Placebo-controlled study

Placebo-controlled studies are a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed to have no real effect. Placebos are most commonly used in blinded trials, where subjects do not know whether they are receiving real or placebo treatment. Often, there is also a further "natural history" group that does not receive any treatment at all. The purpose of the placebo group is to account for the placebo effect, that is, effects from treatment that do not depend on the treatment itself. Such factors include knowing one is receiving treatment, attention from health care professionals, and the expectations of a treatment's effectiveness by those running the research study. Without a placebo group to compare against, it is not possible to know whether the treatment itself had any effect. Patients frequently show improvement even when given a sham or "fake" treatment. Such intentionally inert placebo treatments can take many forms, such as a pill containing only sugar, a surgery where nothing efficacious is actually done (just an incision and sometimes some minor touching or handling of the underlying structures), or a medical device (such as an ultrasound machine) that is not actually turned on. Also, due to the body's natural healing ability and statistical effects such as regression to the mean, many patients will get better even when given no treatment at all. Thus, the relevant question when assessing a treatment is not "does the treatment work?" but "does the treatment work better than a placebo treatment, or no treatment at all?" Therefore, the use of placebos is a standard control component of most clinical trials, which attempt to make some sort of quantitative assessment of the efficacy of medicinal drugs or treatments. Such a test or clinical trial is called a placebo-controlled study, and its control is of the negative type. A study whose control is a previously tested treatment, rather than no treatment, is called a positive-control study because its control is of the positive type. Government regulatory agencies approve new drugs only after tests establish not only that patients respond to them, but also that their effect is greater than that of a placebo (by way of affecting more patients, by affecting responders more strongly, or both). Methodology Single Blind trials In a single-blind experiment, information that could introduce bias or otherwise skew the result is withheld from the participants. In most cases, the subjects do not know if they are receiving an active treatment or a placebo. Blinding an experiment reduces bias and controls for the placebo effect. A classic example of a single-blind experiment is the Pepsi Challenge. A researcher, often a marketing person, prepares cups of cola. One cup is filled with Pepsi, while the other is filled with Coca-Cola. The researcher knows which soda is in which cup but does not reveal this information to the subject. The subject then tries both sodas and is asked which they prefer. In practice, blinding an experiment can be very difficult. The Pepsi Challenge, for example, is only blind if the subjects are unable to discriminate between the two sodas by taste. In some cases, an active placebo may blind an experiment better than a passive placebo. The use of a placebo control is not the only way to blind an experiment. For example, in a blind study on the effectiveness of prayer, the participants are not told who has and has not had prayers said for them. To test the effect of changing the frequency of fluorescent lights on headaches, the light fittings are changed at night in the absence of the office workers. Double-blind trials Because a doctor's belief in the value of a treatment can affect his or her behavior, and thus what his or her patient believes, clinical trials are usually conducted in "double-blind" manner: that is, not only are the patients made unaware when they are receiving a placebo, the doctors are made unaware too. Natural history groups 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, equally matched trial groups, David wrote: "... 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.". The Active drug group (A): who receive the active test drug. The Placebo drug group (P): who receive a placebo drug that simulates the active drug. 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: The efficacy of the active drug's treatment: the difference between A and NH (i.e., A-NH). The efficacy of the active drug's active ingredient: the difference between A and P (i.e., A-P). The magnitude of the placebo response: the difference between P and NH (i.e., P-NH). It is a matter of interpretation whether the value of P-NH indicates the efficacy of the entire treatment process or the magnitude of the "placebo response". The results of these comparisons then determine whether or not a particular drug is considered efficacious. Indexing 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 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. However, in particular cases such as the use of Cimetidine to treat ulcers, a significant level of placebo response can also prove to be an index of how much the treatment has been directed at a wrong target. Implementation issues Adherence The Coronary Drug Project was intended to study the safety and effectiveness of drugs for long-term treatment of coronary heart disease in men. Those in the placebo group who adhered to the placebo treatment (took the placebo regularly as instructed) showed nearly half the mortality rate as those who were not adherent. A similar study of women similarly found survival was nearly 2.5 times greater for those who adhered to their placebo. This apparent placebo effect may have occurred because: Adhering to the protocol had a psychological effect, i.e. genuine placebo effect. People who were already healthier were more able or more inclined to follow the protocol. Compliant people were more diligent and health-conscious in all aspects of their lives. Recognition Appropriate use of a placebo in a clinical trial often requires or at least benefits from a double-blind study design, which means that neither the experimenters nor the subjects know which subjects are in the "test group" and which are in the "control group". This creates a problem in creating placebos that can be mistaken for active treatments. It therefore can be necessary to use a psychoactive placebo, a drug that produces physiological effects that encourage the belief in the control groups that they have received an active drug. A psychoactive placebo was used in the Marsh Chapel Experiment, a double-blind study in which the experimental group received the psychedelic substance psilocybin while the control group received a large dose of niacin, a substance that produces noticeable physical effects intended to lead the control subjects to believe they had received the psychoactive drug. The term "psychoactive placebo" is rare in the literature; but, when it is used, it always denotes a placebo of this type. For example, "Neither the experienced investigator nor the naive [subject] is easily fooled on the matter of whether he has received a psychedelic substance or merely a psychoactive placebo such as amphetamine." History James Lind and scurvy In 1747, James Lind (1716–1794), the ship's doctor on HMS Salisbury, conducted the first clinical trial when he investigated the efficacy of citrus fruit in cases of scurvy. He randomly divided twelve scurvy patients, whose "cases were as similar as I could have them", into six pairs. Each pair was given a different remedy. According to Lind’s 1753 Treatise on the Scurvy in Three Parts Containing an Inquiry into the Nature, Causes, and Cure of the Disease, Together with a Critical and Chronological View of what has been Published of the Subject, the remedies were: one quart of cider per day, twenty-five drops of elixir vitriol (sulfuric acid) three times a day, two spoonfuls of vinegar three times a day, a course of sea-water (half a pint every day), two oranges and one lemon each day, and electuary, (a mixture containing garlic, mustard, balsam of Peru, and myrrh). He noted that the pair who had been given the oranges and lemons were so restored to health within six days of treatment that one of them returned to duty, and the other was well enough to attend the rest of the sick. MRC and randomized trials It used to be thought that the first-ever randomized clinical trial was the trial conducted by the Medical Research Council (MRC) in 1948 into the efficacy of streptomycin in the treatment of pulmonary tuberculosis. In this trial, there were two test groups: those "treated by streptomycin and bed-rest", and those "[treated] by bed-rest alone" (the control group). What made this trial novel 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 could be biased, because those admitting each patient knew to which group that patient would be allocated (and so 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 they would occupy). Recently, an earlier MRC trial on the antibiotic patulin on the course of common colds has been suggested to have been the first randomized trial. Another early and until recently overlooked randomized trial was published on strophanthin in a local Finnish journal in 1946. Non-drug treatments "Talking therapies" (such as hypnotherapy, psychotherapy, counseling, and non-drug psychiatry) are now required to have scientific validation by clinical trial. However, there is controversy over what might or might not be an appropriate placebo for such therapeutic treatments. In 2005, the Journal of Clinical Psychology, devoted an issue to the issue of "The Placebo Concept in Psychotherapy" that contained a range of contributions to this question. As the abstract of one paper noted: Unlike within the domain of medicine, in which the logic of placebos is relatively straightforward, the concept of placebo as applied to psychotherapy is fraught with both conceptual and practical problems. References https://en.wikipedia.org/wiki/Placebo-controlled_study Gary T Chiodo,1 Susan W Tolle,2 and Leslie Bevan3 Placebo-controlled trials good science or medical neglect? / West J Med. 2000 Apr; 172(4): 271–273. https://www.cancer.net/research-and-advocacy/clinical-trials/placebos-cancer-clinical-trials By Aliyev F.