The interaction between stress and chronic pain through the lens of threat learning

Abstract

Stress and pain are interleaved at multiple levels - interacting and influencing each other. Both are modulated by psychosocial factors including fears, beliefs, and goals, and are served by overlapping neural substrates. One major contributing factor in the development and maintenance of chronic pain is threat learning, with pain as an emotionally-salient threat - or stressor. Here, we argue that threat learning is a central mechanism and contributor, mediating the relationship between stress and chronic pain. We review the state of the art on (mal)adaptive learning in chronic pain, and on effects of stress and particularly cortisol on learning. We then provide a theoretical integration of how stress may affect chronic pain through its effect on threat learning. Prolonged stress, as may be experienced by patients with chronic pain, and its resulting changes in key brain networks modulating stress responses and threat learning, may further exacerbate these impairing effects on threat learning. We provide testable hypotheses and suggestions for how this integration may guide future research and clinical approaches in chronic pain.

Keywords: Chronic pain; Cortisol; Fear avoidance model; HPA axis; Learning and memory; Pain; Stress; Threat learning.

Figure 1:. Pain and its modulation.

A. Factors that are known to influence the pain experience are listed. B. The main brain areas/networks implicated in pain and chronic pain. Brain areas overlapping with stress responses are highlighted in red. a/pIns = anterior/ posterior insula, amy = amygdala, d/rACC = dorsal/ rostral anterior cingulate cortex, hippo = hippocampus, I/mPFC = lateral/medial prefrontal cortex, NAc = nucleus accumbens, OFC = orbitofrontal cortex, PAG = periaqueductal grey, RVM = rostral ventromedial medulla, SI/SII = primary/secondary somatosensory cortex.

Figure 2:. Proposed key points of contact for stress, overlaid on an adapted version of the fear avoidance model of chronic pain.

The four points of contact where the HPA axis stress response is argued to interact with threat learning and pain are: [1] Stress may bias our system into perceiving a stimulus or situation with actual or potential tissue damage as highly threatening by increasing attention to the threat and optimizing threat-processing. [2] Pain-related distress (e.g., catastrophizing, fears) may facilitate the activation of the HPA axis stress response, while an HPA axis stress response may also affect aspects of the pain experience. [3] Stress may bias towards inflexible, rule-governed behavior by compromising value-based, flexible goal-directed behavior. [4] Stress may further modulate threat learning. Fear avoidance model adapted from Vlaeyen and colleagues (2016)

Figure 3:. The two major stress response systems and its modulation and timing.

A. The sympathetic adrenal medullary (SAM) and the hypothalamic-pituitary-adrenal axis (HPA) stress responses are depicted, as well as the main brain areas modulating the stress responses. B. The different timings of the multiple stress systems, which need to be taken into account when assessing them. In addition, different ways of quantifying the stress response are depicted. ACTH = adrenocorticotropic hormone, AUCg/i = area under the curve with respect to ground/increase, AVP = Arginine-vasopressin, CRH = corticotropin-releasing hormone, mPFC = medial prefrontal cortex

Figure 4:. Categories of learning involved in (chronic) pain.

The two main types of learning involved in chronic pain, classical (Pavlovian) learning (A) and operant learning (B) are depicted using examples. Note that although in some cases avoiding a behavior that is painful may be adaptive on the short term, avoidance behavior in general is considered maladaptive and has been linked to reduced overall functioning and increased disability. On the right, a brief overview is provided on how these types of learning are relevant for and/or altered in patients with chronic pain.