What is the role of placebo in neurotherapeutics?

ABSTRACT

Introduction

The widespread use of the word ‘placebo’ in the medical literature emphasizes the importance of this phenomenon in modern biomedical sciences. Neuroscientific research over the past thirty years shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and can be robust in both laboratory and clinical settings.

Areas covered

Here the authors describe the biological mechanisms and the clinical implications of placebo effects with particular emphasis on neurology and psychiatry, for example in pain, movement disorders, depression. In these conditions, a number of endogenous systems have been identified, such as endogenous opioids, endocannabinoids, and dopamine, which contribute to the placebo-induced benefit.

Expert opinion

Every effort should be made to maximize the placebo effect and reduce its evil twin, the nocebo effect, in medical practice. This does not require the administration of a placebo, but rather the enhancement of the effects of pharmacological and nonpharmacological treatments through a good doctor–patient interaction.

KEYWORDS:

• Placebo effect
• nocebo effect
• classical conditioning
• expectations
• placebo analgesia
• nocebo hyperalgesia
• Parkinson’s disease
• depression
• social anxiety

Article highlights

• A placebo is an inert treatment with no specific therapeutic properties for the condition being treated. Placebo effects are the positive outcomes that might follow placebo administration and that are due to the psychosocial context surrounding the therapeutic act. There is also evidence that placebo effects can exist in clinical practice, even if no placebo is given.

• Nocebo effects are represented by negative outcomes that follow the administration of an inert treatment.

• When an active treatment is given, the overall response results from both the treatment itself and the psychosocial context in which it is delivered, namely the placebo/nocebo component of the therapy.

• According to Pavlovian conditioning paradigms, aspects of the clinical setting (e.g. physical characteristics of a pill or white coats) can act as conditioned stimuli, eliciting a therapeutic response in the absence of an active principle, just because they have been paired with it in the past.

• Patients’ expectations have a crucial role in the placebo and nocebo effects, whereby patients consciously foresee a positive or negative outcome, based on factors such as verbal instructions, environmental cues, embodied previous experiences, the interaction with care-providers, and the ritual of therapeutic act. This anticipation of the future outcome, in turn, triggers internal changes resulting in specific experiences.

• There is not a single placebo or nocebo effect but many. The most studied and best understood models of placebo and nocebo effects include: pain, Parkinson’s disease, depression, and social anxiety, as well as both immune and endocrine systems.

• The psychosocial stimuli surrounding the patient and the therapy may trigger active process in the patient’s brain, such as the activation of receptorial pathways that are the same as those modulated by drugs, with important implications for clinical trial designs and routine medical practice.

• Some genotypes related to high or poor responsiveness to placebos have been identified in medical conditions such as major depression, social anxiety, and irritable bowel syndrome.

• The effectiveness of the active treatment can be assessed either by eliminating its specific effect (placebo study) or by eliminating the nonspecific effects (hidden treatment administration).

• Every effort should be made to enhance the placebo component in order to maximize the benefit of the therapeutic act. This behavior, which relies mainly on an empathic, skilled, reassuring, and encouraging patient–provider relationship, is perfectly acceptable and does not challenge ethical imperatives.

Abbreviations

CCK cholecystokinin

COMT catabolic enzymes catechol-O-methyltransferase

DLPFC dorsolateral prefrontal cortex

fMRI functional magnetic resonance imaging

GH growth hormone

5-HT 5-hydroxytryptamine, i.e. serotonin

5-HTTLPR serotonin transporter-linked polymorphic region

IFNγ interferon-γ

IL-2 interleukin-2

MAO-A monoamine oxidase A

NPS neurological pain signature

PAG periaqueductal gray

PD Parkinson’s disease

PET positron emission tomography

rACC rostral anterior cingulate cortex

SSRI selective serotonin reuptake inhibitor

SSRIs selective serotonin reuptake inhibitors

TPH2 tryptophan hydroxylase-2

UPDRSm Unified Parkinson's Disease Rating Scale motor

Declaration of interests

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by grants from the Innovative Clinical Training, Trials & Healthcare Worldwide Initiative to Fabrizio Benedetti, and from the Nerve and Muscle Center of Texas to Aziz Shaibani.