• Kaylah Holmes

The Article Series: Neuroscience & The Placebo Affect

The Article series is designed to give female students a platform to share their own academic papers and research on Neuroscience and STEM concentrations that are relevant to today's society.

Hey FemNeuro readers! My name is Elizabeth Schwartz, I’m a 17 year old high school senior at Newark Academy in Livingston, New Jersey. This year I started exploring the field of neuroscience and I found my passion. I love to read, write, learn, and talk about all things neuroscience! Next year I am planning to pursue a major in neuroscience with a focus on the subject's intersection with Public Health. I’m very excited to enter this interesting field and see where my studies take me!"

Read my Neuroethics paper below:

Test or Treatment? A Neurological and Ethical Evaluation of the Placebo Response

Relief of pain and suffering are important aspects of patient care and cannot be overlooked by medical professionals, but many commonly prescribed pain medications can cause significant side effects. In the case of opioids, addiction frequently follows as a consequence of medical treatment of pain. The societal cost of the opioid addiction epidemic has been a matter of intense interest in recent years, costing the U.S. economy an estimated $78.3 billion dollars in direct and indirect costs, and leading to an estimated 33,000 deaths, annually. Although medical providers have an ethical responsibility to provide relief of suffering, pain is not life-threatening, which raises the question: does the benefit of these medications warrant the risk of compromising a patient’s health through addiction and other possible side effects? One option that may be safer, and yet effective for relief of pain, is deliberate use of placebo treatments. However, intentional administration of placebo treatment raises several ethical issues.

A placebo is a physiologically inert treatment provided to a patient with or without their knowledge for the purpose of treating symptoms, or for research purposes in clinical trials. The “placebo response” refers to objective or subjective relief of symptoms in persons receiving theoretically inactive placebo. The use of placebo-controlled trials in research has long been necessary to test and prove the effectiveness of new medications. Clinical trials of pain medications have demonstrated that placebo treatments often provide significant pain relief. Furthermore, proof of significant pain relief, beyond the placebo-treated group, is a requirement for FDA approval for treatments of pain. However, the placebo treatment itself is now being studied as a feasible primary therapy to manage pain.

There is no question about the necessity of a placebo arm in clinical trial. In contrast, several ethical concerns are raised in considering placebo as a stand-alone treatment. Is it ethical to provide a treatment that has no known mechanistic basis for providing relief? Can it ever be ethical to give a patient a placebo treatment without informing them? If the basis of the placebo effect involves withholding information from the patient, this violates the principles of patient autonomy and informed consent that are foundations of medical ethics. In addition, healthcare providers may feel uncomfortable prescribing a treatment that isn’t specifically formulated to treat the pain a patient is experiencing. However, findings from research performed over the past two decades may alleviate that ethical concern.

A large body of scientific evidence indicates that placebo treatments can cause significant changes in brain and neurological function. These effects can even be localized within the brain and attributed to specific neurotransmitter systems. For example, studies using brain imaging methods, such as functional magnetic resonance imaging and positron emission tomography scanning, have determined that relief of pain by the placebo response involves specific parts of the brain. The exact areas of the brain activated depend in part on the type of pain the individual is experiencing, and many of these areas overlap with known pain pathways, including the dorsolateral prefrontal cortex, nucleus accumbens, periaqueductal gray, left anterior cingulate cortex, right precentral and lateral prefrontal cortex, the amygdala, and the left periaqueductal gray, as well as other areas. In addition, different aspects of the placebo response appear to involve specific neurotransmitter systems. For example, expectation of pain relief requires signals from dopamine-secreting neurons, whereas the placebo effect itself largely involves endogenous opioid pathways. Other, non-opioid pathways such as the endocannabinoid system, are also sometimes involved. The fact that specific neurotransmitters in particular areas of the brain mediate the placebo response provides strong evidence that “inert” placebos can provide a real physiologic effect. Therefore, treating with placebo is very different from withholding treatment from the patient. Since there is a rational, scientific basis underlying the placebo response, this ethical concern can be lifted.

Another ethical consideration in using placebo treatments may be whether the placebo response provides adequate pain relief compared to pharmacologically active therapies. But, placebo research has revealed that in some cases, for instance in the treatment of migraine, placebo treatments administered along with strong verbal suggestions can provide relief comparable to treatment with medication. Studies show that placebo is most effective for pain relief when administered by a trusted caretaker, with strong positive statements about the expected effect, and with education about the potential benefits of the placebo response. Additionally, patients given placebo treatments often self-administer less actual opioids, suggesting that placebo treatments can be ethically used to either replace or reduce opioid use for pain relief.

Still, even if placebo is proven to be effective for relief of pain, there remains the ethical concern of deceiving the patient. A deceptive approach can undermine trust, damaging the therapeutic relationship between the patient and healthcare provider, and almost certainly undermining the placebo response itself. However, research suggests that deception is not a necessary component of successful placebo use. Studies conducted using open-labeled placebo (OLP) in both healthy volunteers, and in patients with low back pain and other types of pain, have consistently indicated that placebo treatments can be extremely effective, even with the patient’s full knowledge, if administered properly. In OLP studies, in which participants are explicitly given a placebo treatment along with education on the power of the placebo effect, OLPs have proven to be consistently effective in reducing pain compared to treatment as usual. These studies eliminate the need for the ethically questionable administration of deceptive placebo treatments, as they are not necessary to produce a positive placebo response.

Healthcare providers have an obligation to provide safe and effective relief of suffering to their patients. However, pain medications carry significant risks of side-effects. Additionally, our nation is experiencing the ravages of an opioid epidemic which is partly the result of well-intentioned medical prescriptions. Armed with objective neurobiological evidence that open-label placebos can safely provide relief from pain, and freed from the ethical barrier of applying deception, open-label placebo treatments should be explored further as an alternative method of pain management.

Works Cited (APA)

DeWeerdt, S. (2019). Tracing the US opioid Crisis to its Roots. Nature, 573, S10-S12. doi: 10.1038/d41586-019-02686-2

(2017). The High Price of the Opioid Crisis. The Pew Charitable Trusts. Retrieved July 8, 2020, from

Wampold, B. (2018). The Therapeutic Value of the Relationship for Placebo Effects and Other Healing Practices. International Review of Neurobiology, Volume 139, Chapter 8, pp 191-210. doi: 10.1016/bs.irn.2018.07.019

Vase, L., & Wartolowska, K. (2019). Pain, placebo, and test of treatment efficacy: a narrative review. British Journal of Anaesthesia, doi: 10.1016/j.bja.2019.01.040

Klinger, R., Stuhlreyer,J., Schwartz, M., Schmitz, J., & Colloca, L. (2018).Clinical Use of Placebo Effects in Patients With Pain Disorders. International Review of Neurobiology, 139: pp 107–128. Doi: 10.1016/bs.irn.2018.07.015.

(1998). Guidance for Institutional Review Boards and Clinical Investigators. U.S. Food & Drug Administration. Retrieved July 8, 2020, from

(2016). Code of Medical Ethics Opinion 2.1.1. American Medical Association. Retrieved July 8, 2020, from

Kaptchuk, T., & Miller, F. (2015). Placebo Effects in Medicine. New England Journal of Medicine, doi:10.1056/NEJMp1504023

Faria, V., Fredrikson, M., & Furmark, T. (2008). Imaging the Placebo Response: A Neurofunctional Review. European Neuropsychopharmacology, Volume 18, Issue 7, pp 473-485. doi: 10.1016/j.euroneuro.2008.03.002

Geuter, S., Koban,L., & Wager, T. (2017). The Cognitive Neuroscience of Placebo Effects: Concepts, Predictions, and Physiology. Annual Review of Neuroscience, doi: 10.1146/annurev-neuro-072116-031132

Amanzio, M., Benedetti, F,. Porro, C., Palermo, S., & Cauda, F. (2013). Activation Likelihood Estimation Meta-Analysis of Brain Correlates of Placebo Analgesia in Human Experimental Pain. Human Brain Mapping, 34:pp. 738–752. doi: 10.1002/hbm.21471

Benedetti,F., Mayberg, H., Wager, T., Stohler, C., & Zubieta, J. (2009). Neurobiological Mechanisms of Placebo Responses. The Journal of Neuroscience, 25(45):10390 –10402. Doi: 10.1111/j.1749-6632.2009.04424.x

Enck, P., Benedetti, F., & Schedlowski, M. (2008). New Insights into the Placebo and Nocebo Responses. Cell Press, 9(2):195-206. doi: 10.1016/j.neuron.2008.06.030

Benedetti, F. (2008). Mechanisms of Placebo and Placebo-Related Effects Across Diseases and Treatments. Annual Review of Pharmacological Toxicology, 48:33-60. doi: 10.1146/annurev.pharmtox.48.113006.094711

Benedetti, F., Amanzio, M., Rosato, R., & Blanchard, C. (2011). Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nature Medicine, 17(10):1228-30. doi: 10.1038/nm.2435

Vase, L., & Wartolowska, K. (2019). Pain, placebo, and test of treatment efficacy: a narrative review. British Journal of Anaesthesia, 123 (2): pp 254-262. doi: 10.1016/j.bja.2019.01.040

Klinger, R., Stuhlreyer, J., Schwartz, M., Schmitz, J., & Colloca, L. (2018). Clinical Use of Placebo Effects in Patients With Pain Disorders. International Review of Neurobiology, 139:107-128. doi: 10.1016/bs.irn.2018.07.015.

Colloca, L. (2018). PREFACE Part II: The Fascinating Mechanisms and Implications of the Placebo Effect. International Review of Neurobiology, 139: xvii–xxiii. doi:10.1016/S0074-7742(18)30087-4.

Wampold, B. (2018). The Therapeutic Value of the Relationship for Placebo Effects and Other Healing Practices. International Review of Neurobiology, Volume 139, Chapter 8, pp 191-210. doi: 10.1016/bs.irn.2018.07.019

Stohler, C., & Zubieta, J. (2009). Neurobiological Mechanisms of Placebo Responses. Annals of the New York Academy of Sciences, 1156:198-210. doi: 10.1111/j.1749-6632.2009.04424.x.

Carvalho, C., Caetano, J., Cunhac, L., Rebouta, P., Kaptchukd, T., & Kirsch, I. (2016). Open-label placebo treatment in chronic low back pain: a randomized controlled trial. Pain, 157(12):2766-2772. doi: 10.1097/j.pain.0000000000000700

Locher, C., Nascimento, A., Kirsch, I., Kossowsky, J., Meyer, A., & Gaab, J. (2017). Is the Rationale More Important Than Deception? A Randomized Controlled Trial of Open-Label Placebo Analgesia. Pain, 158(12):2320-2328. doi: 10.1097/j.pain.0000000000001012



2020 FemNeuro inc.