peptic ulcer|gastric]] or [[Peptic ulcer|duodenal ulcers]]. His meta-study revealed that the placebo treatments were, in many cases, just as effective in treating ulcers as the active drug: of the 1692 patients treated in the 31 trials, 76% of the 916 treated with the drug were "healed", and 48% of the 776 treated with placebo were "healed".<ref>These results were confirmed by the direct post-treatment [[endoscopy]] of the treated area.</ref> He also found that German placebos were "stronger" than others; and that, overall, different physicians evoked quite different placebo responses in the same clincal trial.<ref>Moerman (1983), p.15.</ref>

Further examination revealed that many of these trials had been conducted in such a way that the gap between the active drugs and the placebo controls was "not because [the trials' constituents] had high drug effectiveness, but because they had low placebo effectiveness".<ref>Moerman (1983), p.13.</ref>

In some trials, placebos were effective in 90% of the cases, whilst in others the placebos were only effective in 10% of the cases. Moerman argues that "what is demonstrated in [these] studies is not enhanced healing in drug groups, but reduced healing in placebo groups".<ref>Moerman (1983), p.14.</ref>

Moerman also noted the results of two studies (one conducted in Germany, the other in Denmark), which examined "ulcer [[relapse]] in healed patients". Each study showed that the rate of relapse amongst those "healed" by the active drug treatment was ''five times'' that of those "healed" by the placebo treatment.<ref>Moerman (1983), pp.14-15. This led Moerman to remark: “we may be able to go so far as to say that while [the active drug] “heals” ulcers, placebo treatment can “cure” ulcer disease” (p.14).</ref>

These results of a 90% placebo response rate, and a placebo-healed relapse rate 20% that of the active drug seems to indicate that the drug ''Cimetidine'' was not effective in inhibiting gastric acid secretion.

However, given our more recent knowledge that the majority of gastric or duodenal ulcers are '''not''' due to excessive gastric acid secretion caused by [[stress]] or [[spicy food]], but are due to the presence of the [[bacterium]] known as [[helicobacter pylori]], it is highly significant that this high response rate and low relapse rate can now be interpreted in a different way: it is indicating that the drug's prescribers had chosen the wrong target (and, as a consequence, the wrong drug) for their therapeutic intervention.

==Biological substrates of the placebo response==

A "placebo response" can amplify, diminish, nullify, reverse or, even, divert the action of an "active" drug.

Because a "placebo response" is just as significant in the case of an "active" drug as it is in the case of an "inert" dummy drug, the more that we can discover about the mechanisms that produce "placebo responses", the more that we can enhance their effectiveness and convert their potential efficacy into actual relief, healing and cure.

Recent research<ref>For example: Ploghaus, Becerra, Borras & Borsook (2003); Finniss & Benedetti (2005); Benedetti, Mayberg, Wager, Stohler & Zubieta (2005).</ref> strongly indicates that a "placebo response" is a complex psychobiological phenomenon, contingent upon the psychosocial context of the subject, that may be due to a wide range of neurobiological mechanisms (with the specific response mechanism differing from circumstance to circumstance).

The very existence of these "placebo responses" strongly suggest that "''we must broaden our [[concept]]ion of the limits of [[endogenous]] human control''";<ref>Benedetti, Mayberg, Wager, Stohler & Zubieta (2005), p.10390.</ref> and, in recent times, researchers in a number of different areas have demonstrated the presence of biological [[substrate]]s, unique brain processes, and [[neurological]] correlates for the "placebo response":
* 2001: de la Fuente-Fernández and colleagues reported their [[Positron emission tomography|'''PET''']] scan findings on test subjects with [[Parkinson's disease]].
* 2002: Petrovic and colleagues reported their '''PET''' scan findings on test subjects in a trial of [[opioid|opioid analgesia]].
* 2002: Mayberg and colleagues reported their '''PET''' scan findings on test subjects with [[Clinical_depression#Major clinical depression|unipolar depression]].
* 2004: Wager and colleagues reported their '''[[fMRI]]''' scan findings on test subjects in a trial of placebo analgesia.
* 2004: Lieberman and colleagues reported their '''PET''' scan findings on test subjects with [[Irritable bowel syndrome]].
* 2006: Bingel and colleagues reported their '''fMRI''' scan findings on test subjects in a trial of placebo analgesia.
* 2006: Zubieta and colleagues reported their '''PET''' scan findings on test subjects in a trial of placebo analgesia.
* 2006: Sarinopoulos and colleagues reported their '''fMRI''' scan findings on test subjects in a trial neural responses to a highly aversive bitter taste.

A complex fMRI-centred study by McClure, et al. (2004) on the brain responses of subjects who had previously expressed a preference for one or other of two famous, almost identical soft drinks,<ref>That is, [[Pepsi]] and [[Coca-Cola|Coke]].</ref> demonstrated that "[[brand]] information", which "significantly influences subjects’ expressed preferences", is processed in an entirely different brain area from that which is activated in blind taste tests (when their "preferences are determined solely from sensory information").<ref>McClure, Jian, Tomlin, Cypert, Montague & Montague (2004), p.385.</ref> This supports the claim that there are unconscious brain processes that activate the "placebo response".

==Ethical concerns==

[[Bioethicist]]s have raised many concerns about the use of placebos in both clinical medicine and medical research. Most of these concerns have been addressed in the modern conventions for the use of placebos in research; however, some issues remain subject to debate.

From the time of the [[Hippocratic Oath]] questions of the ethics of medical practice have been widely discussed, and codes of practice have been gradually developed as a response to advances in scientific medicine.

The '''[[Nuremberg Code]]''', which was issued in August 1947, as a consequence of the so-called [[Doctors' Trial]] which examined the outrageous [[Nazi human experimentation|human experimentation]] conducted by [[Nazism|Nazi]] doctors during [[World War II]], offers ten principles for legitimate medical research, including [[informed consent]], absence of [[coercion]], and [[beneficence]] towards experiment participants.

In 1964, the [[World Medical Association]] issued the '''[[Declaration of Helsinki]]''',[http://www.wma.net/e/policy/b3.htm] which specifically limited its directives to health research by physicians, and emphasized a number of additional conditions in circumstances where "''medical research is combined with medical care''".<ref>The significant difference between the 1947 '''Nuremberg Code''' and the 1964 '''Declaration of Helsinki''' is that the first was a set of principles that was ''suggested'' '''to''' the medical profession by the "Doctors’ Trial" judges, whilst the second was ''imposed'' '''by''' the medical profession upon itself.</ref> Paragraph 29 of the Declaration makes specific mention of placebos:

:''29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.''

In 2002, World Medical Association issued the following elaborative announcement:
:''Note of clarification on paragraph 29 of the WMA Declaration of Helsinki''
:''The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:''
::''— Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or''
::''— Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.''
:''All other provisions of the Declaration of Helsinki must be adhered to, especially the need for appropriate ethical and scientific review.''

In addition to the requirement for informed consent from all drug-trial participants, it is also standard practice to inform all test subjects that they may receive the drug being tested or that they may receive the placebo.

==See also==
{{col-begin}}
{{col-break}}
* [[Adverse effect (medicine)]]
* [[Autosuggestion]]
* [[Belief]]
* [[Charm]]
* [[Clinical trial]]
* [[Culture-specific syndrome]]
* [[Efficacy]]
* [[Expectation]]
* [[Hypnotic susceptibility]]
* [[Intention]]
* [[E. Morton Jellinek]]
{{col-break}}
* [[Medication]]
* [[Nocebo]]
* [[Observer-expectancy effect]]
* [[Optimism]]
* [[Pessimism]]
* [[Pharmacology]]
* [[Placebo (origins of technical term)]]
* [[Post hoc ergo propter hoc]]
* [[Psychosomatic illness]]
* [[Scientific control]]
* [[Self-fulfilling prophecy]]{{col-break}}
* [[Simulator]]
* [[Stigmata]]
* [[Subject-expectancy effect]]
* [[TGN1412]]
* [[Therapeutic effect]]
* [[Thomas theorem]]
* [[Unintended consequence]]
* [[Uses of the term placebo]]
{{col-end}}

==Notes==
<references/>

==References==

* Benedetti, F., Mayberg, H.S., Wager, T.D., Stohler, C.S. & Zubieta, J., "Neurobiological Mechanisms of the Placebo Effect", ''Journal of Neuroscience'', Vol.25, No.45, (November 2005), pp.10390-10402.
* Bingel, U., Lorenz, J., Schoell, E., E. Schoell, Weiller, C. & Büchel, C., "Mechanisms of Placebo Analgesia: rACC Recruitment of a Subcortical Antinociceptive Network", ''Pain'', Vol.120, Nos.1-2, (January 2006), pp.8-15.
* Colloca, L. & Benedetti, F., "Placebos and Painkillers: Is Mind as Real as Matter?", ''Nature Reviews Neuroscience'', Vol.6, No.7, (July 2005), pp.545-552.
* David, F.N., ''Probability Theory for Statistical Methods'', Cambridge University Press, (Cambridge), 1949.
* de la Fuente-Fernández, R., Ruth, T.J., Sossi, V., Schulzer, M., Calne, D.B. & Stoessl, A.J., "Expectation and Dopamine Release: Mechanism of the Placebo Effect in Parkinson's Disease", ''Science'', Vol.293, No.5532, (10 August 2001), pp.1164-1166.
* De Pascalis, V., Chiaradia, C. & Carotenuto, E., "The Contribution of Suggestibility and Expectation to Placebo Analgesia Phenomenon in an Experimental Setting", ''Pain'', Vol.96, No.3, (April 2002), pp.393-402.
* Finniss, D.G. & Benedetti, F., "Mechanisms of the Placebo Response and Their Impact on Clinical Trials and Clinical Practice", ''Pain'', Vol.114, Nos.1-2, (March 2005), pp.3-6.
* Herbert, J.D. & Gaudiano, B.A., "Introduction to the Special Issue on the Placebo Concept in Psychotherapy", ''Journal of Clinical Psychology'', Vol.61, No.7, (July 2005), pp.787-790.
* ''Journal of Clinical Psychology'', Vol.61, No.7, (July 2005): Special Issue on ''The Placebo Concept in Psychotherapy''.
* Lieberman, M.D., Jarcho, J.M., Berman, S., Naliboff, B.D., Suyenobu, B.Y., Mandelkern, M. & Mayer, E.A., "The Neural Correlates of Placebo Effects: A Disruption Account", ''NeuroImage'', Vol.22, No.1, (May 2004), pp.447-455.
* Mayberg, H.S., Silva, J.A., Brannan, S.K., Tekell, J.L., Mahurin, R.K., McGinnis, S. & Jerabek, P.A., "The Functional Neuroanatomy of the Placebo Effect", ''American Journal of Psychiatry'', Vol.159, No.5, (May 2002), pp.728-737.
* McClure, S.M., Jian, L., Tomlin, D., Cypert, K.S., Montague, L.M. & Montague, P.R., "Neural Correlates of Behavioral Preference for Culturally Familiar Drinks", ''Neuron'', Vol.44, No.2, (14 October 2004), pp.379-387.
* Medical Research Council, "Streptomycin Treatment of Pulmonary Tuberculosis: A Medical Research Council Investigation", ''British Medical Journal'', No.4582, (30 October 1948), pp.769-782.
* Moerman, D.E., "General Medical Effectiveness and Human Biology: Placebo Effects in the Treatment of Ulcer Disease", ''Medical Anthropology Quarterly'', Vol.14, No.4, (August 1983), pp.3, 13-16.
* Petrovic, P., Kalso, E., Petersson, K.M. & Ingvar, M., "Placebo and Opioid Analgesia-Imaging a Shared Neuronal Network", ''Science'', Vol.295, No.5560, (1 March 2002), pp.1737-1740.
* Ploghaus, A., Becerra, L., Borras, C. & Borsook, D., "Neural Circuitry Underlying Pain Modulation: Expectation, Hypnosis, Placebo", ''Trends in Cognitive Sciences'', Vol.7, No.5, (May 2003), pp.197-200.
* Sarinopoulos, I., Dixon, G.E., Short, S.J., Davidson, R.J. & Nitschke, J.B., "Brain Mechanisms of Expectation Associated with Insula and Amygdala Response to Aversive Taste: Implications for Placebo", ''Brain, Behavior, and Immunity'', Vol.20, No.2, (March 2006), pp.120-132.
* Wager, T.D., Rilling, J.K., Smith, E.E, Sokolik, A., Casey, K.L., Davidson, R.J., Kosslyn, S.M., Rose, R.M. & Cohen, J.D., "Placebo-Induced Changes in fMRI in the Anticipation and Experience of Pain", ''Science'', Vol.303, No.5661, (20 February 2004), pp.1162-1167.
* Yoshioka, A., "Use of Randomisation in the Medical Research Council’s Clinical Trial of Streptomycin in Pulmonary Tuberculosis in the 1940s", ''British Medical Journal'', Vol.317, No.7167, (31 October 1998), pp.1220–1223.
* Zubieta, J., Yau, W., Scott, D.J. & Stohler, C.S., "Belief or Need? Accounting for Individual Variations in the Neurochemistry of the Placebo Effect", ''Brain, Behavior, and Immunity'', Vol.20, No.1, (January 2006), pp.15-26.

==Additional references==
* Charcot, J.M., "The Faith-Cure", ''The New Review'', Vol.VIII, (January 1893), pp.18-31.
* Di Blasi, Z., Harkness, E., Edzard, E., Georgiou, A. & Kleijnen, J., "Influence of Context Effects on Health Outcomes: A Systematic Review", ''The Lancet'', Vol.357, No.9258, (10 March 2001), pp.757-762.
* Goddard, H.H., "The Effects of Mind on Body as Evidenced by Faith Cures", ''American Journal of Psychology'', Vol.10, No.3, (April 1899), pp.431-502.
* Hahn, R.A. & Kleinman, A, "Belief as Pathogen, Belief as Medicine: "Voodoo Death" and the "Placebo Phenomenon" in Anthropological Perspective", ''Medical Anthropology Quarterly'', Vol.14, No.4, (August 1983), pp.3, 16-19.
* Houston, W.R., "The Doctor Himself as a Therapeutic Agent", ''Annals of Internal Medicine'', Vol.11, No.8, (February 1938), pp.1416-1425.
* Kaptchuk, T.J., "Intentional Ignorance: a History of Blind Assessment and Placebo Controls in Medicine", ''Bulletin of the History of Medicine'', Vol.72, No.3, (Fall 1998), pp.389-433.
* Kirsch, I., "Response Expectancy as a Determinant of Experience and Behavior", ''American Psychologist'', Vol.40, No.11, (November 1985), pp.1189-1202.
* Kirsch, I., "Response Expectancy Theory and Application: A Decennial Review", ''Applied and Preventive Psychology'', Vol.6, No.2, (Spring 1997), pp.69-79.
* Lorenz, J., Hauck, M., Paura, R.C., Nakamura, Y., Zimmermann, R., Bromm, B. & Engela, A.K., "Cortical Correlates of False Expectations During Pain Intensity Judgments — A Possible Manifestation of Placebo/Nocebo Cognitions", ''Brain, Behavior, and Immunity'', Vol.19, No.4, (July 2005), pp.283-295.
* McGlashan, T.H., Evans, F.J. & Orne, M.T., "The Nature of Hypnotic Analgesia and Placebo Response to Experimental Pain", ''Psychosomatic Medicine'', Vol.31, No.3, (May-June 1969), pp.227-246.
* Merton, R.K., "The Unanticipated Consequences of Purposive Social Action", ''American Sociological Review'', Vol.1, No.6, (December 1936), pp.894-904. [http://www.compilerpress.atfreeweb.com/Anno%20Merton%20Unintended.htm]
* Miller, F.G., "William James, Faith, and the Placebo Effect", ''Perspectives in Biology and Medicine'', Vol.48, No.2, (Spring 2005), pp.273-281.
* Miller, F.G., "Sham Surgery: An Ethical Analysis", ''The American Journal of Bioethics'', Vol.3, No.4, (Fall 2003), pp.41-48.
* Perlman, L, "Nonspecific, Unintended, and Serendipitous Effects in Psychotherapy", ''Professional Psychology: Research and Practice'', Vol.32, No.3, (June 2001), pp.283–288.
* Pyysiäinen, I., "Mind and Miracles", ''Zygon'', Vol.37, No.3, (September 2002), pp.729-740.
* Shapiro, A.K., "A Contribution to a History of the Placebo Effect", ''Behavioral Science'', Vol.5, No.2 (April 1960) pp.109-135.
* Shapiro, A.K., "Semantics of the Placebo", ''Psychiatric Quarterly'', Vol.42, No.4, (December 1968), pp.653–695.
* Staats, P., Hekmatb, H. & Staats, A., "Suggestion/Placebo Effects on Pain: Negative as Well as Positive", ''Journal of Pain and Symptom Management'', Vol.15, No.4, (April 1998), pp.235-243.
* Stam, H.J., ''Hypnotic Analgesia and the Placebo Effect: Controlling Ischemic Pain'', (Ph.D. Dissertation), Carleton University, (Ottawa, Canada), 1984.
* Stam, H.J. & Spanos, N., "Hypnotic Analgesia, Placebo Analgesia, and Ischemic Pain: The Effects of Contextual Variables", ''Journal of Abnormal Psychology'', Vol.96, No.4, (November 1987), pp.313–320.
* Stewart-Williams, S. & Podd, J., "The Placebo Effect: Dissolving the Expectancy Versus Conditioning Debate", Psychological Bulletin, Vol.130, No.2, (March 2004), pp.324-340.
* Wilson, I., ''The Bleeding Mind: An Investigation into the Mysterious Phenomenon of Stigmata'', Paladin, (London), 1991.

==External links==

* [http://www.studentbmj.com/issues/02/02/education/12.php What modifies a healing response]

Latest revision as of 10:51, 13 December 2006

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