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Abstract

The term placebo is widely used to indicate a perceived health-related improvement following administration of a treatment lacking a therapeutically acknowledged active component. For a long time placebo response meaning “I shall please” or “I shall be acceptable or pleasing” was something of a mystery, at best linked to but not altogether explicable within the clinical encounter. Attempts at explanation tended to be psychological, based on the probability that response to a placebo was a consequence of the patient’s own expectation of beneﬁt, conﬁdence, and trust in the practitioner or unawareness of the “dummy” nature of treatment. What was lacking was a scientiﬁc theory and detailed understanding of the underlying psychology, and more importantly knowledge of just how a patient’s thoughts and beliefs might result in biochemical and cellular changes which mimic some of those caused by medicinal drugs. Recent research has begun to unravel important aspects of the phenomenon.

The ethical implications of placebo use either in clinical practice or as a baseline comparator in clinical trials turn on important aspects of duty of care toward patients, autonomy, informed consent, and trust.

Introduction

Use of the term placebo is commonplace in healthcare. Its origin derives from the Latin expression placebo, meaning “I shall please” or “I shall be acceptable or pleasing,” and has been widely employed in therapeutics to indicate a perceived health-related improvement following administration of a treatment that contains no generally acknowledged active component. Although there are serious ethical reservations, this phenomenon has sometimes been used to “treat” demanding patients who are lacking symptoms relevant to treatment but who might be given an inert placebo. The placebo may reinforce a patient’s determination or anticipation of getting better. Much more commonly, an inert placebo arm is frequently used in the evaluation of new drugs. The method employs John Stuart Mill’s Method of Difference (Mill 1858, pp. 230–233), where use of a placebo for comparison provides a baseline in randomized controlled trials (RCTs) permitting the beneﬁcial or deleterious characteristics of drugs to be deduced. The randomized and double-blinded controlled trial (RCT) has been referred to as the gold standard in drug evaluation.

No potential therapy either physical or pharmacological can be rendered immune from the context in which it is administered. Indeed, to state this more clearly, it can be said that the outcome of all therapeutic interventions may be qualitatively or quantitatively inﬂuenced both by the process of intervention and by circumstances beyond the properties of the drug itself or the physical therapy technique. This much has been known since 1799 when John Haygarth, a British physician at the Bristol Inﬁrmary and at the Bath Mineral Water Hospital in the UK, conducted a comparative trial with genuine Perkin’s metallic tractors (alloy rods claimed to alleviate a range of painful rheumatic and muscular ailments when brushed over the affected region) and simulated rods made from a variety of nonmetallic materials of similar appearance. The results of the trial indicated that patients reported similar beneﬁcial response from both the Perkin’s rods and the fake ones. Haygarth concluded that it was the patients’ imagination that was responsible and not a characteristic of either type of rod. Somewhat earlier, the Scottish physician William Cullen had employed the term placebo in a lecture given in 1772 describing having given a placebo treatment to a Mr Gilchrist, whom he regarded as “absolutely incurable” and “hastening fast to his fate” (Kerr et al. 2008).

The role of patient imagination or expectation of a beneﬁcial response can be a powerful element in therapeutic treatment. During the Second World War, an American anaesthetist, Henry Knowles Beecher, observed that in the absence of morphine, soldiers given a saline injection by a nurse but told that they were receiving potent pain relief responded well. Following the war, Beecher investigated further and in his paper “The Powerful Placebo” (1955, p. 1606) asserted that “It is evident that placebos have a high degree of therapeutic effectiveness in treating subjective responses, decided improvement, interpreted under the unknowns technique as a real therapeutic effect, being produced in 35.2 2.2 % of cases.” That roughly one-third of successful therapeutic treatment is due to the patient’s expectation is generally held to be the case, with the major exception of antibiotic or similar therapy.

It is not unreasonable to suppose that before development of a greater understanding of the nature of disease and the pharmacological basis of drug action, it was not possible to clearly distinguish between a beneﬁcial response due to drug action and the inﬂuence of the practitioner and/or a patient’s self-belief. Retrospective consideration of some of the treatments known in antiquity indicates that although some, such as those derived, for example, from the opium poppy and Ephedra species, and later cinchona bark and digitalis, have manifest pharmacological therapeutic properties, the vast majority do not (Galen’s pharmacopeia included some 820 remedies, mostly of questionable value but which largely dominated Western medicine for 1500 years, Czerniak and Davidson 2012). Indeed, Haygarth’s recognition of the importance of the patient’s imagination in therapeutic response did little to suppress the availability of many established medicines of little or no therapeutic value throughout the nineteenth century and beyond, nor quash the continuing appetite for quack medicines by the members of the public.

The role of the community healer and traditional medicine (TM) is ubiquitous throughout the world with a long history. “WHO (2002, p. 1) indicates that “Traditional medicine” is a comprehensive term used to refer both to TM systems such as traditional Chinese medicine, Indian ayurveda, and Arabic unani medicine and to various forms of indigenous medicine. TM therapies include medication therapies – if they involve use of herbal medicines, animal parts, and/or minerals – nonmedication therapies, and spiritual therapies.” As with modern Western allopathic medicine which generally supports the biomedical model of disease, traditional medicine is every bit as dependent on a combination of the active principle(s) within a therapy and the inﬂuence of the practitioner and/or a patient’s expectation or self-belief.

The Mechanism Of Therapeutic Expectation

Is It All In The Mind?

Mommaerts and Devroey (2012, p. 44) suggest that “using the term placebo effect puts emphasis on how an external event (such as the taking of a drug) gets translated into a discernible internal event (such as feeling better or the lowering of blood pressure). In this, the external event is not the ﬁnal cause but a precipitating factor inducing something within the person that itself leads to the consequences of the placebo effect.” Furthermore, although there is a tendency for the term placebo to be associated with medicinal drugs, “placebos can also be objects (syringes, a copper bracelet), rituals (physical examination, anamnesis), places (doctor’s ofﬁce), relationships (with doctors, selfhelp groups), thoughts (about performances of medicine), and other entities such as touch, words, social interventions, a tattoo, or a surgery scar. In fact, anything that has meaning to someone can act as a placebo” (Mommaerts and Devroey 2012, p. 44). In many respects, this is the common link between Western medicine and traditional medicine. All of the items, objects, and procedures associated with therapeutics have meaning within the relevant cultural context and perspective, East or West, and have potential mind–body consequences.

Following Mommaerts and Devroey, we can consider how an external event (such as the taking of a drug or placebo or employment of an inert device) gets transformed into a discernible physiological or other internal event. The authors identify that placebo relief may be associated with or inﬂuenced by expectation or psychological factors such as personal faith or hope or belief, or alternatively by classical conditioning. Although human beings are unique individuals each with a personal spectrum of hopes, desires, and susceptibilities, a high measure of consistency is to be expected within groups that have a shared culture. Classical conditioning theory is associated with the Russian scientist Ivan Pavlov, and his observations with dogs deprived of food which salivated at the sight of Pavlov’s assistant (a conditioned response), whereas expectancy theory indicates that placebo effects are products of expectations mediated by explicit (consciously accessible) expectancies. It is not altogether clear which theory is more important or more relevant, with respect to placebo, and it may be that both play a part according to circumstances. For a fuller discussion see Stewart-Williams and Podd (2004) and Klinger et al. (2007).

Irrespective of these considerations, it is perhaps surprising that there is evidence that the use of open-label placebo (pure placebos without deception) may be of value in some cases. In a randomized controlled trial of placebo in irritable bowel syndrome (IBS), Kaptchuk et al. (2010) found that “patients are willing to take openlabel placebos and that such a treatment may have salubrious effects. Further research is warranted in IBS and perhaps other illnesses to conﬁrm that placebo treatments can be beneﬁcial when provided openly and to determine the best methods for administering such treatments.” Such ﬁndings may suggest that some patients can and do suspend rational judgment under clinical supervision even though advised that their treatment is nontherapeutic.

Does Personality Have A Role To Play In Placebo Response?

This would appear to be an important and potentially fruitful area for research to address one of the fundamental questions concerning variable placebo response. In a limited study, Geers et al. (2005) investigated whether dispositional optimism (a generalized positive outcome expectancy for the future) is a possible predictor of placebo response in healthy college students. Dispositional optimism is associated with active behavioral and mental coping when faced with adversity. Their experimental results indicate that dispositional optimism can inﬂuence placebo response to experimental pain. The study supports the broader notion that personality variables alter placebo response and that optimism appears to relate to positive placebo responding, whereas pessimism relates to negative placebo responding. Geers et al. theoretical position is that optimism is a moderator rather than a mediator of placebo responding: “Moderating variables are factors that inﬂuence the strength and/or direction of the relation between a predictor and a criterion variable, whereas mediating variables refer to the intermediary processes between a predictor and a criterion variable” (Geers et al. 2005, p. 7).

Jakšić et al. (2013, p. 17) support the need to further investigate the extent to which personality plays a relevant role in the placebo effect. “The idea that people with speciﬁc personal characteristics are more prone to placebo response seems intuitive and also easy to investigate. The earlier wave of placebo research suggested that placebo responders were individuals with certain personality characteristics: anxious, emotionally labile, suggestible, dependent on others, and churchgoing.” But the majority of investigators claimed that there is no such thing as a placebo-responding personality, that is, placebo response cannot be predicted from dispositional variables and most studies failed to produce strong or consistent ﬁndings. For example, they note some researchers have found that an individual with a positive placebo response in one set of trial circumstances will fail to respond in others. There do not appear to be identiﬁable and universal “placebo reactors” or “placebo non-responders.” Nevertheless, Jakšić et al. (2013) suggest that despite such reservations further exploration to provide a better understanding of placebo-related personality traits would facilitate the use of placebo in clinical practice and improve the methodology of clinical trials.

The healthcare professional may exert considerable inﬂuence on the therapeutic expectation of the patient and this is reﬂected in the well-known term “bedside manner.” And autosuggestive elements of therapy are not conﬁned to human personality. Nonspeciﬁc effects, for example, from the appearance (size/shape/color) and taste/ﬂavor of solid-dose medicines such as tablets or capsules can contribute signiﬁcantly to therapeutic expectation.

Changes In Brain Metabolism

It is perhaps a small step from psychological aspects associated with placebo response, at least in theory, to consider what might be identiﬁed in the way of detectable changes in the brain. Factors associated with pain reduction are primary and are most clearly understood. Neuroimaging with positron emission tomography (PET) has been used to measure and monitor cerebral blood ﬂow and functional resonance imaging (fMRI) has revealed that placebo analgesic response is associated with reduced neural activity in painprocessing areas of the brain and spinal cord (Benedetti and Amanzio 2011). Release of endogenous endorphins, opioids, and nonopioid mediators are implicated in placebo-induced pain reduction and active anticipation of pain may be associated with dopamine release.

These discoveries simply indicate some of the mechanisms and substances that are likely to be associated with placebo response. They do not clarify why there should be individual differences within groups of responders or nonresponders. Recent work in genetic screening suggests the possibility of signiﬁcant genetic differences that may help to provide a partial answer and the term placebome (a set of variants in 11 genes potentially linked to the placebo effect) is coming into use.

Hall et al. (2015) indicate placebo responses are emerging as a legitimate series of biological reactions that must be rigorously characterized to facilitate efﬁcient pharmaceutical development and optimal clinical care. Predicting who will be a placebo responder could be of value to both researchers and patients. In drug development, detecting a difference between active intervention and the placebo control is an underlying goal of RCTs. Being able to identify and exclude individuals who are more likely to respond to placebos could enhance trial designs seeking to ﬁnd such a difference.

The Ethics Of Placebo

Placebo effects are ubiquitous in all therapeutic interventions. The primary reason is that it is impossible to isolate therapeutic treatment from the atmosphere or context in which it is undertaken. This applies to treatment by a health professional or from a family member or by self-medication. We are all conditioned to a variety of health-related systems depending on cultural upbringing and there is an expectation of beneﬁcial effects from treatment.

It is generally accepted that placebos can be classiﬁed as either “pure placebo” where the means or substances of treatment are as far as possible totally inert (in practice this is not wholly achievable as widely used lactose, for example, is not acceptable to lactose-intolerant patients) or “impure placebo” where the treatment is pharmacologically active but not for the condition under treatment.

Placebos are employed both in clinical and healthcare practice and routinely as a baseline comparator in the assessment of new therapies. The role of placebo in healthcare practice continues to be controversial. Indeed the question can be asked whether it is ever ethically justiﬁable to use a placebo in clinical practice. The question would appear to turn on the practitioner’s recognition that there is no available suitable treatment for the patient, an assessment of relative commitments regarding beneﬁcence and nonmaleﬁcence, and above all, respect for patient autonomy and informed consent. But if the patient is told that they are being given an inert placebo, this may (seriously) undermine their expectation of beneﬁcial effect. So, the question can be further divided, that is, disclosure to the patient that they are being given a placebo or nondisclosure (failure to respect patient autonomy and obtain informed consent). It seems clear that it is totally unacceptable to give a placebo solely to mollify a patient (disrespect for autonomy, consent, deception, and dishonesty). All in all, it is extremely difﬁcult to satisfactorily justify undisclosed use of placebo treatment (see Asai and Kadooka 2013). An open relationship between patient and practitioner is inconsistent with undisclosed placebo use but is enhanced by frank discussion in which the patient is fully appraised of the situation in which active therapy is unavailable or inappropriate.

The use of placebo controls in (double blind – the “gold standard”) clinical studies is similarly a source of contention, though for a rather different reason than with clinical practice. There is no question of justiﬁcation for participants in clinical trials not being made fully aware of the nature of comparative studies. Their participation is conditional on informed consent, being aware that the placebo-controlled study is comparative and that neither they nor their practitioner should be able to distinguish between active and placebo treatment, apart from at least potentially experienced effectiveness or its lack and possibly adverse effects. Justiﬁcation for placebo-controlled studies or active comparator studies is based on a scientiﬁc justiﬁcation that the effectiveness and/or adverse effect proﬁle of the test drug is unknown but at least potentially may offer advantages over other currently available treatment(s). So where are the ethical problems?

Healthcare practitioners are obligated to prescribe the most effective treatment available, consistent perhaps with local constraints such as affordability. The treatment and health of the patient should not be impeded or put at risk by the possibility of receiving placebo rather than an acknowledge drug. Therapeutic results must be carefully monitored and the duration of treatment must be strictly deﬁned. Consequently, placebo treatments are generally contraindicated in life-threatening conditions. It can be argued that, unless there are particular reasons not to do so, and of course, informed consent and autonomous decision is vital, patients should be generally encouraged to participate in placebo-controlled studies where relevant and where appropriate. There is perhaps an important consideration that for all patients (and this applies to the vast majority of the population), everyone beneﬁts, at least collectively, from advances in health care and therapeutics. Clinical evaluation of new medicinal drugs is a vital part of this, and clinical trial volunteers contribute greatly to a common good of therapeutics.

Conclusion

The term placebo is widely employed in health care and therapeutics but perhaps most importantly in the evaluation of new pharmaceutical medicines and other interventions. Although presumed to be entirely biologically inert with no therapeutic effectiveness and therefore suitable as a baseline against which potential therapies might be evaluated, progressive studies have begun to reveal some unexpected properties of placebos and implications. It is now generally accepted that use of a placebo is invariably context susceptible. The very nature of the therapeutic encounter (both practitioner and therapy) is one of expectation of care and beneﬁt, and to an extent, placebo conveys this expectation. Continuing studies indicate that there may be a genetic underpinning of placebo response which may eventually become an important, discriminating aspect in clinical trials. Ethical reservations about the use of placebo are largely associated with questions of beneﬁcence, patient autonomy, trust, and informed consent.

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