Placebo effects: the need for a new perspective and conceptualization

KEYWORDS:

• Placebo
• drug
• clinical trials
• medical practice

1. Definition

Defining a drug is not difficult. It is a molecule that produces a biological effect by acting on one or more biochemical pathways, e.g. by binding to a receptor or by modifying the activity of an enzyme. Conversely, defining a placebo is not an easy task. It is usually defined as an inert substance with no pharmacological action, although this definition is not complete, as placebos are made of many things, such as words, rituals, symbols, and meanings. Therefore, a placebo is not the inert substance alone, but rather its administration within a complex psychosocial context. Indeed, a placebo is the whole ritual of the therapeutic act.

The confusion about the words placebo and placebo effect comes from the different usage that they have for the clinical trialist and the neuroscientist/psychologist. The former is interested in any improvement that may take place in the group of patients who take the inert substance, and this improvement can be due to plenty of factors, such as the spontaneous remission, regression to the mean, and patient’s expectations of benefit. By contrast, the neuroscientist is only interested in the improvement that derives from the patient’s expectations, namely, an active process occurring in the patient’s brain. Clinical trials are only aimed at establishing whether the patients who take the true treatment are better off than those who take the placebo, whereas the neurosciences want to understand what is going on in the patient’s brain when a placebo is given, i.e. when a therapeutic ritual is performed. By using this neuroscientific approach, the placebo effect represents an excellent model to understand how the human brain works [1–3] and may have profound implications for both medical practice and clinical trials [4].

2. The common mechanisms of placebos and drugs

One of the most interesting and challenging aspects of placebo research is related to the new emerging concept that placebos activate the same biochemical pathways that are activated by drugs [1], which represents quite an interesting challenge from both an evolutionary and a neurobiological perspective. Humans are endowed with endogenous systems that can be activated by verbally induced positive expectations, therapeutic rituals, healing symbols, and social interactions, and these systems include both endogenous opioids and endocannabinoids in placebo analgesia [5] and dopamine in Parkinson-related placebo responses [6]. When morphine is administered, it binds to opioid receptors and inhibits pain transmission, but at the same time the ritual of its administration induces the activation of the same opioid receptors, involving a descending pain modulating network that goes from the cortex down to the spinal cord [7,8]. Similarly, when an anti-Parkinson dopaminergic drug is given, it stimulates dopamine receptors, but at the same time the ritual of its administration activates the same dopamine receptors [6], along with substantial changes in neuronal activity in the basal ganglia [9]. More recent findings indicate that the cyclooxygenase pathway can be affected by placebos as well [10], thus suggesting an intricate set of mechanisms, including enzymatic activity, that can be activated by psychosocial stimuli, such as patients’ expectations of improvement and different therapeutic rituals.

3. The differences between placebos and drugs

It goes without saying that clear-cut differences between placebo and drugs do exist. First, as far as we know today, the duration of the effect of a drug is longer than that of a placebo. For example, the effect of the powerful anti-Parkinson drug, apomorphine, lasts on average much more than a placebo. The mean duration of apomorphine is around 90 min, whereas the mean duration of the placebo effect is about 30 min [1]. Second, the variability of the response is different, such that the clinical response is much more variable after placebo administration than after apomorphine [1]. As far as the magnitude of the response is concerned, the effect following placebo administration can be as large as the effect following drug administration. For example, some good placebo responders may show a reduction of the UPDRS (Unified Parkinson’s Disease Rating Scale) up to 50%, as occurs for anti-Parkinson drugs [1]. The placebo effect can be even larger in pain, where pain reduction can be of 5–6 points on a scale ranging from 0 = no pain to 10 = unbearable pain, as occurs in irritable bowel syndrome, where the analgesic response to a placebo has been found in a study to be larger than that to lidocaine [11]. However, it is important to point out that only a small percentage of placebo responders may show such huge effects.

4. Some possible implications

Several important questions arise as to what use we make of this new knowledge, perspective, and conceptualization of placebo effects. Two opposite questions can be posed, depending on the setting where placebos are administered. In routine clinical practice, one wants to maximize the placebo effect, so that the main question is ‘How can we decrease variability and increase duration and magnitude of placebo effects?’. By contrast, in the clinical trials setting we want to minimize the placebo response, so that the question is ‘How can we decrease variability, duration and magnitude of placebo effects?’ [4,12].

As to the first question, by using a learning procedure we can decrease variability and increase duration and magnitude. To do this, a pharmacological preconditioning can be carried out, whereby a real drug is administered for several days in a row, then it is replaced with a placebo. By using this approach, most patients show huge placebo responses, which indicates that learning plays a key role in the placebo effect [5]. This could be useful in routine medical practice, for it is possible to reduce drug intake in the long run [13]. As to the second question in the setting of clinical research, future trials should be aimed at assessing patients’ expectations in order to better interpret the therapeutic outcome following placebo and verum administration [4].

It is also worth remembering that placebos may also show effects similar to those of the ergogenic drugs used in sport to increase physical performance. This raises important ethical and legal issues for anti-doping agencies, since placebos, that are detectable neither in blood nor in urine, have been found to increase performance by activating the endogenous opioid system [14]. Thus the question is: Is it ethical to use placebo procedures in sport to mimic the ergogenic action of drugs? This is certainly an exciting biological and ethical challenge for future research.

5. Expert commentary

We need to change our perspective about placebo effects and conceptualize them in a different way, so that they can be considered as phenomena worthy of scientific inquiry.

A better understanding of the similarities and differences between drugs and placebos represents an important challenge for future research, which will surely lead to better medical practice and better interpretation of clinical trials. The crucial starting point is the understanding of the biological underpinnings and their relationship to drug action. We believe that both medical practice and clinical trials, as well as human biology and neuroscience, will benefit from this new knowledge.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.