“Primum non nocere”: First, do no harm.
Placebos and medical research have tainted histories, as both were often used in deceptive, coercive, and abusive ways. Medical ethics deals with moral imperatives, duties, and obligations of clinicians to the patients and to the society in a reciprocal relationship.
Placebo-Controlled Trials Are Morally Problematic
Psychiatric disorders are chronic, fluctuating conditions that produce significant morbidity and considerably increased risk for suicide.2 There are several risk factors for decisional incapacity associated with psychiatric disorders. Dubois et al.3 recently reviewed 25 years of National Institutes of Health-funded empirical research studies. The majority of these studies included patients with schizophrenia during remission, when they are more likely to have negative symptoms, which decreases their capacity to give informed consent more so than during psychotic episodes.4 Two other reports found that during medication-free schizophrenia trials, participants’ ability to reason decreased significantly and increased the potential of the reemergence of serious symptoms.5,6 Furthermore, compared with that of healthy controls, the ability to make decisions is significantly lower in patients with mania associated with bipolar disorders and in patients with mild cognitive impairments.7,8 Mann et al.9 found significantly greater suicidal ideation in patients given placebos compared with those enrolled in the antidepressant arm of the study; however, Kim and Holloway10 reported that use of placebos in antidepressant and antipsychotic trials did not increase mortality by suicide in the placebo arm. Khan et al.11 analyzed the suicide risk in the placebo arm of seven U.S. Food and Drug Administration (FDA)-approved antidepressant trials and reported that of 19,639 patients, 130 attempted and 34 committed suicide, equating to an annual rate of 757 suicides per 100,000 depressed patients — 70 times higher than in the general population; however, this was not significantly different from the numbers found in the treatment arm.
Obtaining informed consent during a research study is contingent upon the participants’ ability to provide detailed information, willingness to voluntarily participate in the study, and unimpaired capacity to consent. Researchers must respect the autonomy and self determent of research participants.
Signing a consent document does not mean that a participant has given informed consent, however. Systematic evaluations have shown that participants in randomized trials recall information poorly, are not often aware of the placebo arm of treatment, and often have therapeutic misconception about their individual benefits. A study by Applebaum et al.12 revealed that 44% of the study’s participants did not know that participation did not ensure receiving the desired treatment and not a “dummy” pill.
Ethical opposition to placebo-controlled trials relies on principles of non-malfeasance and individualized benefits.13 Patients randomized to the placebo arm of a study fail to receive standard effective treatment for their condition, thus violating the moral obligation of physician-investigator and the rights of patient volunteers.14 Stricter criteria have been proposed by Striner,15 which include setting a high bar for informed consent, not allowing physician-investigators to enroll their own patients into the study, and having an external agency to monitor adverse effects. In a thought-provoking article in the New England Journal of Medicine, Rothman and Michaels16 asserted that placebo-controlled trials are always unethical. They cited the guidance of the Declaration of Helsinki, endorsed by the World Medical Association, in their opposition: “When treatment of a proven efficacy exists, every patient in clinical trials, including the control group, should receive the best diagnostic and therapeutic method.”17 This would rule out even non-inferiority trials against an active drug that is not the best-proven treatment.18 Medical ethicists also believe that “psychic distress” experienced by participants in the placebo arm is a matter of moral concern and argue whether a patient will be harmed or only discomforted by a placebo should not be determined solely by physicians.19 Placebo trials of maintenance treatment also raise ethical issues as they require a no-treatment arm, by their very nature, and risk relapse.20
Weijer21 proposed that since placebo-controlled trials lack clinical utility, clinical trials should test whether treatment is superior or equivalent in efficacy to standard effective treatment when a reasonable doubt exists concerning the relative efficacy of two treatments. This approach, where patient volunteers are not randomized to a treatment known to be inferior to an available clinical treatment, is called clinical equipoise.22
The medical ethicists are also concerned about the concept of “authorized deception” in clinical research. Honesty, integrity, authenticity with respect for persons, beneficence, and justice were stressed in the Belmont report in 1979 and laid the foundation for regulations regarding ethics and human subjects research in the U.S.23 In “authorized deception,” the patients give explicit permission to use placebos in a condition called balanced placebo design.24 This is a useful research tool to understanding the placebo effect in itself but violates the fiduciary relationship with the patient, especially if the deception in research is conducted by a clinician who has a prior clinician-patient relationship with the study participant, as it undermines the patient’s faith in trustworthiness of doctors and even the medical establishment. It also raises ethical concerns because it can be corrupting for the professionals, as well. As in all clinical research, an acceptable balance must be struck between promoting valuable knowledge and protecting the rights and well-being of participants.
Proponents of placebo-controlled trials point to limited efficacy and often intolerable side-effects of standard treatments in psychiatry, as well as the high rate of placebo response in randomized, controlled trials (from 25% to 50% or more) across a range of psychiatric diagnoses, including panic disorder, depression, and schizophrenia.2 Even though the FDA does not require placebo controls, it gives placebo a tacit nod of approval when “risk of death or serious harm is not at stake.” It also points out non-superiority of active control trials in pain control and psychiatric drugs. The proponents also state that active comparator trials require larger sample sizes, add cost and significant delay to the process of drug development, and expose more people to side effects.
Not all placebo-controlled trials pose special ethical problems. When no effective treatment exists for a given disorder, placebo comparison with an experimental agent or with the clinically available ineffective agent is permissible. Similarly, trials testing experimental drugs against placebo in treatment refractory patients are not ethically suspect because, for these patients, standard treatment has proven ineffective. Patients who have only a partial response to standard medications may undergo an add-on experimental treatment with placebo among the patient volunteers, all of whom also receive standard treatment. Doctors, in general, are specially trained to be good clinicians but are seldom taught even the fundamentals of ethical research.
The Use of Placebos in Everyday Practice
In the era of paternalistic practice of medicine, using inert pills was considered a benevolent deception, and no one doubted the intentions of the physicians to benefit the patients by any means.
Some physicians use placebos knowingly, and some may use them unknowingly (ie, off-label use of drugs, homeopathic doses, and practitioners of CAM). Additionally, placebo effects are embedded in every treatment and drug regimen, thus used unwittingly.
Some physicians are known to use inert or impure agents in a deceptive manner.25 Although the use of sugar pills or saline injections are rare, the use of impure placebos seems to be on the rise.26 In a review of studies from 12 different countries, the frequency of use and motivation of practitioners indicated that prevalence varied from 17% to 80% among physicians and was growing incrementally among general practitioners compared to hospital-based physicians.27 Antibiotics (35%), vitamins (25%), sedatives (20%), over-the-counter analgesics (15%), and sub-therapeutic doses of drugs (12%) were commonly prescribed “impure” placebos for non-indicated reasons. The common reasons given for using these were to stop the patient from complaining, to placate a demanding patient, or that, “there is an outside chance that it might help.” Twenty-eight percent offered them to distinguish between psychogenic and physiological causes of illness — a notion that is not only unethical, but also false, risky, and unjustified.28 More than 90% of doctors using them thought impure placebos were partially or completely effective. Hrobarjtsson29 calls this practice “unethical, unnecessary, and an unprofessional way to practice medicine.” Based on his analysis of 114 trials covering randomized, controlled trials with no treatment group, Hrobarjtsson found no statistically significant effect on binary outcomes or on continuous observer reported outcomes.30 The American Medical Association sees no ethical problem if the physician informs the patient that she is providing an inert substance.31
Lichtenberg et al.32 suggested guidelines for using placebos in clinical practice. These include that the physician’s intention must be benevolent; that placebos are given to assuage the patient suffering, not to mollify or silence; and that, when ineffective, placebos should be immediately be withdrawn.
Brown33 is an advocate of openly giving placebo as a treatment for depression. At least two studies suggested that placebos, even when given openly without an element of deception, have the same magnitude of response as a patient getting drug treatment.34,35 The clinical utility has been questioned by others, indicating only a transient response to placebos, a failure of response in severe depression, and also impacting credibility of psychiatrists as artful and manipulative.
Another ubiquitously harmful effect from placebo administration is described as the “nocebo effect,” a term that has been the focus of attention lately.36 The nocebo effect arises mainly from anticipation of and information about negative outcomes and prior experience of harmful consequences. Research demonstrates that detailed disclosure of possible adverse effects produce more side effects, causes patients to discontinue the medication, and mimics the drug’s side effects in the placebo arm of the drug under investigation as outlined in Table 1.
Nocebo Effects in Clinical Trials
Similarly, when patients are switched from branded to generic medications, patients may experience loss of benefits and increased side effects.39
The consequences of nocebo effects related to negative expectancy and anxiety in clinical practice are described by Barsky et al.40 and include nausea, dizziness, fatigue, headache, insomnia, and difficulty concentrating. They also occur as background side effects in the general population; therefore, it is extremely helpful to take a nocebo history before starting patients on medications. Even the use of negative words and suggestions in routine clinical care may have unintended consequences of nocebo effects with increasing anxiety and pain perception.41 This creates a “catch-22” of information disclosure. Too little information is antithetical to obtain informed consent, harms patient autonomy for independent decision, and erodes our fiduciary relationship with the patient. Furthermore, thanks to a bombardment of information available in the Physicians’ Desk Reference, package inserts, on the Internet, and in media advertising, it can make a situation ripe for legal liabilities. Giving too much information increases the probability that side effects will occur, increasing the possibility of non-adherence and treatment dropouts.
How does one reconcile these opposing ethical imperatives and simultaneously obtain informed consent and minimize nocebo-related risks? As outlined by Colloca and Miller42 and Häuser et al,36 promising methods include strategies of framing information, or the authorized concealment approach, taking nocebo history and educating patients about placebo responses, promoting optimal therapeutic relationships and effective management of symptoms.
One influenza vaccination study briefings demonstrated that “95% of patient tolerated the procedure well” (positive framing), instead of saying “5% reported side effects” (negative framing). The positive framing group had fewer side effects and less work absenteeism.43 In authorized concealment, patients are given a choice not to be told about relatively mild and transient effects of the drugs because it is more likely they will feel they have those side effects if they are informed of them in advance. They are also given the option to receive a list of side effects and be asked which ones they would always want to know about and which they would prefer not to know about prior to taking the drug. This is akin to therapeutic privilege, where the patient chooses not to be informed; however, it may have limited application in clinical practice.
Ethical issues have a particular relevance to psychiatric research and clinical practice, arising from unique vulnerabilities of our patients with regard to cognitive deficits and their comprehension and reasoning abilities. For a conscientious clinician, using placebos ethically may be an oxymoron. In addition to numerous ethical principles stipulated in guidelines of medical organizations, we should also set our moral compass by the ancient refrain, “primum non nocere” in providing patient care.
- Smith CM. Origin and uses of primum non nocere — above all, do no harm!J Clin Pharmacol. 2005;45(4):371–377. doi:10.1177/0091270004273680 [CrossRef]
- Miller FG. Placebo-controlled trials in psychiatric research: an ethical perspective. Biol Psychiatry. 2000;47(8):707–716. doi:10.1016/S0006-3223(00)00833-7 [CrossRef]
- Dubois J, Bante H, Hadley WB. Ethics in psychiatric research: a review of 25 years of NIH-funded empirical research projects. AJOB Prim Res. 2011;2(4):5–17. doi:10.1080/21507716.2011.631514 [CrossRef]
- Dunn LB. Capacity to consent to research in schizophrenia: the expanding evidence base. Behav Sci Law. 2006;24(4):431–445. doi:10.1002/bsl.698 [CrossRef]
- Roberts LW, Warner TD, Nguyen KP, et al. Schizophrenia patients’ and psychiatrists’ perspectives on ethical aspects of symptom re-emergence during psychopharmacological research participation. Psychopharmacology (Berl). 2003;171(1):58–67. doi:10.1007/s00213-002-1160-9 [CrossRef]
- Moser DJ, Reese RL, Schultz SK, et al. Informed consent in medication-free schizophrenia research. Am J Psychiatry. 2005;162(6):1209–1211. doi:10.1176/appi.ajp.162.6.1209 [CrossRef]
- Depp CA, Cain AE, Palmer BW, et al. Assessment of medication management ability in middle-aged and older adults with bipolar disorder. J Clin Psychopharmacol. 2008;28(2):225–229. doi:10.1097/JCP.0b013e318166dfed [CrossRef]
- Karlawish J, Rubright J, Casarett D, et al. Older adults’ attitudes toward enrollment of non-competent subjects participating in Alzheimer’s research. Am J Psychiatry. 2009;166(2):182–188. doi:10.1176/appi.ajp.2008.08050645 [CrossRef]
- Mann JJ, Goodwin FK, O’Brien CP, Robinson DS. Suicidal behavior and psychotropic medication. Accepted as a consensus statement by the ACNP Council, March 2, 1992. Neuropsychopharmacology. 1993;8(2):177–183.
- Kim SY. Benefits and burdens of placebos in psychiatric research. Psychopharmacology (Berl). 2003;171(1):13–18. doi:10.1007/s00213-003-1458-2 [CrossRef]
- Khan A, Warner HA, Brown WA. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the Food and Drug Administration database. Arch Gen Psychiatry. 2000;57(4):311–317. doi:10.1001/archpsyc.57.4.311 [CrossRef]
- Appelbaum PS, Roth LH, Lidz CW, Benson P, Winslade W. False hopes and best data: consent to research and the therapeutic misconception. Hastings Cent Rep. 1987;17(2):20–24. doi:10.2307/3562038 [CrossRef]
- Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 4th ed. New York, NY: Oxford University Press; 1994.
- Freedman B, Glass KC, Weijer C. Placebo orthodoxy in clinical research. II: Ethical, legal, and regulatory myths. J Law Med Ethics. 1996;24(3):252–259. doi:10.1111/j.1748-720X.1996.tb01860.x [CrossRef]
- Streiner DL. Placebo-controlled trials: when are they needed?Schizophr Res. 1999;35(3):201–210. doi:10.1016/S0920-9964(98)00126-1 [CrossRef]
- Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med. 1994;331(6):394–398. doi:10.1056/NEJM199408113310611 [CrossRef]
- Brody BA. The Ethics of Biomedical Research: International Perpective. New York, NY: Oxford Univeristy Press; 1998.
- Levine RJ. The need to revise the Declaration of Helsinki. N Engl J Med. 1999;341(7):531–534. doi:10.1056/NEJM199908123410713 [CrossRef]
- Mason JK, Smith AM. Law and Medical Ethics. 4th ed. London, Dublin, Edinburgh: Butterworths Law; 1994.
- Lieberman JA, Stroup S, Laska A, et al. Issues in clinical research design: principles, practices, and controversies. In: Pincus HA, Lieberman JA, Ferris S, eds. Ethics in Psychiatric Research: A Resource Manual for Human Subjects Protection. Washington D.C.: American Psychiatric Associaton; 1999.
- Weijer C. Placebo-controlled trials in schizophrenia: are they ethical? Are they necessary?Schizophr Res. 1999;35(3):211–218; discussion 227–236. doi:10.1016/S0920-9964(98)00127-3 [CrossRef]
- Freedman B. Equipoise and the ethics of clinical research. N Engl J Med. 1987;317(3):141–145. doi:10.1056/NEJM198707163170304 [CrossRef]
- National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principals and Guidelines for the Protection of Human Subjects Research. Washington D.C.: U.S. Government Printing Office; 1979.
- Miller FG, Wendler D, Swartzman LC. Deception in research on the placebo effect. PLoS Med. 2005;2(9):e262. doi:10.1371/journal.pmed.0020262 [CrossRef]
- Brody H. The lie that heals: the ethics of giving placebos. Ann Intern Med. 1982;97(1):112–118. doi:10.7326/0003-4819-97-1-112 [CrossRef]
- Colloca L, Miller FG. Harnessing the placebo effect: the need for translational research. Philos Trans R Soc Lond B Biol Sci. 366(1572):1922–1930.
- Fässler M, Meissner K, Schneider A, Linde K. Frequency and circumstances of placebo use in clinical practice — a systematic review of empirical studies. BMC Med. 2010;8:15. doi:10.1186/1741-7015-8-15 [CrossRef]
- Kinnaert P. Placebo and placebo effects (second part): ethical aspects. Rev Med Brux. 2007;28(1):39–44.
- Hrobjartsson A. Clinical placebo interventions are unethical, unnecessary, and unprofessional. J Clin Ethics. 2008;19(1):66–69.
- Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001;344(21):1594–1602. doi:10.1056/NEJM200105243442106 [CrossRef]
- Bostick NA, Sade R, Levine MA, Stewart DM Jr, American Medical Association Council on Ethical and Judicial Affairs. Placebo use in clinical practice: report of the American Medical Association Council on Ethical and Judicial Affairs. J Clin Ethics. 2008;19(1):58–61.
- Lichtenberg P, Heresco-Levy U, Nitzan U. The ethics of the placebo in clinical practice. J Med Ethics. 2004;30(6):551–554. doi:10.1136/jme.2002.002832 [CrossRef]
- Brown WA. Placebo as a treatment for depression. Neuropsychopharmacology. 1994;10(4):265–269; discussion 271–288. doi:10.1038/npp.1994.53 [CrossRef]
- Park LC, Covi L. Nonblind placebo trial: an exploration of neurotic patients’ responses to placebo when its inert content is disclosed. Arch Gen Psychiatry. 1965;12:36–45. doi:10.1001/archpsyc.1965.01720340008002 [CrossRef]
- Kaptchuk TJ, Kelley JM, Deykin A, et al. Do placebo responders exist?Contemp Clin Trials. 2008;29(4):587–595. doi:10.1016/j.cct.2008.02.002 [CrossRef]
- Häuser W, Hansen E, Enck P. Nocebo phenomena in medicine: their relevance in everyday clinical practice. Dtsch Arztebl Int. 2012;109(26):459–465.
- Mondaini N, Gontero P, Giubilei G, et al. Finasteride 5 mg and sexual side effects: how many of these are related to a nocebo phenomenon?J Sex Med. 2007;4(6):1708–1712. doi:10.1111/j.1743-6109.2007.00563.x [CrossRef]
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- Weissenfeld J, Stock S, Lüngen M, Gerber A. The nocebo effect: a reason for patients’ nonadherence to generic substitution?Pharmazie. 2010;65(7):451–456.
- Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA. 2002;287(5):622–627. doi:10.1001/jama.287.5.622 [CrossRef]
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Nocebo Effects in Clinical Trials
Sulfinpyrazone vs. Aspirin: inclusion of “possible gastrointestinal (GI) side effects” in briefing in two of the three study centers led to six-fold increase in study dropouts from subjective, minor GI symptoms. Not so in the third center where that briefing was omitted.31
Finasteride in Benign Postatic Hyperplasia: 45% incidence of sexual dysfunction in group that was informed of this possible effect, 15% in the non-informed group.37
Higher rate of adverse effects (ie, dry mouth, fatigue, blurred vision, constipation) in the tricyclic antidepressant placebo arm than in selective serotonin reuptake inhibitors placebo arm.38