Published: 7 March 2019

Publications

The nocebo effect

Prescriber Update 40(1): 14–15

March 2019

What is it?

The nocebo effect is the opposite of the placebo effect. It describes a situation where a negative outcome occurs due to a belief that the intervention will cause harm. It is a sometimes forgotten phenomenon in the world of medicine safety. The term nocebo comes from the Latin ‘to harm’.

For adverse reactions to medicines, nocebo implies that patients are more likely to experience an adverse effect if they expect or are worried about the adverse effect. The adverse effects may be physically experienced by the patient and are often clinically diagnosable¹. An example of the nocebo effect is the severe adverse effects experienced by patients taking a placebo during a clinical trial.

Some experts state that the nocebo effect may have a larger effect on clinical outcomes than the placebo effect as negative perceptions are formed much faster than positive ones¹.

The nocebo effect can be influenced by ‘media storms’. Widespread dissemination of concerns about an adverse reaction to a medicine leads to an increase in the number of reports of the adverse reaction. For example, in 2013, British media highlighted the adverse effects, including muscle pains, of statins following an article in the British Medical Journal². An estimated 200,000 patients stopped taking statins within six months of the story being published, many due to adverse reactions. There was also an increase in the number of adverse reaction reports of rhabdomyolysis with statins during this time. This incident has since been attributed to the nocebo effect¹.

The nocebo effect can also play a role in patients’ experience with generic medicines. Pre-existing scepticism around generic medicines may be a cause of the side effects some patients experience when changing from an innovator “branded” product to a generic product. A 2015 Finnish report showed that around a quarter of patients discontinued an approved infliximab biosimilar due to a perceived loss of efficacy or an increase in side effects³. Other studies have shown that perception of cost (believing that because generics are cheaper they are less effective) can enhance the nocebo effect⁴. Due to the New Zealand funding situation, there have been numerous instances where the perception of cost may have enhanced the nocebo effect⁵.

What can be done about it?

It is important to remember that non-verbal communication may also trigger a nocebo response⁶.

Some patients appear to be at higher risk of experiencing nocebo effects. Women, patients with anxiety and depression, those with a pessimistic outlook and strongly influenced by their environment may need more careful counselling to avoid inadvertent initiation of the nocebo effect⁶.

The risk of nocebo can be reduced by ensuring a good balance between explaining both the positive and negative effects of the treatment, and ensuring the patient understands the treatment’s rationale¹. Framing the adverse effects of a medicine positively may help to reduce the role of nocebo⁶. For example, ‘Most people who take generic brand X notice no difference to innovator brand Y, but a small number of patients may notice a difference’ compared to ‘Some patients find that generic brand X is not as effective as innovator brand Y’.

The nocebo effect can also be reduced by providing information to patients about the adverse effects of a medicine in context, and checking their understanding¹.

References

1. Brasil R. 2018. Nocebo: the placebo effect’s evil twin. The Pharmaceutical Journal 300(7911): 05. DOI: 10.1211/PJ.2018.20204524 (accessed 22 January 2019).
2. Abrahamson JD, Rosenberg HG, Jewel N, et al. 2013. Should people at low risk of cardiovascular disease take a statin? British Medical Journal 347: f6123. DOI: https://doi.org/10.1136/bmj.f6123 (accessed 22 January 2019).
3. Nikiphorou E, Kautiainen H, Hannonen P, et al. 2015. Clinical effectiveness of CT-p13 (infliximab biosimilar) used as switch from Remicade (infliximab) in patients with established rheumatic disease. Report of clinical experience based on prospective observational data. Expert Opinion on Biological Therapy 15(12): 1677–83. DOI: 10.1517/14712598.2015.1103733 (accessed 22 January 2019).
4. Tinnermann A, Geuter S, Sprenger C, et al. 2017. Interactions between brain and spinal cord mediate value effect in nocebo hyperalgesia. Science 358(6359): 105–8. DOI: 10.1126/science.aan1221 (accessed 22 January 2019).
5. Medsafe. 2018. Brand switches in New Zealand (presented at the 175^th meeting of the Medicines Adverse Reaction Committee) 30 October 2018. URL: www.medsafe.govt.nz/committees/MARC/reports/175-Brand%20Switches%20in%20New%20Zealand.pdf (accessed 5 February 2019).
6. Planès S, Villier C and Mallaret M. 2016. The nocebo effect of drugs. Pharmacology Research & Perspectives 4(2): e00208. URL: www.ncbi.nlm.nih.gov/pmc/articles/PMC4804316/ (accessed 29 January 2019).