Nocebo and pain: An overview of the psychoneurobiological mechanisms

Abstract

Introduction: Nocebo effects are defined as adverse events related to negative expectations and learning processes that are involved in the modulation of the descending pain pathways. Research over the last couple of decades has illustrated that behavioral, psychoneurobiological and functional changes occur during nocebo-induced pain processing.

Objectives: We aimed to review published human and non-human research on algesia and hyperalgesia resulting from negative expectations and nocebo effects.

Methods: Herein, we searched and comprehensively reviewed scientific literature providing informative knowledge about the psychoneurobiological bases of the nocebo effect in the field of pain with an emphasis on how pain processes are shaped by both cognitive and non-cognitive factors.

Results: Negative expectations are formed through verbal suggestions of heightened pain, prior nociceptive and painful experiences and observation of pain in others. Susceptibility to the nocebo effect can be also influenced by genetic variants, conscious and nonconscious learning processes, personality traits and psychological factors. Moreover, providers' behaviors, environmental cues and the appearance of medical devices can induce negative expectations that dramatically influence pain perception and processing in a variety of pain modalities and patient populations.

Conclusion: Importantly, we concluded that nocebo studies outline how individual expectations may lead to physiological changes underpinning the central integration and processing of magnified pain signaling. Further research is needed to develop strategies that can identify nocebo-vulnerable pain patients in order to optimize the psychosocial and therapeutic context in which the clinical encounter occurs, with the ultimate purpose of improving clinical outcomes.

Keywords: Negative expectations; allodynia; hyperalgesia; nocebo effects; pain modulation.

Figure 1.

Verbal suggestions and conditioning elicit the same magnitude of nocebo effects. (A) Allodynic and hyperalgesic pain profiles. Allodynia refers to pain in response to a stimulus that does not normally elicit any pain and hyperalgesia refers to increased pain from a stimulation that normally induces low pain. Adapted from Ref. 66 (Republished with permission of The American Physiological Society, from Sandkuhler J. Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 2009;89:707–58. Permission conveyed through Copyright Clearance Center, Inc. (B) Contribution of verbal suggestions and classical conditioning to nocebo responses. Low and high nonpainful tactile stimuli were turned into painful experiences after study participants were told about the possibility to experience high pain. Similarly, low pain was perceived as painful ones, with or without being exposed to high pain via the classical conditioning. Thus, allodynic and hyperalgesic effects may be triggered by suggestions alone. A different trend was observed in the placebo analgesia condition in which experience matters more than being informed about pain relief. Data from Ref. 34. The red arrow indicates the stimulation intensity. The gray arrow indicates the switch between allodynia and hyperalgesia.

Figure 2.

Nocebo effects persist over time. Pain reports for the context group (red) and the control group (blue). The left part shows the pain reports on a visual analog scale from 0 (no pain) to 100 (worst pain imaginable) during 8 consecutive days of experimental testing. The same participants were tested for pain sensitivity after 90 days and the control group showing habituation to pain but not the context group. Importantly, the fMRI data indicated a higher activation of the right parietal operculum compared to the control group. Adapted from Ref. 65. Republished with permission of The Society for Neuroscience, from Rodriguez-Raecke R, Doganci B, Breimhorst M, Stankewitz A, Buchel C, Birklein F, May A. Insular cortex activity is associated with effects of negative expectation on nociceptive long-term habituation. J Neurosci 2010;30:11363–8. Permission conveyed through Copyright Clearance Center, Inc. The red marks indicate the activation in the right pariental operculum and the red circle shows a zoomed activation area.

Figure 3.

Nocebo effects at the level of spinal cord. Study participants were informed that a cream would increase pain experience. During the acquisition phase, the level of pain was surreptitiously enhanced to simulate increased pain because of the cream. During the testing phase in the fMRI, the pain intensities were identical. Participants reported higher pain to the heat stimuli delivered to a lower intensity level. The fMRI results indicated an increase of activity in the left ipsilateral dorsal horn, suggestive of nocebo-induced hyperactivity. Adapted from Ref. 47. Republished with permission of The Society for Neuroscience, from Geuter S, Buchel C. Facilitation of pain in the human spinal cord by nocebo treatment. J Neurosci 2013;33:13784–90. Permission conveyed through Copyright Clearance Center, Inc. The red arrow indicates activity in the ipsilateral dorsal horn and the blue box indicates the spinal sagittal section. *p < 0.050.

Figure 4.

Nocebo algesia and hyperalgesia are triggered by an individual's negative expectancies around a treatment or intervention, its efficacy, and its potential outcomes. These expectations can be shaped by verbal suggestions or instructions, the individual's prior experience and conditioning with the same or related treatments, as well as by the observation of others in pain (social observation/vicarious learning) and individual psychological characteristics such as personality factors. This complex interplay of cognitive-affective factors leads to physiological changes that can initiate as well as promote algesic and hyperalgesic states including anxiety changes along with an activation of the hypothalamic–pituitary–adrenal (HPA) axis and the cholecystokinin (CCK) system. Hypoactivity of the mesolimbic dopaminergic and of the endogenous opioid systems have been observed following exposure to a nocebo procedure. Neurophysiological changes in the brain include increased activity of the nCF region, the insular cortex, the hippocampus, the periaqueductal gray area (PGA), the hippocampus and the ipsilateral dorsal horn, as well as decreased connectivity between the anterior cingulate cortex (ACC) and the fusiform gyrus. Finally, EEG recordings have also shown increased levels of low-frequency α-waves associated with nocebo-induced pain.