Placebo and Nocebo Effects and Why They Matter in Clinical Practice
Until the 19th century, the doctor and their rituals were the primary ‘therapeutic agent’ in healthcare. However, the development of more effective treatments and increased use of technology in clinical practice has led some doctors to overlook the art of medicine and neglect their role as therapeutic agents.
What makes an effective doctor?
A decade ago, Verghese et al. observed that
By learning more about the therapeutic importance of the physician’s ‘style’ or ritual and studying outcomes, including patient satisfaction and adherence, we may be able to understand and amplify the benefits of our therapies. [Verghese et al., 2011]
We believe that considering placebo and nocebo effects in clinical practice is one strategy to improve patient satisfaction and health outcomes.
Hippocrates alluded to the placebo effect when he remarked that:
The patient, though conscious that his condition is perilous, may recover his health simply through his contentment with the goodness of the physician. [Hippocrates, Harvard University Press]
THE PLACEBO AND NOCEBO EFFECT
The placebo effect is often misunderstood. While the placebo response refers to all health changes that occur after administration of an inactive treatment, the placebo effect refers to the beneficial effect of any intervention (active or inactive) that occurs due to patient expectations and perceptions, the patient-doctor relationship, and the treatment environment.
It operates mainly through psychological mechanisms such as expectancy and conditioning and neurobiological mechanisms relating to the release of endogenous opioids, endocannabinoids, dopamine, oxytocin and vasopressin. [Colloca and Barsky, 2020]
More significant placebo effects are seen in patients with pain, depression, fatigue and Parkinson’s disease. [Evers et al., 2018]
The counterpoint to the placebo effect is the nocebo effect. Nocebo effects permeate clinical practice. A well-described example is an anticipatory nausea associated with the sight or smell of hospitals in patients receiving chemotherapy.
One study found that up to 30% of patients report this anticipatory nausea by their fourth chemotherapy cycle. [Kamen et al., 2014]
Nocebo effects can impact medication adherence. A recent treatment re-challenge study of people who had discontinued statin treatment because of perceived adverse effects showed that 90% of adverse effects associated with statins were also associated with placebos. [Wood et al., 2020]
The nocebo effect is associated with a history of prior negative experiences with medical care, lack of confidence in the treating doctor, high anxiety levels, and somatisation. [Data-Franco and Berk, 2013]
There is an underappreciation among doctors of their role in enacting placebo and nocebo effects. Few doctors believe that their expectations about a medication can induce side effects in patients. [Kampermann et al., 2017]
Despite those expectations, this subconsciously influences the way they frame the medication’s risks and benefits to the patient.
HARNESSING THE PLACEBO AND NOCEBO EFFECTS
Step 1 – Consider those at risk of nocebo effects.
- While all patients can experience nocebo effects, some may be at increased risk.
- Patients with a history of adverse healthcare experiences, prior medication sensitivity and high levels of anxiety will often require more time devoted to their concerns and clarification (and potential correction) of their treatment expectations. [Data-Franco and Berk, 2013]
- Identifying those at risk and anticipating and addressing their concerns at an early stage is time well invested.
Step 2 – Tailor your approach.
- Several cognitive heuristics used when appraising information about treatments are associated with both placebo and nocebo phenomena.
You can learn more about cognitive biases in medicine through videos by Prof Jill Klein.
- Patients require guidance about how to contextualise and interpret information about a treatment, and doctors accurately can employ awareness of these heuristics to enhance placebo effects.
- One strategy is to utilise the anchoring bias and highlight the likely benefits of medication before the potential adverse effects.
- Another is to convey information with a positive frame (e.g., “75 of 100 people taking this medication will not have nausea but even if you do, it will most likely be gone after one week” rather than “25% of people will experience nausea with this medication”). [Barnes et al., 2019]
Step 3 – Know your medications.
- Doctors should remain up to date with common nocebo effects associated with the classes of medications they prescribe.
- For antidepressants, sexual and anticholinergic effects tend to be ‘direct pharmacological’ adverse effects, while negative thoughts and headaches tend to be primarily driven by nocebo effects. [Sinyor et al., 2020]
- Differentiating between adverse events that are treatment-related, coincidental, or nocebo responses is often challenging.
- However, considering if the reaction is plausibly related to the medicine (i.e., has the reaction been reported in the literature as a possible side effect, how soon after initiation of treatment did the adverse event occur and does this fit with the known onset of action) and the patient’s past treatment history can be informative.
Step 4 – Respect the rituals of the doctor-patient relationship
- Doctors can enhance the placebo effect by bolstering the therapeutic relationship. This involves addressing the patient with warmth, empathy and unconditional positive regard.
- Maintaining this professionalism requires attention to one’s self-care.
- Additionally, respect for the age-old rituals of medicine such as physical examination where indicated can also enhance the doctor-patient relationship, improve trust and facilitate reassurance. [Verghese et al., 2011]
Step 5 – Optimise direct time with your patients.
- There are bureaucratic constraints that limit the amount of time doctors can spend with patients.
- Inadequate time with patients risks inadequate formation of a therapeutic alliance, cursory or absent physical examination and inadequate provision of tailored education about treatments – key ingredients to harness the placebo effect and mitigate the nocebo effect.
- If the caring role of the doctor is diminished, the placebo effect will be diminished.
- Consideration of how best to optimise time with patients (e.g., streamlining or delegating administrative tasks) is always worthwhile.
Evidence-based treatments in psychiatry have risks and benefits that are powerfully modulated by placebo and nocebo phenomena.
Increasing our understanding of these phenomena and incorporating these insights into clinical care may boost the acceptability and effectiveness of treatments and thereby improve patient outcomes.
There is more research needed to evaluate the practical strategies to harness the placebo effect and mitigate the nocebo effect in clinical practice.
Hippocrates, Jones WHS, Withington ET, Smith WD, Potter P, Heraclitus, et al. Hippocrates. Cambridge, Massachusetts. Harvard University Press. 1923.