Placebo hypoalgesia: above and beyond expectancy and conditioning

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Highlights

  • Placebo analgesia is changed through biological, cognitive, and social factors.

  • Pharmacological conditioning can produce placebo effects over time.

  • The quality of doctor-patient interactions can improve or impede treatment outcomes.

  • Placebos raise concerns in areas of clinical practice, disparities, and doping.

Placebo hypoalgesia provides pain relief for individuals via the expectation of a beneficial or therapeutic outcome, while nocebo hyperalgesia results in increased pain in response to anxious anticipation of harmful outcomes. These forms of placebo pain modulation can be induced through repeated associations, verbal cues, and social interactions. Understanding these methods of pain modulation can provide greater insight into the psychosocial contexts of pain modulation, as well as develop novel approaches to pain management.

Introduction

The terms placebo (Latin for I shall please) and nocebo (Latin for I shall harm) describe the positive and negative aspects of cognitive modulation of behaviors, responses, and outcomes [1••]. Since the pioneering publication by physician Henry K. Beecher in 1955 highlighted the significant evidence suggesting the tangible benefits induced by placebos [2], placebo research has propelled experimental and clinical use to reduce symptoms in a variety of conditions including asthma [3], irritable bowel syndrome [4], anxiety [5], Parkinson’s Disease [6], depression [7], and addiction [see Ref. 8].

The most studied and clinically applied placebo and nocebo knowledge is centered on pain [1••,9, 10, 11, 12, 13, 14, 15]. Pain is an incredibly subjective experience, often being molded by a variety of components that creates a unique sensation for the individual (See Figure 1). Placebo-induced hypoalgesia and nocebo-induced hyperalgesia, refer to the reduction and heightening of pain experience due to cognitive modulations [1••]. From a psychological standpoint, two broad mechanisms, namely expectancy and conditioning, have been reported as the primary mechanisms that elicit placebo and nocebo effects [4,11,9,16, 17, 18]. Only until recently the two broad mechanisms of expectancy and conditioning have not been simplistically reduced and viewed as alternative and conflicting forces, but rather complementary in their essential roles for forming placebo and nocebo effects [19••]. More specifically, learning can be cognitively mediated and can elicit analgesia when relationships between events are acquired and verbal instructions can amplify the effect of automatic processes [20]. Here, we illustrate the psychosocial and behavioral mechanisms behind placebo-induced hypoalgesia and nocebo-induced hyperalgesia, as well as point to future areas of later research.

Section snippets

Conditioning

Ivan Pavlov’s seminal experiment with dogs developed the classical conditioning paradigm that now forms the basis for a major mechanism facilitating placebo-induced hypoalgesia. In this classic experiment, Pavlov noticed that a dog begins to salivate (i.e. the unconditioned response - UR) when it saw and smelled of food (i.e. unconditioned stimulus - US). Pavlov began to pair the scent and sight of food with the sound of a bell (i.e. the neutral stimulus - NS). Eventually, Pavlov began to only

Expectancy

Kirsch originally posited an earlier alternative perspective to the conditioning framework based on an expectancy model: a placebo or nocebo produces an effect because the individual expects it to do so [18]. The individual in question must synthesize information from the external environment, as well as internal beliefs and prior experiences, to form a response expectancy [18]. The expectancy model involves mechanisms that facilitate potential placebo and nocebo effects. Complex psychosocial

Social learning

Social observational learning involves gaining, processing, and synthesizing information from others as an observer without experiencing the event first hand [see Ref. [33]]. Colloca and Benedetti performed the first experiment to determine the role of observational social learning in placebo-induced analgesia [34]. The subjects were divided into three experimental groups, each assigned an unique means of inducing placebo analgesia: first, observing a demonstrator showing an analgesic effect

Beyond expectancy versus conditioning

While expectancy and conditioning models are often pitted against one another as opposing theories, more research has begun to detail the interactions between the models [1••,36,37••]. Conditioning paradigms contribute to expectancy held since learning through prior experience can influence internal beliefs regarding treatments, clinicians, and other environmental factors. Klinger et al. demonstrated this with a study involving subjects with or without atopic dermatitis, as the subjects were

Do we people respond differently to placebos?

Personality traits have only recently been linked to the occurrence of placebo responsiveness in individuals. Links between hypnotic suggestibility, dispositional optimism, and empathy have all been correlated (yet no causal effects) to placebo hypoalgesia. Dispositional optimism refers to an individual’s ability to have confidence about the positive or successful outcome of the future. Past literature have shown a correlation between an individual’s degree of dispositional optimism and the

Applications of placebo effects

A crucial element to the formation of placebo-induced analgesia is the communication between the intended subject and the clinician or researcher involved. Often, a unique psychosocial interaction between patients and clinicians may elicit certain expectations of benefit and healing. Benedetti [44,45] explored the intricacies between placebos and the relationship between doctors and their patients, emphasizing the internal beliefs and memories held by the patient that meld with the sensory and

Gaps in placebo and nocebo research

There is lack of literature revealing interactions between psychiatric disorders and pain relief via placebo-induced hypoalgesia. Considering that in 2011, it was estimated that a little less than 1 in 5 U.S. adults suffered from a mental illness in the previous year [8], a growing subset of the population will have psychiatric conditions that may or may not interfere with the potential therapeutic benefits gained from placebos indicating a need for a new avenue for future research. Also,

Conclusions

With problematic and debilitating pain plaguing millions of individuals across the globe, the growing number of funding going towards researching novel methods of pain reduction validate the need to continue to push the boundaries of effective treatments. Once written off as a nuisance variable to control for or as a sham treatment meant to maliciously deceive, placebo effects have been validated to show remarkable effects on pain modulation. While various perspectives have revealed much needed

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This research was supported by University of Maryland Strategic Partnership: MPowering the State (LC), University of Maryland Scholars Program (CO) and the National Institute of Dental and Craniofacial Research (NIDCR, R01DE025946, LC).

References (47)

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