Published: 7 March 2019 Prescriber Update 40(1): 14–15 March 2019 Key Messages
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
The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
There are various examples including: (a) Carbon tetrachloride and ethanol (ethyl alcohol) are individually toxic to the liver, but together they produce much more liver injury than the sum of their individual effects on the liver. (b) The much higher incidence of lung cancer resulting from occupational exposure to asbestos in smokers (compared to exposed non-smokers). (c) The toxicity of some insecticides notably pyrethrin (from chrysanthemums) and synthetic pyrethrins (pyrethroids) can be increased many times by the addition of compounds which themselves are not insecticides. These synergists are sesamin, sesamolin, piperonyl butoxide, MGK-264 (bicycloheptenedicarboximide) and sesamex. Piperonyl butoxide is perhaps the most widely used synthetic pyrethrin synergist. The insecticide activity of pyrethrins increases tenfold when 1 part piperonyl butoxide is mixed with 9 parts pyrethrin. There are no reports available on toxic effects on humans resulting from the exposure to piperonyl butoxide. (d) Barbiturate drugs have a greater effect on the central nervous system (CNS) by causing CNS depression when taken with general anesthetics, alcohol (acute consumption) narcotic analgesic (pain reliever) and other sedative hypnotic drugs. (Adapted from: Klaassen, C., 2007. "Casarett and Doull's Toxicology: The Basic Science of Poisons. 7 th Edition")
A paradoxical reaction happens when a person experiences the opposite of what the drug is intended to do. If a patient responds to medication in a contradictory or opposite way to what is expected, it is said to have had a paradoxical effect. An example of this is pain relief medication causing increased pain. Benzodiazepine treatment can sometimes result in paradoxical reactions in susceptible individuals causing an increase in anxiety, agitation, hallucinations at the onset of sleep, aggressiveness, hyperactivity, irritability, hyperactive behavior, insomnia and exacerbation of seizures in epileptics. Tolerance, akathisia and withdrawal can sometimes feel like paradoxical reactions, but this is often not a true paradoxical reaction by definition. Central features of paradoxical reactions are emotional lability, agitation, excessive movement, and confusion. This may be associated with increased autonomic activity including tachycardia, hypertension, and tachypnea. Unfortunately, there is no uniform definition of a paradoxical reaction. Attacks of rage and violent behavior, including assault (and even homicide), have been reported, particularly after benzodiazepine intravenous administration but also after oral administration. Less dramatic increases in irritability and argumentativeness are much more common and are frequently remarked upon by patients or by their families. Such reactions are similar to those sometimes provoked by alcohol. They are most frequent in anxious and aggressive individuals, children, and the elderly. The rate of paradoxical reactions following benzodiazepine administration is estimated to be 1-2%. Risk factors found for developing a paradoxical reaction from benzodiazepines include alcoholism, extremes of age, and psychiatric comorbidity. The neurobiology of paradoxical reactions is unclear. Genetic variability may play a part in some idiosyncratic reactions. One report worth noting documented a pair of identical twins who both experienced dramatic reactions to midazolam. The association between an increased rate of PR in people with alcoholism might relate to changes in GABA receptors and GABAergic pathways induced by alcoholism (e.g. differences in receptor subunit composition). See also: KINDLING 
Failure to diagnose that the patient is experiencing this reaction may lead to a progressive increase of the benzodiazepine dose, in an attempt to “control” the misdiagnosed emerging symptoms of the paradoxical reaction leading to an increase or worsening of the paradoxical reaction symptoms, as opposed to their improvement, while simultaneously significantly lengthening the time the patient may have to spend tapering off the benzodiazepine. |
A drug reaction that causes an opposite effect than what is expected is a (an)
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