Nocebo: Placebo’s Evil Twin

March 22, 2019

Nocebo is sometimes referred to as “placebo’s evil twin,” “negative placebo effects,” or “the other side of placebo.”  Nocebo effects are negative effects that are induced by nocebos: fake, non-specific treatments, procedures, therapies, or medications.

Studies suggest that nocebo effects can contribute to a variety of medical symptoms, including adverse events in clinical trials and medical care and public health “mass psychogenic illness” outbreaks. It is reasonable to suggest nocebo effects play a big role in sickness. Consider the condition called hypochondria. Hypochondria reflects a tendency to believe one has some sort of illness even when there is no physiological basis for illness. Hypochondriacs report feeling bad often and sometimes spend lots of money and time visiting different care providers, and they often can’t find out what is wrong. They learn to expect sickness often, associate it with a variety of phenomena, and frequently seek out new treatments and cures. They are susceptible to a range of nocebo-induced effects. The mere thought of being sick may have a big impact on subjective feelings of sickness.     

Primary mechanisms of nocebo effects include negative expectations and classical conditioning. The term nocebo, Latin for “I will harm,” was coined by Walter Kennedy in 1961 as the counterpart of placebo; Latin for “I will please” (Kennedy 1961). The term was introduced a few years after Henry Beecher published his important paper on the placebo effect.

Research Says

In a three-part study, including different participants for each measured outcome, conducted by Benedetti and colleagues (2003), pain, motor performance in Parkinsonian patients, and hormonal levels were measured. A primary concern for the researchers was determining how classical conditioning and expectations influence placebo/nocebo effects.

The effects of opposing verbal suggestions on arm pain in healthy volunteers and on motor performance in Parkinsonian patients was analyzed. In the third part of the study the researchers measured the effects of opposing verbal suggestions on hormonal secretion. It was found that verbally induced expectations of pain relief/elevated pain and motor improvement/worsening antagonized completely the effects of a conditioning procedure. The expectations were the primary determinant of outcomes; they were independent of conditioning procedure. Regarding hormonal secretion, they found that verbally induced expectations of increase/decrease of growth hormone (GH) and cortisol did not influence the secretion of these hormones. However, if a preconditioning was performed with an agonist that stimulates GH and inhibits cortisol secretion, a significant increase of GH and decrease of cortisol plasma concentrations were found after placebo administration, although opposite verbal suggestions were given. These findings indicate that verbally induced expectations have no effect on hormonal secretion, whereas they affect pain and motor performance. This suggests that placebo effects are mediated by conditioning when unconscious physiological functions such as hormonal secretion are involved, whereas they are mediated by expectation when conscious physiological processes such as pain and motor performance come into play. Benedetti and colleagues concluded: “In the present study, conditioning appears to play a crucial role in the placebo [and nocebo] responses of human unconscious physiological functions, whereas expectations replace conditioning when conscious perception is involved (e.g., pain and motor performance)” (Benedetti et al. 2003).

The mechanism(s) explaining placebo or nocebo effects depends on the context. In some cases conditioning and expectations (specifically conscious expectations) may drive the effect, while in others cases conditioning and expectations may occur independently. In a meta-analysis conducted by Petersen and colleagues (2014) it was shown that when nocebo effects were induced by a combination of verbal suggestions and conditioning, the effect size was larger than in studies where nocebo effects were induced by verbal suggestions alone.

In Kirsch’s book How Expectancies Shape Experience (1999) he provides many citations and references for the study of placebo and nocebo effects. He reports on a range of interesting cases involving nocebo and nocebo-related phenomena. In one study college students were told they would be administered an electric current, so they should expect a headache. Although no current was administered, approximately 71 percent reported headaches. Even after they were told no current had been administered, they continued to report headaches. In one case an asthmatic patient, who had an allergy to roses, showed an allergy to both real and plastic roses. In an investigation of hospitalized patients who had suffered heart attack and who were depressed, it was shown they were 4.6 to 6.9 times more likely to die from heart disease than patients who had suffered a heart attack but were not depressed. Chronic depression may lead to a wide range of additional health problems. A key factor associated with depression is negative expectation.  

Studies were conducted investigating open versus hidden interruptions of morphine in postoperative patients (Colloca et al. 2004). In the open condition patients were told morphine had been stopped, and in the hidden condition morphine was stopped without telling them anything. After stopping morphine administration the pain increase was greater in the open condition versus the hidden condition. Ten hours after morphine administration stopped, significantly more patients from the open interruption than those in the hidden interruption requested more pain medicine. The researchers concluded that the pain of those in the open condition was heavily influenced by fear and negative expectations.

Nocebo administration leads to anxiety, and this activates independent biochemical pathways: CCK-ergic system and HPA axis (Benedetti 2009). The pronociceptive (activation of receptors associated with pain) and anti-opioid activity of the CCK-ergic system occurs in various brain regions. The CCK-ergic systems heavily involve neurons in the brainstem of humans and non-human animals. Elevated activity of the HPA axis indicates increases in sympathetic nervous system activity, which may lead to negative outcomes if sustained for long periods. The HPA axis involves the hypothalamus, pituitary gland, and adrenal glands.

High levels of pain involve increased activity in several brain regions, including areas of the prefrontal cortex, insula, and thalamus. As magnitude of expected pain increases, increased activation is seen in the pain-associated areas of the brain. In contrast, expecting decreased pain reduces activity of pain-related brain regions. Nocebo effects have also been found to be associated with decreased dopamine and anti-opioid activity in the nucleus accumbens (often referred to as the “brain’s pleasure center”).        

Nocebo phenomena have been demonstrated in various contexts: pain, motor performance (including sporting events), psychological ailments, different types of health-related issues, and in everyday life.

Consider the following example of a nocebo phenomenon that occurs outside of the lab. When I coach people in weight training, it isn’t uncommon for me to manipulate the weight they are using without them knowing the weight. This can be done when people are using a selectorized weight training device, such as a lat-pulldown. They are seated in a position where they can’t see the amount of weight they are using. I choose the weight, and often the weight is much heavier than they realize. I had a client perform lat-pulldowns with three plates (30 lbs) for three consecutive workouts (thirteen to fifteen reps, three sets). My client thought they were using two plates. In a fourth lat-pulldown training session I told the client “now we are moving up the weight to 30 lbs.” She performed only nine reps for each set. Her other training movements within the same workout improved, so it is unlikely that she was just having a bad day on the lat-pulldown. I suspect the poor performance was due to nocebo.      

References

Bendetti, F. 2009. Placebo Effects: Understanding the Mechanisms in Health and Disease. Oxford: Oxford, University Press.  

Bendetti, F., A. Pollo, L. Lopiano, et al. 2003. Conscious expectation and unconscious conditioning in analgesic, motor and hormonal placebo-nocebo responses. Journal of Neuroscience 23: 4315–4325.

Colloca, L., L.  Lopiano, M. Lanotte, et al. 2004. Overt versus covert treatment for pain, anxiety and Parkinson’s disease Lancet Neurology 3: 679–684.

Kennedy, W.P. 1961. The nocebo reaction. Medical World 95: 203–205.

Kirsch, I. 1999. How Expectancies Shape Experience. Washington, D.C.: American Psychological Association.  

Petersen, G., N. Finnerup, L. Colloca, et al. 2014. The magnitude of nocebo effects in pain: A meta-analysis. Pain 155(8): 1426–1434.