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13 Articles in Volume 18, Issue #6
Authorities’ Use of Big Data May Harm—or Help—Your Chances of Investigation
Gaps in the Pharmacist’s Pain Management Role
How can cyproheptadine manage complicated chronic pain cases?
Letters to the Editor: Trackable Pills; Buprenorphine; CRPS Diagnosis
Managing a New High-Dose Opioid Patient
Managing Opioid Use Disorder
Medication Selection for Comorbid Pain Management (Part 2)
Mobile Trackers and Digital Therapeutics
New Insights in Understanding Chronic, Central Pain
Nocebo Effects: How to Prevent them in Patients
Polarizing Topics in Chronic Pain
The Fight to End Peripheral Neuropathy
Urine Drug Monitoring

Nocebo Effects: How to Prevent them in Patients

Clinical setting, past experience with a particular treatment, and other factors may play a role in patients’ expectancies of—and reactions to—pain care.
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Certainly most clinicians have heard of the placebo effect at some point in their career, often with a negative connotation, referring to it as a nuisance variable in research or as a mere product of positive expectations and suggestibility of patients. As more research has been conducted over time, it has been discovered that not only is the placebo effect a true neurobiological phenomenon involving complex contextual, cognitive-shaping factors affecting patient expectancies, but also that it may be influenced by genetic factors.1,2

Placebo effects have significantly impacted clinical and health outcomes in pain management,3-6 Parkinson’s Disease,7,8 immunity,9,10 and irritable bowel syndrome (IBS)11,12 as well as the pharmacological activity of certain medications.13-15 Particularly, placebo analgesia, or a placebo-induced reduction of pain perception, has been the most studied type of placebo effect.14 But what happens when the context creating the expectancy is negative instead of positive? What mechanisms come into play, and how are these mechanisms relevant to pain management?

Adverse events related to negative expectancies in a patient are called “nocebo effects.” In this article, the main mechanisms associated with the nocebo effect, the importance of preventing nocebo algesia and hyperalgesia (ie, the occurrence and worsening of nocebo-induced pain, respectively), and practical strategies that may help reduce nocebo effects in pain practice settings are discussed.

Nocebo versus Placebo

Patients may form negative expectancies through conscious and subconscious processes that influence learning and the interpretation of social cues. Verbal suggestions, social observation, instructional learning, conditioning, personality traits, and genetic factors, for example, all play a role in the formation of individual expectancies and expectations. Expectations refer to consciously identifiable predictions about the likelihood of an event, and form part of the larger umbrella of expectancy.16 On the other hand, expectancies refer to all factors that lead to expectations as well as those factors that occur without conscious control or prediction, such as when conditioning processes lead to effects that contradict a person’s belief of the occurrence of an event. Nocebo effects were initially identified as adverse effects reported by placebo groups participating in clinical trials. Subjects that received an inert placebo would typically describe the side effects associated with the active medication being studied, all of which had been mentioned during the informed consent process.17 In addition, nocebo effects may refer to the negative effects of an active drug that cannot be attributed to the pharmacokinetics of the drug, as well as to a reduction of expected efficacy.14

Research on the nocebo effect in pain management has predominately focused on pain modulation, with studies demonstrating an influence on descending pain pathways as a result of various environmental, clinical, and interpersonal contextual triggering factors.17,4,18 Overall, the psychoneurobiology of nocebo-induced hyperalgesia involves complex interactions between the brain regions associated with pain perception, social behaviors, memory, and anxiety, as well as with the biochemical and hormonal changes involving mainly cholecystokinin (CCK), the HPA-axis,19 and the opioidergic system.14,17

The Nocebo Effect on Pain Modulation and Patient Expectations: Research to Date

The aforementioned triggers may be facilitated through different contextual factors that overall convey a potential for harm. In fact, some researchers have suggested that nocebo effects are an evolutionary mechanism designed to prevent harm, whereas placebo effects promote safety and appetitive behaviors.20 Below are some examples of scenarios that have been identified as activators of nocebo effects, followed by clinical implications for each case.

Negative Suggestions

Negative suggestions are forms of verbal or written communication that directly invoke negative expectations in individuals. For example, a study showed that the pharmacological efficacy of remifentanil was significantly decreased after patients were told the infusion was stopped during a heat-pain modulation test. Although the infusion had not actually been halted, participants experienced a significant exacerbation of pain even while still receiving remifentanil. Functional MRI conducted during the test correlated an increased activity in the hippocampus.14

A randomized controlled study of women undergoing an epidural injection for labor pain tested two groups. One group was told, “you are going to feel a big bee sting; this is the worst part of the procedure” and another group was told, “we are going to give you a local anesthetic that will numb the area and you will be comfortable during the procedure.”21 The bee-sting group reported significantly higher pain responses. Results demonstrated that the framing and style of communication related to the same information can have a significant impact on pain responses.

Last updated on: September 5, 2018
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Invoking the Placebo Effect
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