Placebo (medicine)
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Placebos in clinical trials
Placebo simulators are a standard control component of most clinical trials which attempt to make some sort of quantitative assessment of the efficacy of new medicinal drugs;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). 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 randomly selected,David (1949), p.28:
equally matched trial groups: 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
- 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).
- 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).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".
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 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.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.
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, 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 gastric or 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".These results were confirmed by the direct post-treatment endoscopy of the treated area. 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.Moerman (1983), p.15.
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".Moerman (1983), p.13.
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".Moerman (1983), p.14.
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.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).
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 researchFor example: Ploghaus, Becerra, Borras & Borsook (2003); Finniss & Benedetti (2005); Benedetti, Mayberg, Wager, Stohler & Zubieta (2005). 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 conception of the limits of endogenous human control";Benedetti, Mayberg, Wager, Stohler & Zubieta (2005), p.10390. and, in recent times, researchers in a number of different areas have demonstrated the presence of biological substrates, unique brain processes, and neurological correlates for the "placebo response":
- 2001: de la Fuente-Fernández and colleagues reported their 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 analgesia.
- 2002: Mayberg and colleagues reported their PET scan findings on test subjects with 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.
Ethical concerns
Bioethicists 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 human experimentation conducted by 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,[link] 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".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. 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.
- 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.