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Biomedical Research

Placebos and The Placebo Effect in Clinical Trials

Placebos are drugs or treatments that have no therapeutic value. Despite this, they have shaped modern clinical trials, as well as stirred controversy, all while providing hope for future treatments capitalizing on its beneficial effects.

Introduction

Something as simple as giving a sugar pill or a saline injection has proven to have beneficial effects for a patient. Because while the treatment itself has no therapeutic value, the patient’s belief that they are being medically treated or their trust in the physician can improve symptoms. That improvement of symptoms is called the placebo effect. Placebos come in various forms, and while an ethical controversy is attached to the use of placebos, it can’t be ignored that they play an important part in modern clinical trials and may play a part in future treatments.

Placebos in Clinical Trials

Currently, a drug must outperform a placebo in a clinical investigation and have “substantial evidence of effectiveness” to be approved by the FDA (Katz). However, treatments were not always held to this standard. In the past, placebos were not used in clinical trials or practice, but this changed after it became suspected that some cases of improved symptoms were not because of an effective drug or treatment but because of psychological factors–later identified as the placebo effect. Thus the placebo effect began to be taken into account during clinical trials for new drugs and treatments. Having control groups with placebos is critical in determining whether results are due to the treatment’s effectiveness or the placebo effect. 

Placebos ensure that the results obtained and symptoms reported by participants are due to the drug, and not because of any demand characteristics. The awareness of receiving a drug may result in subjects falsely reporting relief from symptoms of the disease, and not because of the drugs being tested. As a result, while the experimental group receives the drug, a control group is given a placebo that looks identical but is sugar or water-based, to ensure that all results are due to the drug, improving the validity of the study. Furthermore, to avoid researcher bias, most experiments use double-blind trials, where both researchers and participants are unaware of which group receives the placebo. This is optimal, as both the patients’ report of symptoms and the researcher’s analysis is uninfluenced by the knowledge of which participants were in what group, improving the reliability and validity of the study (“Placebo”). 

However, placebos are not limited to drugs or medication, with placebo surgery showing increasing success. Because the simple act of administering anesthesia or making an incision without any further operation being done has proved to play a role in determining the efficacy of procedures and surgeries. For instance, percutaneous coronary intervention (PCI) is done to treat angina- chest pain caused by reduced blood and oxygen reaching the heart, which is often treated by placing a stent to widen arteries. A 2018 ORBITA study questioned the effectiveness of the stent itself. In the study, participants with stable angina were randomly assigned into groups that would receive either PCI or a placebo procedure (where no stent was placed). After six weeks, their heart was put under stress through rigorous exercise, to test out the hypothesis of the placebo effect. The study found that the endpoint times of exercise of participants who had received PCI were no different than those who received the placebo procedure, alluding to the idea that the improvement of symptoms and reported success of PCI may be at least partially attributed to the placebo effect (Al-Lamee).

In the study, three participants in the placebo group experienced major bleeding, and other complications occurred (Al-Lamee). This brings up controversies over placebo surgery and the use of placebos themselves in studies and practice.

Ethical Evaluation

The controversy around placebos in research is because of the ethicality of the procedure itself. Because the participants in clinical trials that receive placebos act as controls, and while they may experience the ‘placebo effect’, they are still denied a drug that may have a higher success rate. In addition, critics argue that clinical trials involving placebo surgery result in unnecessary surgeries that run the same risks as regular procedures, as a cut is still made and anesthesia may still be used (Ford-Martin). For instance, in the ORBITA trial, the three placebo-receiving patients that had major bleeding experienced those risks. However, they only received the placebo procedure and can only experience the placebo effect, instead of the benefits of a stent or other procedures (Al-Lamee). Thus, critics argue that the use of a placebo created unnecessary risks and pain, for almost no benefit.

Therefore, there are guidelines for using placebos in clinical practice, and participant consent is a major focus because failure to obtain consent undermines the trust in a physician-patient relationship, affecting all future treatments for a patient. However, when consent is obtained, the given placebo may help relieve symptoms at least temporarily in situations where there is no well-known treatment. The placebo may even be effective when the patient knows that it will be used but doesn’t know when it was given or what exactly the placebo treatment looked like. 

For instance, in a study that had an open-lid placebo treatment for chronic low back pain, participants in the study were told they were receiving the placebo medication and made aware of its lack of active ingredients. Part of the group then continued the usual treatment for chronic low back pain, while another group also took the placebo medication as well as usual treatment. Participants reported their pain intensity by rating their pain levels on a scale of 0-10, in addition to rating difficulties in completing daily activities. At the end of the study, participants who had received the placebo reported a 30% reduction in usual pain levels despite being aware of the placebo and its effect, or lack thereof (Carvalho). While it may not be true for every case or condition, the placebo effect may still work even when patients are aware of its presence.

Conclusion

For all its controversies and debates on effectiveness, the placebo has shown to have a significant impact on treating patients for various conditions. A systematic review focusing on the effectiveness of placebo treatments for migraine prophylaxis showed 58% responded positively to sham surgery, and 22% responded positively to oral placebo medicine. Those that responded positively to the placebo treatments experienced a reduction in migraine frequency of at least 50% (Meissner).

The use of placebos has helped determine the efficacy of medications and procedures during clinical trials. The positive effects shown by placebos provide hope that the phenomenon known as the placebo effect can be developed into a viable form of treatment in the future. Therefore, despite our limited understanding of the phenomenon and the constant debate on its ethicality, the effectiveness of placebos cannot be questioned; and its use in clinical trials ensures that all drugs, procedures, and treatments are fully understood, before being introduced to the public.

Michelle Li, Youth Medical Journal 2020

References

Al-Lamee, Rasha et al. “Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial.” Lancet (London, England) vol. 391,10115 (2018): 31-40. DOI:10.1016/S0140-6736(17)32714-9

Carvalho, Cláudia et al. “Open-label placebo treatment in chronic low back pain: a randomized controlled trial.” PAIN vol. 157,12 (2016): 2766-2772. DOI: 10.1097/j.pain.0000000000000700

Ford-Martin, Paula, et al. “Placebo Effect.” The Gale Encyclopedia of Alternative Medicine, edited by Deirdre S. Hiam, 5th ed., vol. 4, Gale, 2020, pp. 2101-03. Gale Health and Wellness, link.gale.com/apps/doc/CX7947800689/HWRC?u=mlin_m_newtnsh&sid=HWRC&xid=8c95ff85. Accessed 31 Oct. 2020.

Katz, Russell. “FDA: evidentiary standards for drug development and approval.” NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics vol. 1,3 (2004): 307-16. DOI:10.1602/neurorx.1.3.307

Meissner, Karin et al. “Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis.” JAMA internal medicine vol. 173,21 (2013): 1941-51. DOI:10.1001/jamainternmed.2013.10391

“Placebo.” The Gale Encyclopedia of Science, edited by K. Lee Lerner and Brenda Wilmoth Lerner, 5th ed., Gale, 2014. Gale in Context: Science, link.gale.com/apps/doc/CV2644031732/SCIC?u=mlin_m_newtnsh&sid=SCIC&xid=571744c6. Accessed 31 Oct. 2020.

“Placebo Effect.” The Gale Encyclopedia of Psychology, edited by Jacqueline L. Longe, 3rd ed., vol. 2, Gale, 2016, p. 895. Gale in Context: Science, link.gale.com/apps/doc/CX3631000593/SCIC?u=mlin_m_newtnsh&sid=SCIC&xid=e0f33bb6. Accessed 31 Oct. 2020.”Use of Placebo in Clinical Practice.” American Medical Association, http://www.ama-assn.org/delivering-care/ethics/use-placebo-clinical-practice. Accessed 31 Oct. 2020.

By Michelle Li

Michelle Li is a high school junior in Massachusetts. She hopes to pursue medicine in the future and is especially interested in pediatrics.

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