Fear of pain in children and adolescents with neuropathic pain and complex regional pain syndrome

Abstract

A significant proportion of children and adolescents with chronic pain endorse elevated pain-related fear. Pain-related fear is associated with high levels of disability, depressive symptoms, and school impairment. Because of faulty nerve signaling, individuals with neuropathic pain and complex regional pain syndrome may be more prone to develop pain-related fear as they avoid use of and neglect the affected body area(s), resulting in exacerbated symptoms, muscle atrophy, maintenance of pain signaling, and ongoing pain-related disability. Not surprisingly, effective treatments for elevated pain-related fears involve exposure to previously avoided activities to downregulate incorrect pain signaling. In the context of intensive interdisciplinary pain treatment of youth with neuropathic pain, decreasing pain-related fear is associated with improved physical and psychological functioning, whereas high initial pain-related fear is a risk factor for less treatment responsiveness. An innovative approach to targeting pain-related fear and evidence of a neural response to treatment involving decoupling of the amygdala with key fear circuits in youth with complex regional pain syndrome suggest breakthroughs in our ability to ameliorate these issues.

Figure 1. Model with Functional Disability and Depression as Concurrent Outcome

For functional disability (a) the FAM was robustly upheld. For depressive symptoms (b), additional direct pathways for pain catastrophizing and fear of pain were necessary for acceptable model fit. Solid lines are significant at p < .05. Error variances were not included in the figure for simplicity and interpretability. Italicized regression coefficients are non-significant pathways. ^†denotes values that significantly differ from one another within a specific pathway.

Figure 2. Interpersonal Fear Avoidance Model of Pain (IFAM)

a. In the IFAM model, a child or adolescent develops pain, often in response to an event; although, it can also begin spontaneously. In the context of the child’s pain experience, (s)he either responds with progressive confrontation and acceptance of pain in his/her life for now or continues to perceive the presence of pain as threatening. This expression of threat and fear is observed and interpreted by the parent and reciprocally interacts with a parent’s own catastrophic thinking about his/her child’s pain. This, in turn, leads to hypervigilance and persistent fear in the child and parent. In the context of heightened fear, the child avoids activities that (s)he perceives as potentially harmful to his/her with parent protective behavior providing further encouragement for avoidance behavior. Ultimately, this leads to declines in child functioning and limitations in the life of the parent/caregiver. b. Child fear and catastrophizing and parent behavior had a direct and indirect influence on child avoidance behavior, while parent fear and catastrophizing indirectly influenced child avoidance. Overall, the model accounted for 20% of the variance in functional disability, X²(30) = 46.95, CFI = .97, RSMEA = .06 (CI=.02–.09). Child avoidance is measured with the Avoidance of Activities subscale of the Fear of Pain Questionnaire, Child report (FOPQ). Child disability is measured with the Functional Disability Inventory (FDI). Parent Avoidance is measured with the Parent Avoidance subscale of the Parent Fear of Pain Questionnaire (PFOPQ). PCS-C: Pain Catastrophizing Scale, Child report; ARCS: Adult Responses to Child’s Symptoms; PCS-P: Pain Catastrophizing Scale, Parent report.

Figure 3. Neural Pathways of Fear Learning

In fear conditioning, an emotionally neutral conditioned stimulus (CS; e.g., movement) is presented with an aversive unconditioned stimulus (US; pain). The CS and US converge at the lateral nucleus (LA). The LA then connects with the centromedial nucleus (CM), controlling the expression of the conditioned fear responses (CR) in the brain stem and hypothalamus. Projections from the hippocampus to the basal nucleus (B) of the amygdala process contextual information during conditioning, while the insula and anterior cingulate (ACC) influence threat encoding. During extinction learning, inhibitory connections between the ventromedial prefrontal cortex (vmPFC) and intercalcated (ITC) cell masses are established. During extinction recall, these connections inhibit fear expression through projections to the CM. Inhibitory connections between the vmPFC and LA may also regulate fear expression through the CM. Contextual modulation of extinction expression is mediated by projections from the hippocampus to the vmPFC and/or LA. Adapted from[20; 53].

Figure 4. Connectivity strength by levels of pain-related fear in patients (Left Amygdala)

Across time, areas associated with fear circuitry were consistently associated with higher pain-related fear scores. Key: MTG: middle temporal gyrus; BS: brain stem; Hi: hippocampus; Ins: insula; FrP: frontal pole; ACC: anterior cingulate cortex; SFG: superior frontal gyrus; Cb: cerebellum; MeFG: medial frontal gyrus.

Figure 5. Treatment Response from Time 1 to Time 2: Decrease in functional connectivity and pain-related fear

Paired analysis of amygdala connectivity changes within patients is depicted in green while connectivity changes that correlated with changes in pain-related fear are displayed in red. Many of the amygdala connectivity decreases were correlated with decreases in pain-related fear after treatment, suggesting that changes in intrinsic brain functional connectivity can be linked to symptom improvement. Key: MFG: middle frontal gyrus; Ins: insula; SMA: supplementary motor area; ACC: anterior cingulate cortex; MCC: middle cingulate cortex; FOP: frontal opercular cortex.