The Nocebo Effect: How Negative Expectations Can Make Pain Worse

By Pat Anson

You’ve probably heard of the placebo effect – the phenomenon where a patient’s symptoms improve after receiving a sham or fake medical treatment. Although not fully understood, experts think the placebo effect occurs when someone believes a treatment will work, which tricks the brain into releasing endorphins and other hormones that relieve pain and help us feel better.

Less well known is the nocebo effect, which works the opposite way. When patients think a treatment won’t work or may even cause harm, their pain and other symptoms will get worse, not better.

German researchers wondered whether the placebo or nocebo effect was stronger, and enrolled 104 healthy volunteers in a study to find out.

“While many studies have explored placebo and nocebo effects individually, few have directly compared the two in the same people over time,” says co-lead author Katharina Schmidt, PhD, a researcher in the Department of Neurology at University Duisburg-Essen, Germany. “We set out to determine whether negative expectations towards treatment have a stronger or longer-lasting effect on pain perception than positive ones.”

The volunteers were given two sham treatments one week apart. On the first day, participants were exposed to short bursts of heat pain after being led to believe that they would feel either pain relief (placebo), increased pain (nocebo), or no change (control).

The expectations were created using a combination of verbal suggestions from researchers and a fake pain relief treatment – a sham nerve stimulator that appeared real but delivered no actual relief. Participants were then asked to rate the intensity of their pain on a scale between 0 (not painful) and 100 (unbearably painful). Unbeknownst to the participants, researchers adjusted the heat stimulus to reinforce their expectations – making it less painful in the placebo condition and more painful in the nocebo condition.

In the second session, the heat stimulus was kept identical for the placebo, nocebo and control groups, allowing researchers to test whether expectations formed on the first day continued to shape the participants’ pain perception.

The results, published in a reviewed preprint in eLife, show that both placebo and nocebo suggestions significantly influenced pain perception – but the nocebo effect was stronger.

On the first day, participants in the nocebo group rated their pain an average of 11.3 points higher than the control group; while the placebo group rated their pain only 4.2 points lower than the control group.

When participants returned one week later for the second session, the patterns persisted. The nocebo effect remained stronger than the placebo effect, with participants in the nocebo group rating their pain 8.9 points higher than the control group. The findings in the placebo group were more modest, with average pain ratings just 4.6 points lower than the control group.

“This suggests that people are more likely to expect and feel worse outcomes than better ones,” says Schmidt. “It reflects a ‘better-safe-than-sorry’ strategy – humans may have evolved to be more attuned to potential threats, making negative expectations carry more weight.”

Schmidt and her colleagues found that participants who experienced a strong placebo or nocebo effect on the first day were more likely to show the same response a week later. Psychological factors were also involved. Participants who rated the researcher in the sham sessions as highly competent were more susceptible to nocebo effects – possibly because they found the negative suggestions more believable.

“Our findings highlight the enduring nature of both placebo and nocebo effects in pain, with nocebo responses showing consistently greater strength over time,” said senior author Ulrike Bingel, MD, Director of the Interdisciplinary Center for Pain Medicine and Translational Pain Research at the University Duisburg-Essen. “While we often focus on boosting positive expectations in patients, we show that it may be just as important – if not more so – to avoid unintentionally creating negative ones, which appear to be more easily triggered.”

Bingel said the study demonstrates the need for better communication between patients and practitioners in real-life clinical settings. Negative or positive outcomes for patients can be triggered by how doctors and nurses communicate with them. In other words, a good bedside manner can improve patient outcomes.

“Positive framing, avoiding unnecessary emphasis on side effects, and building a trusting relationship can all reduce the risk of triggering nocebo responses. In a time when cost-effectiveness in healthcare is essential, preventing nocebo effects should be a key strategy for improving treatment outcomes,” said Bingel.

A recent study found that about a third of patients with irritable bowel syndrome (IBS) falsely believe that gluten or wheat trigger their symptoms. This may be a nocebo effect, where patients experience IBS symptoms after eating what they consider unhealthy food, even when there is no evidence that they are sensitive to wheat or gluten. 

Study Finds ‘Nocebo Effect’ of Statins Cause Pain

By Pat Anson, Editor

An industry funded study is adding more fuel to a sometimes heated debate over statins – and whether the cholesterol-lowering drugs cause muscle pain and weakness.

Research involving nearly 10,000 patients published in The Lancet medical journal suggests that people taking Lipitor – the brand name for the statin atorvastatin -- are more likely to report muscle aches and other side effects, but only if they knew there were taking the drug.

This is what is called the “nocebo effect” – the opposite of the placebo effect – where people complain of side effects because they expect to have them.

"Just as the placebo effect can be very strong, so too can the nocebo effect. This is not a case of people making up symptoms, or that the symptoms are 'all in their heads'. Patients can experience very real pain as a result of the nocebo effect and the expectation that drugs will cause harm,” said lead author Peter Sever of the National Heart and Lung Institute at Imperial College London.

“What our study shows is that it's precisely the expectation of harm that is likely causing the increase in muscle pain and weakness, rather than the drugs themselves causing them."

Sever said complaints about the side effects overstate how common the problems are and discourage people from taking statins, resulting in "thousands of fatal and disabling heart attacks and strokes, which would otherwise have been avoided."

“These results will help assure both physicians and patients that most AEs (adverse effects) associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects,” he said.

The study was funded by Servier Research Group, Leo Laboratories and Pfizer – the maker of Lipitor. Five of the eight co-authors reported potential conflicts of interest, including payments from Pfizer and other drug makers that manufacture statins.  

Only about 2 percent of the patients taking Lipitor in The Lancet study reported having muscle pain, a finding that is substantially at odds with previous research.

For example, in a study at the Cleveland Clinic last year, 42 percent of patients taking Lipitor reported muscle pain and weakness. Other studies have found muscle pain in 5% to 29% of statin users.

The Food and Drug Administration considered the problem serious enough that in 2014 it required warning labels on statins, cautioning that some statins can cause a muscle injury called myopathy, which is characterized by muscle pain or weakness. In rare instances, the FDA says statins can also cause liver injury, diabetes and memory loss.

Another study this week, published in JAMA Internal Medicine, linked statin use to back pain conditions such as spondylosis and intervertebral disc disorders. The study involved over 13,000 military veterans and their families.

“To our knowledge, this study is the first to report greater odds of back disorders among statin users compared with the odds of nonusers in a population with equal access to and the same cost of health care,” said Una Makris, MD,  of the VA North Texas Health Care System in Dallas. “Our results provide additional motivation to further investigate the overall influence of statin therapy on musculoskeletal health, specifically if prescribed for primary prevention in physically active individuals.”