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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.

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.

Similarly, in a clinical environment, a patient receiving negative disclosures related to a pending treatment (eg, explanation of pain medication’s side effects, details provided through informed consent of a procedure) may experience nocebo algesia or hyperalgesia, or a decreased effectiveness in their treatments. By avoiding overemphasizing negative information regarding a treatment or by balancing negative with positive information, a clinician may help to prevent nocebo effects in the patient.22,18 Another aspect that may help to promote placebo and prevent nocebo involves explaining upfront the mechanism of action of a therapy, as well as its potential placebo and nocebo effects.23 Some studies have shown that providing a rationale can enhance placebo responses when the placebo is given openly with an honest positive interaction.3,12

Social Interactions and Observational Learning

Researchers have increasingly demonstrated that pain modulation can be learned and modified through social processes and that it can have sex-specific effects.17,14,25,26 Individuals that interact with or observe another person experiencing a negative outcome (eg, increased pain) or receiving negative disclosures related to a treatment may experience an increase of pain or note side effects themselves. Although more research is needed to specifically identify the mechanisms behind the social modulation of pain, neurobiological studies point to factors such as the activity of neuropeptides, such as oxytocin and vasopressin, as well as empathy, mirror processes, and mentalizing.27

Clinical settings in which patients may directly interact with or observe other patients in pain, as well as other patients’ responses while receiving a treatment or interacting with medical personnel, may facilitate nocebo effects. The complexity of social behavior makes this factor especially challenging, as many social and environmental factors may be at times uncontrollable, for example when a patient is exposed to negative suggestions within their communities or through media outlets. Practitioners may be able to regain some of that control by exploring the expectations, beliefs, or preferences of patients and using that information to thwart—in advance—any negative anticipations that might influence clinical outcomes.

Negative Conditioning and Learning

Past negative individual experiences and associative learning may shape a patient’s expectations regarding a future treatment. For example, a patient who has had repeated suboptimal or negative experiences with a specific treatment regime or health professional may experience an exacerbation of side effects or a reduction in treatment efficacy, regardless of the actual pharmacological or physiological action of the treatment.17 Classical conditioning has been widely studied in the context of placebo and nocebo, where repeated stimuli are presented in association with cues that can later trigger the same effect without the stimulation being present. These effects may extinguish with time, but they also may persist—even when an individual is aware of the conditioning paradigm, especially if strong associations have been occurring for a long period of time.17,28-30

Further, nocebo algesia and hyperalgesia may occur if a patient has experienced failed treatments in the past; these effects may be more pervasive with longer durations of unsuccessful treatments. Facilitating positive associations with the treatment plan may help prevent conditioned nocebo responses. For example, patients may be encouraged to take their medications during positive moments, as this can help build an association between analgesic effects and positive experiences.18 A clinician could also try to help the patient reconsider any negative memories or expectations they have about a particular treatment to help prevent further consolidation of nocebo effects.18 This may be achieved by exploring a patient’s beliefs and expectations through targeted questioning techniques. Before considering either approach, it is important to account for the patient’s social history and environment, as well as for previous experiences within the healthcare system and related medical treatments; this information may help determine the patient’s susceptibility to experience nocebo effects.

Patient–Practitioner Interactions

The simple act of seeing a doctor has been shown to engage a context of healing that is part of the therapeutic process.31 Having an interaction that is business-like, instead of warm and empathic, and where the physician’s competence and experience may be questioned, however, can lead to nocebo effects. One study associated those characteristics with a decreased efficacy of a placebo intervention related to a provoked immune response.32 Furthermore, it has been demonstrated that the beliefs of healthcare staff can translate into subtle behaviors and cues that influence patient expectations.33 In addition, receiving treatments without a social interaction—such as through automated equipment, known as “hidden administration,” can significantly decrease the efficacy of analgesic medication.34,35,18

Positive practitioner characteristics, namely warmth and competence, induced a placebo-mediated anti-histaminic response after individuals received a histamine prick.32 In general, the literature shows that uncaring interactions that convey a message of invalidation and lack of warmth may trigger nocebo effects. Avoiding negative communication and interactions with a patient may help to shape a safe and positive environment that not only promotes placebo effects but that also reduces nocebo effects.

Personality Traits

Multiple researchers have identified the influence of individual personality traits on endogenous pain modulation and nocebo effects. Some of these traits include: anxiety,36,37 pessimism,38,39 pain catastrophizing,40,25 and harm avoidance.38 Importantly, different traits may interact with each other to produce a large variation on nocebo effects among individuals,16 and some of these traits may influence the perception of verbal communication.38 Thus, personality traits may impact the nocebo effect even if they do not directly influence expectations per se.16

The benefit of measuring expectations and personality traits in order to individualize approaches to pain management has been posited.16 Similar to exploring patient expectations, awareness of personality traits may help clinicians to individualize interactions with specific patients to avoid potential nocebo triggers. Since personality traits have the potential to influence even the understanding of verbal suggestions and social cues, they present a target for improving the clinical encounter.


The mechanisms of expectancy described may be best understood as contextual factors that, together, may create a psychosocial setting that a patient perceives, even subconsciously, as harmful. Nocebo and placebo effects are an inherent part of every therapeutic encounter, and patients with chronic pain may be more vulnerable to experiencing nocebo effects due to the nature of their disease, its comorbidities, and potentially their psychosocial environment. More research is warranted to promote clinical guidelines for managing negative expectations in the pain practice setting. Nonetheless, pragmatic strategies related to patient–practitioner interaction, clinical setting, and context may be implemented to help minimize and prevent the consolidation of negative expectations.

Last updated on: September 5, 2018
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