Placebo Ethics

I. Introduction

The most powerful human organ is the brain. It controls our thoughts, feelings, experiences, emotions, and our perceptions. It operates through organic molecules called neurotransmitters. These neurotransmitters are the vehicle through which we experience our world, including pain and disease. We can easily convince ourselves that we are taking a real medication when we are actually consuming an inert substance called a placebo. Placebos are inert or somewhat inert medical agents that do not have any real medical efficacy, and are used as a way to determine whether or not medical interventions really are useful. According to the National Institutes of Health, the “placebo effect is a beneficial health result coming from a person’s expectation that a clinical intervention…such as a pill, procedure, or injection…will help them [recover from the disease].” There are many more definitions for placebos and the placebo effect, but this essay will argue based on these definitions.

Placebos have important implications for medicine. They can clue us in to the true nature of disease and illness and can help in the study of nonspecific factors in the treatment setting that are related to clinical improvement. These nonspecific factors include the clinician-patient relationship, fostering of hope, and the patient’s trust in authority (Hedges and Burchfield, 2005). Studying placebos in depth can give us methods for enhancing these nonspecific sources of benefit. For example, studies have shown that there are neurobiological factors that may be involved in how the placebo effect works; expectations of pain relief are mediated by portions of the prefrontal cortex that trigger endogenous opioids and endocannabinoids.

This essay will cover three topics and give some recommendations regarding the use of placebos. The first section will cover the necessity of placebos in pharmacological research. The second will cover the fact that when used correctly, placebos are ethically admissible in pharmacological research. The third discusses the use of placebos in clinical practice. The last section gives some recommendations for the use of placebos and acts as a conclusion.

II. Placebos are necessary for pharmacological research

Placebo-controlled clinical trials are the gold standard in pharmacological research. They are used to test the efficacy of new drugs. Because the placebo effect is so unpredictable in clinical trials, it must be observed through a controlled study arm in clinical trials. If the tested drug is no more effective in treating a drug than a placebo, then it deemed to be useless as a clinical treatment. For the purposes of this study, the words “patient” and “subject” may be used interchangeably when discussing pharmacological research.

Randomized, placebo-controlled clinical trials are a type of study in which participants are randomly assigned to one of two or more clinical interventions. Randomization prevents selection bias. Selection bias is important to avoid, as researchers should not be picking subjects that they think will respond better to treatments to be in the clinical trial. They are generally either single or double blind. In single-blind studies, subjects do not know which intervention they are getting, but the researchers directly interacting with the subjects do know which intervention the subjects are getting. In double-blind studies, neither the subjects nor those directly interacting with them know which intervention the subject is getting. Blindness is required in randomized clinical trials as patients should not know which intervention they are getting; this would change the outcome of the clinical trial.

Subjects in randomized placebo-controlled clinical trials will either be in an active treatment arm or in a placebo arm. A flowchart describing the research design of a general randomized placebo-controlled clinical trial is to the left. There are more intricacies in the design of randomized placebo-controlled clinical trials, but those are unnecessary for this essay and will therefore not be discussed.

Placebos can tell us whether a presently-used treatment is effective. For example, a trial studied the efficacy of acupuncture in treating pain. Traditional acupuncture has been used for hundreds if not thousands of years as a viable and effective treatment for pain, but the study found that inserting needles in non-acupuncture points had the same effect on pain as inserting needles in acupuncture points (Brim & Miller, 2013). This means that acupuncture is no more effective than a sham treatment imitating acupuncture. Sham treatments are the surgical equivalent of placebos: a surgeon (or in this case, an acupuncturist) will give local or general anesthetic, make an incision, and then stitch up the incision. Sham treatments make the different intervention arms of surgical clinical trials as similar as possible to control for the placebo effect as much as possible.

Using placebos in clinical trials is necessary in determining the effectiveness of drugs; without placebos, many useless drugs would be used and distributed. However, there are some ethical concerns surrounding the use of placebos in clinical research.

III. Placebos may be ethically admissible

If people knew about the ineffectiveness of acupuncture, they may be warier in approaching alternative medicine as it would prevent them from needlessly pricking themselves with needles. Expectations play a large role in the placebo effect. If patients expect that their pain will go away or ease, then their pain may lessen. Placebos may help in the detection of adverse events in in the accurate assessment of clinical benefits of the treatments tested.

One argument against the use of placebos in clinical research is the involvement of deception. The idea is that if researchers use placebos, they are deceiving people into thinking that they’re getting treated for something that they’re not actually getting treated for; this disrespects patient autonomy.

A solution to this is that if subjects know that they are taking a placebo, the placebo effect may work the same. In an IBS study, the researchers told subjects that they would be subjected to placebos for a certain length of time, they found that “after three weeks, … people who were taking placebos did much better than those in the comparison group” (Flatow, 2012). While this is only a single study and should be replicated, it challenges the conventional wisdom that if you know you’re taking a placebo, you’re not going to be affected by the placebo effect. This could play a role in the blindness of future randomized placebo-controlled clinical trials. It could be possible that trials can tell subjects that they will be getting placebos; this would eliminate the issue of deception in clinical trials.

The current approach for informed consent is to tell participants that their sham/placebo arm will provide no benefit. In their article, Brim and Miller pointed out that a statement in informed consent documents was directly contradicted by the results of many studies: the example given was a sham-controlled trial for a Parkinson’s disease treatment. All participants in the study had equivalent improvement regardless of their trial arm allocation, and the benefit patients received was largely due to the placebo effect. Those receiving sham surgery directly benefited from the trial with fewer adverse events reported compared with the procedure arm of the trial.

Sham-controlled trials are generally considered more appropriate a control than those with no physical interventions as they are as similar to the trial arm as possible. Making the control group and variable group as similar as possible makes the study more objective and is a better trial design. Patients that are exposed to the sham treatment will be exposed to the same risks, but generally have faster recovery times, have better symptom control, and report fewer problems during recovery.

There are some direct benefits to subjects when using placebos in clinical trials. In Parkinson’s disease treatments, placebos help the brain release dopamine. Dopamine is a natural mood improver and pain reducer. The amount of placebo-mediated dopamine can be controlled by the expectation level of the patient and duration of placebo effect, and can be equivalent to clinically used Parkinson’s disease drugs. Giving more information about the placebo effect is more respectful of persons because it provides more information for informed consent. Studies have found that the more invasive and stressful a procedure is, the greater the placebo response.

The use of placebos in trials prevents the use of ineffective “treatments” that would subject a large number of people to something that won’t help them and may actually harm them through side effects. No-medication periods are justified ethically if the periods are short and known about (Kolber, 2007). For certain conditions, using placebos in trials should be considered ethically admissible:

  • Depression: While it can be claimed that the advent of a variety of antidepressants make trials for new ones unnecessary, the difference in improvement rates between drug-treated and placebo-treated non-endogenous patients is not big enough to make placebo controls unethical.
  • Schizophrenia: Placebo-controlled trials of antipsychotic agents can still be acceptable on the condition that escape treatment is provided by applying well thought-through exit criteria for a reasonable time after a patient’s possible relapse.
  • Epilepsy: Patients should be kept on their baseline medication regardless of whether the placebo or intervention are given.
  • Alzheimer’s Disease: Placebos may actually be ethically preferable here. Current medications are only effective in 23% of patients and placebo treatments do not pose unacceptable risk.

 

IV. Placebos should not be used in clinical practice

Despite what one may think, placebos are used in clinical practice. “Unlike most people, many clinicians construe placebo as more than inert nothings” (Harris & Raz, 2012). Surveys from Europe, North America, and the Middle East consistently show the clinical use of placebos, predominantly impure and active ones. 20% of clinicians in Canada report using placebos in clinical practice. Fewer reported using inert substances, and many more used at least one form of treatment in situations without expected or demonstrated clinical efficacy. In the US, 45% of clinicians use placebos; in Denmark, this proportion is 86%. Countries use more impure placebos than pure ones. Germany has especially lax rules regarding placebos, and the German Medical Association actually encourages clinicians to use placebos (Kupferschmidt, 2011).

A questionnaire done in Israel found that 60% of the 89 surveyed medical professionals use placebos (Nitzan & Lichtenberg, 2004). Among those, 63% prescribed a placebo at least once a month or more, 68% told patients they were receiving actual medication, 28% considered placebos to be a diagnostic tool, and 94% reported that they found placebos to be a diagnostic tool. Using placebos as a diagnostic tool is unethical as the patient is prevented from receiving real treatment from their doctor. Prescribing a placebo as a real medicine is obfuscation and damages patient autonomy.

The tendency to equate placebos with nothing is simplistic and dismisses large bodies of research concerning active placebos, impure placebos, and what placebos should or should not contain (Harris and Raz, 2012). Placebos involve everything in a doctor’s interaction with their patients, including: words, gestures, eye contact, empathy, and compassion. According to Dr. Kaptchuk in an NPR interview, the placebo is also about “medical symbols, white coats, diplomas, and prescription pads.”

Unless disclosed to the patient, prescriptions for unproven active interventions infringe on patient autonomy and informed consent because unlike pure placebos, impure ones may cause adverse side effects. Clinicians often prescribe placebos for the wrong reasons, including: to prove the patient “wrong,” to give to “undeserving” patients, standard treatments aren’t working, or to act out against “difficult” patients (De Deyn & D’Hooge, 1996). This reasoning in prescribing placebos to patients is clearly unethical as the paternalistic nature of these arguments puts patients at a medical disadvantage. Patients come to doctors for a reason, and giving them ineffective placebos that may have adverse side effects certainly does not adhere to the Hippocratic oath.

V. Recommendations

Physicians must avoid deception when administering placebos by informing the patient that a placebo may be used. According to Bostick et al., “a placebo must not be given entirely to mollify a difficult patient, because doing so serves the convenience of the physician more than it promotes the patient’s welfare.” Informed consent forms should include both the risks and the benefits of the placebo effect in risk-benefit disclosures. Because placebos can release dopamine, endogenous opioids, and endocannabinoids, their painkilling properties should be discussed in formal consent forms. In their article on sham-controlled trials, Brim and Miller posit that the following paragraph be included in informed consent forms:

The trial you are enrolling in seeks to compare treatment T for patients with condition C to a control treatment called a ‘sham,’ in which no T will be performed. The sham is a comparison for T and is not designed to benefit you; however, there is the possibility you may benefit from being assigned to either the treatment or the control ‘sham’ arm of the trial due to a real biological reaction your body has to being in a medical environment, and your own expectations of benefit from being enrolled in this trial. This reaction, called ‘the placebo effect,’ has been shown to relieve some symptoms of C. The probability and magnitude of any benefit from either T or sham is uncertain.

Informing subjects of the placebo effect shouldn’t affect the placebo effect itself, and telling people that there may be benefits will increase involvement in placebo and sham-controlled clinical trials. We should teach medical students about the power of the placebo effect, as it may give them motivation to improve their bedside manner. In placebo-controlled trials, some things should be considered, including:

  • whether a useful intervention exists and whether it has serious side effects
  • the placebo run should not last too long
  • placebo treatment should not subject patients to unacceptable risk
  • and informed consent should (as always) be adequate and freely given

If placebos were not used in clinical trials, many ineffective treatments would be used in clinical practice. Ineffective treatments – by definition – do not adequately treat patients, so it is ethically imperative that the most effective drugs are tested and prescribed. The only proven way to separate effective drugs from ineffective ones is to see if they perform better than placebos in a randomized placebo-controlled clinical trial. In this way, placebos are ethically required to ensure that future patients get the best treatment possible.

Replicating studies multiple times is also required, as a single study is hardly proof of the effectiveness of a drug. If a drug is shown to be more effective than a placebo in multiple different studies, only then should it be considered proven to be more effective than a placebo. This means that there must be many studies involving randomized, placebo-controlled study arms.

While placebos are a necessary tool and the golden standard for determining the efficacy of medical interventions, it is necessary to maintain patient autonomy and avoid unnecessary deception. Subjects in clinical trials should have the right to leave whenever they desire to, and should not be exposed to unnecessary risk. Placebos, when used correctly, do not pose unnecessary risk in trials, but they are clearly unethical in clinical practice. In clinical practice, the motives are often selfish on the behalf of the clinicians and do not operate in the patient’s best interest.

While use of placebos in clinical trials are ethically admissible in individual trials and ethically imperative in the large scheme of medicine, the use of placebos in clinical practice should not be allowed as placebos in clinical practice are used to quell patients that clinicians find difficult to death with.

 

 

 

Works Cited

Akobeng, AK. (2005) Understanding randomised controlled trials Archives of Disease in Childhood

Bauml, J., et al. (2014). Expectancy in Real and Sham Electroacupuncture: Does Believing Make It So? Journal of the National Cancer Institute. Monographs, 2014(50), 302–307. http://doi.org/10.1093/jncimonographs/lgu029

Bostick, A. et al. (2008) “Placebo Use in Clinical Practice: Report of the American Medical Association Council on Ethical and Judicial Affairs,” The Journal of Clinical Ethics. pp. 58-61

Brim, R., & Miller, F. (2013). The potential benefit of the placebo effect in sham-controlled trials: Implications for risk-benefit assessments and informed consent. Journal of Medical Ethics, 39(11), 703-707. Retrieved from http://www.jstor.org/stable/43282873

De Deyn, P., & D’Hooge, R. (1996). Placebos in Clinical Practice and Research. Journal of Medical Ethics, 22(3), 140-146. Retrieved from http://www.jstor.org/stable/27717752

Dunlop, B., & Banja, J. (2009). A Renewed, Ethical Defense of Placebo-Controlled Trials of New Treatments for Major Depression and Anxiety Disorders. Journal of Medical Ethics, 35(6), 384-389. Retrieved from http://www.jstor.org/stable/27720349

Enck, P., et al. (2011). The placebo response in clinical trials: More questions than answers. Philosophical Transactions: Biological Sciences, 366(1572), 1889-1895. Retrieved from http://www.jstor.org/stable/23035544

Flatow, I. (Host). (2012, Jan 6). One Scholar’s Take On The Power of The Placebo. [Radio broadcast episode.] http://www.npr.org/2012/01/06/144794035/one-scholars-take-on-the-power-of-the-placebo

Harris, C., & Raz, A. (2012). Deliberate use of placebos in clinical practice: What we really know. Journal of Medical Ethics, 38(7), 406-407. Retrieved from http://www.jstor.org/stable/23273287

Hedges, D., & Burchfield, C. (2005). The Placebo Effect and Its Implications. The Journal of Mind and Behavior, 26(3), 161-179. Retrieved from http://www.jstor.org/stable/43854452

Kolber, Adam J. (2007) “A Limited Defense of Clinical Placebo Deception,” Yale Law & Policy Review: Vol. 26: Iss. 1, Article 3.

Kupferschmidt, K. (2011, July 12). More placebo use promoted in Germany. Canadian Medical Association Journal. Retrieved from http://www.cmaj.ca/content/183/10/E633.full

Placebo Effect. (2016, October 21). Retrieved April 7, 2017, from https://nccih.nih.gov/health/placebo

Nitzan, U., & Lichtenberg, P. (2004). Questionnaire Survey on Use of Placebo. BMJ: British Medical Journal, 329(7472), 944-946. Retrieved from http://www.jstor.org/stable/25469300