What is a placebo?
Why placebos are used in pharmaceutical research
The placebo effect
Modern developments and alternatives to placebos
References
Placebos typically serve as a control treatment in clinical trials to determine the efficacy of a novel intervention in a non-biased manner. Despite the widespread use of placebos in pharmaceutical research, it is equally important to consider the role of the ‘placebo effect’ in both research and the clinical treatment of patients.
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What is a placebo?
According to the United States National Cancer Institute (NCI), a placebo is defined as an inactive substance or other intervention that closely resembles and is administered the same way as an active drug or treatment1.
In general, placebos can be classified as ‘pure’ or impure.’ Pure placebos refer to inert substances such as starch, lactose, saline, talc, or dextromaltose, but impure placebos have known pharmacological activities. Some examples of impure placebos include vitamins, minerals, antibacterials, or psychotropic susbtances2.
Typically, placebos are used in clinical trials as a control intervention to evaluate the potential efficacy and safety of a novel treatment. However, current estimates indicate that up to 40% of prescriptions function as a placebo, with one United Kingdom survey indicating that up to 77% of physicians regularly use placebos in their clinical practice.
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Why placebos are used in pharmaceutical research
Double-blind randomized controlled trials (RCTs) are experimental studies that compare the efficacy of an approval-seeking drug to a placebo. The role of the placebo in double-blind RCTs is to provide a nearly identical intervention aside from the active ingredient to confirm the factual efficacy of the intervention as compared to that of a substance with no effect3.
Often considered the ‘gold standard’ for evaluating the efficacy of a pharmacological intervention, these trials provide the best possible opportunity to determine whether an active treatment is effective.
Placebo-controlled RCTs are associated with numerous advantages, including reduced bias due to the blinding of both healthcare providers and patients to ensure that any treatment effect is not influenced by knowledge of whether the patient received the active drug or placebo.
Despite the widespread use of placebos in clinical research, the ethical implications of placebos have remained a central topic of debate in the medical community for several decades. Although many scientists argue that the incorporation of placebos in clinical trials is imperative to ensure the efficacy of a novel medical treatment, others argue that similar study designs that compare the novel treatment to an already existing effective treatment should be utilized to prevent unnecessary pain to the patient4.
‘’Those who reject the use of placebo-controlled trials argue that they violate the therapeutic obligation of physicians to offer optimal care.4”
Importantly, placebos are more restricted in pediatric clinical trials due to the inability of these patients to consent to treatment. However, placebos will be used in children and other vulnerable patients, such as those who have cancer or serious psychiatric diseases, when there is a lack of evidence supporting a particular treatment or when the placebo effect is variable.
The power of the placebo effect - Emma Bryce
The placebo effect
‘’The placebo effect refers to those particular beneficial health changes that are observed after a placebo administration or application, which are attributed to the placebo mechanisms exclusively.”
Whereas the placebo effect is characterized by changes that are specifically attributable to placebo mechanisms, the placebo response consists of all health-related changes that arise from the inactive treatment5. Thus, the placebo response encompasses the placebo effect, as well as the natural tendency of the health condition to improve and the Hawthorne effects of attention and measurement.
Over the past several decades, various clinical trials have been performed to understand better the placebo effect and the potential health impacts of this phenomenon. This research has led to the use of placebos as primary treatment, with open-label placebos (OLPs) like ‘Zeebo Relief Pure Honest Placebo” now available for prescription in an effort to improve the transparency of placebo treatments.
To date, eleven studies have assessed the effect of OLPs in patients as compared to no treatment or treatment as usual, with a significant and medium-sized effect observed due to OLP treatment2.
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Modern developments and alternatives to placebos
During an RCT, the efficacy of a novel treatment is determined by calculating the difference in outcomes between the drug and placebo groups. However, various factors may contribute to the effectiveness of a placebo intervention, including the natural history of the disease, geographical location of the clinical trial, patients' and researchers’ biases, co-interventions, and the placebo effect itself6.
Several methods, including alternative study designs, have been proposed to mitigate the placebo response in RCTs. For example, sequential parallel comparative designs, which are conducted in two stages, reduce the likelihood that a clinical trial will fail due to a lack of separation between the placebo and drug treatment or insufficient power.
Previous studies have indicated that neutralizing patient expectations for the potential therapeutic benefit of an intervention during a clinical trial, particularly in studies that rely on subjective patient-reported outcomes, can mitigate the placebo effect.
Providing patients with guidance on how to accurately report their bodily sensations and subjective responses to treatments can further reduce the placebo response in RCTs.
‘’Implementing effective methods to reduce the placebo response can reduce the time, costs, and efforts involved in bringing new treatments to market, hopefully leading to the increased drug discovery and ultimately higher availability of better treatments for patients.6”
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References
- “Definition of a placebo” [Online]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/placebo.
- von Wernsdorff, M., Loef, M., Tuschen-Caffier, B., & Schmidt, S. (2021). Effects of open-label placebos in clinical trials: a systematic review and meta-analysis. Scientific Reports 11. doi:10.1038/s41598-021-96604-0.
- Severus, E., Laber, E., & Lipkovich, I. (2015). Double-Blind Randomized Placebo-Controlled Trials in the Treatment of Affective Disorders: Problems and Alternatives. Current Treatment Options in Psychology 2; 262-270. doi:10.1007/s40501-015-0050-9.
- Gupta, U., & Verma, M. (2013). Placebo in clinical trials. Perspectives in Clinical Research 4(1); 49-52. doi:10.4103/2229-3485.106383.
- Haflioadottir, S. H., Juhl, C. B., Nielsen, S. M., et al. (2021). Placebo response and effect in randomized clinical trials: meta-research with focus on contextual effects. Trials 22(493). doi:10.1186/s13063-021-05454-8
- Evans, K., Colloca, L., Pecina, M., & Katz, N. (2021). What can be done to control the placebo response in clinical trials? A narrative review. Contemporary Clinical Trials 107. doi:10.1016/j.cct.2021.106503.
Further Reading