Pain and Its Assessment

Biological Factors

Pain is normally evoked by the activation of high-threshold sensory neurons. Primary sensory neurons, or afferents, detect sensory input to peripheral tissues including the skin, muscles, and joints, and relay that sensory information to the central nervous system. Second-order neurons in the spinal cord in turn relay information to the thalamus and various midbrain structures ( Fig. 8.2 ). Many afferents are sensitive to mechanical force, whereas others are sensitive to temperature, chemicals, or combinations thereof. A specific type of afferent may respond to a particular stimulus and, therefore, play a key role in how we sense that stimulus. The traditional distinction between low-threshold Aβ fibers (which are thickly myelinated and fast conducting) and high-threshold C and Aδ fibers (which are unmyelinated or thinly myelinated and slower conducting) is sufficient to account for many aspects of sensory coding.

Noxious stimuli cause (or at least have the potential to cause) tissue damage. Such stimuli are sensed by high-threshold C and Aδ afferents called nociceptors. Activation of nociceptors evokes pain, referred to as nociceptive pain . This normally serves an important protective role by triggering withdrawal from the noxious stimulus and teaching one to avoid such stimuli in the future, thus minimizing injury in the short and long term. The importance of this “alarm” is highlighted by individuals with congenital insensitivity to pain. Yet injury without pain is far less common than the converse, namely pain that is disproportionate to injury, inflammation, or other signs of pathology.

The explanation for disproportionate pain lies in the amplification of pain signals as a result of sensitization at different points along the pain pathway ( Fig. 8.3 ). Peripheral sensitization increases the excitability of nociceptors, with several consequences. First, a hyperexcitable nociceptor responds more vigorously than normal to a noxious stimulus, resulting in hyperalgesia , or exaggerated pain in response to noxious stimulation. Second, reduction of its threshold allows a nociceptor to be activated by weaker-than-normal stimuli, resulting in allodynia , or pain in response to innocuous stimulation. Third, a sufficiently large reduction in threshold will cause the nociceptor to become spontaneously active, generating action potentials in the absence of any sensory input and causing spontaneous pain. Nociceptors are sensitized by prostaglandins and cytokines including tumor necrosis factor-alpha (TNF-α), interleukin 1β (IL-1β), and IL-6. ^, Inflammation caused by release of cytokines from immune cells can be exacerbated by the release of proinflammatory peptides like calcitonin gene-related peptide (CGRP) and P from activated nociceptors, creating a vicious cycle referred to as neurogenic inflammation. Among peripheral neurons, only those innervating inflamed areas become sensitized, resulting in heightened pain sensitivity that is limited to sites of inflammation, referred to as primary hyperalgesia.

Central sensitization also causes pain signals to be amplified, but through changes occurring in the central nervous system. Central sensitization was originally defined as a prolonged but reversible increase in the excitability of spinal pain circuits triggered by nociceptor input, ^, but it has come to be associated with diverse neuroplastic changes that amplify pain signals centrally. Such changes are increasingly recognized to play an important role in the chronic pain associated with rheumatic diseases, helping to explain pain that is disproportionate to peripheral inflammation. Unlike primary hyperalgesia associated with peripheral sensitization, central sensitization causes heightened pain sensitivity that extends beyond sites of inflammation, which is referred to as secondary hyperalgesia. This occurs because each central neuron receives input from multiple afferents and their receptive field (i.e., the body area to which they respond to stimulation) is therefore larger than the receptive fields of individual afferents. If a central neuron becomes sensitized, its responsiveness to all of its inputs—from afferents originating inside or outside areas of peripheral inflammation—is increased.

Peripheral and central sensitization are not mutually exclusive; on the contrary, the former often contributes to the latter. Nor are central neuroplastic changes limited to spinal circuits; instead, changes in the early stages of pain processing tend to drive plasticity in areas further downstream, including in the thalamus and cortex. Furthermore, descending pathways whose activity depends in part on cortical signals reflecting one’s cognitive and emotional states (e.g., catastrophizing, anxiety) modulate processing at the spinal level. The somatosensory system can experience diverse maladaptive changes that affect how pain signals are processed and experienced. Similar changes can occur in neuropathic and dysfunctional forms of chronic pain. This knowledge is important for managing chronic pain because maladaptive neuroplastic changes, even if initially triggered by peripheral sensitization, may persist long after peripheral inflammation has resolved and may require additional interventions. Susceptibility to such neuroplastic changes has a strong genetic and epigenetic component, and the latter can reflect a broad range of environmental factors including such things as traumatic early life experiences.

Based on analysis of the Danish nationwide rheumatology registry, 22% of adult patients with inflammatory arthritis had neuropathic pain features identified based on a painDETECT questionnaire (PDQ) score greater than 18, and that number increases to 47% when patients with a PDQ score of 13 to 18 are included. Smaller studies have reported similar results. Further to this point, it has long been recognized that fibromyalgia, considered a form of dysfunctional pain, occurs in many individuals with rheumatic disorders. A recent meta-analysis reported the prevalence of fibromyalgia in adult patients with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis to be 21%, 13%, and 18%, respectively, compared with a prevalence of around 1% to 5% in the general population. Such data do not speak directly to the underlying biological mechanisms, but nonetheless hint at certain commonalities and are certainly important to consider when assessing and treating chronic pain. Similar patterns have not been studied in pediatric populations but may exist.

Several studies have reported reduced pain thresholds and reduced pain tolerance in patients with JIA, including those with active and quiescent disease. ^, These lowered pain thresholds and tolerance have been correlated with increased reported pain, consistent with peripheral and central sensitization contributing to the pain experience in JIA. Furthermore, many patients continue to experience moderate to severe pain despite adequate treatment with disease-modifying therapy, biologics, and nonsteroidal antiinflammatory drugs. ^, A survey of pediatric rheumatologists highlighted that pediatric patients continue to experience moderate to severe pain despite adequate treatment with disease-modifying therapy and nonsteroidal antiinflammatory drugs. For example, an electronic diary study (three times per day for 1 month) found that although most participants were under treatment with a disease-modifying antirheumatic drug (79%) or a biological agent (47%), they continued to report pain in 66% of all e-diary entries. Across the entire study period, not one participant was completely pain-free, and 86% of participants reported at least one high pain level. Similarly, Lomholt et al. found that, on average, children treated with anti-TNF agents experienced degrees of pain comparable to children receiving standard treatment. Overall, more children in the anti-TNF group reported no pain compared with the standard treatment group. However, a similar percentage of children in each group reported experiencing pain on every day of the study period. Among children who reported pain in the diary, the intensity of pain was greater in the anti-TNF group. These findings are similar to those of Anink et al., who reported on a longitudinal sample of 43 children with JIA who had received etanercept for a median of 8.5 years. They found that chronic pain remained more prevalent than expected in the presence of low levels of disease activity and disability.

Psychological Factors

Psychological factors involve emotion and cognition. Emotion is the more immediate reaction to nociception and is more midbrain based. For example, there is strong correlational support for the link between negative emotions, particularly anxiety and depression, and increased pain and pain-related inference in children with JIA. Daily stressful events and negative mood have been linked to increased pain, stiffness, and fatigue in youth with polyarticular JIA. Cognitions then attach meaning to the emotional experience and can trigger additional emotional reactions and thereby amplify the experience of pain, thus reinforcing a vicious cycle of nociception, pain, distress, and disability. For example, pain catastrophizing (rumination or preoccupation with pain-related thoughts, magnification or exaggeration of the threat value of pain, and helplessness in ability to cope with pain), pain-related fear, and pain acceptance have emerged as key factors associated with and predictive of pain-related outcomes in pediatric chronic pain. Studies specifically in children with JIA have found that cognitive coping strategies such as emotion-focus avoidance (catastrophizing and expressing negative emotions) and cognitive self-instruction (primarily wishful thinking) were related to greater pain and emotional distress whereas strategies such as cognitive refocusing (distraction) and feelings of self-control over pain were associated with less pain.