Pain: A Statistical Account.

Perception is seen as a process that utilises partial and noisy information to construct a coherent understanding of the world. Here we argue that the experience of pain is no different; it is based on incomplete, multimodal information, which is used to estimate potential bodily threat. We outline a Bayesian inference model, incorporating the key components of cue combination, causal inference, and temporal integration, which highlights the statistical problems in everyday perception. It is from this platform that we are able to review the pain literature, providing evidence from experimental, acute, and persistent phenomena to demonstrate the advantages of adopting a statistical account in pain. Our probabilistic conceptualisation suggests a principles-based view of pain, explaining a broad range of experimental and clinical findings and making testable predictions.

Perceptual Inference in Chronic Pain: An Investigation Into the Economy of Action Hypothesis.

OBJECTIVE: The experience of chronic pain critically alters one's ability to interact with their environment. One fundamental issue that has received little attention, however, is whether chronic pain disrupts how one perceives their environment in the first place. The Economy of Action hypothesis purports that the environment is spatially scaled according to the ability of the observer. Under this hypothesis it has been proposed that the perception of the world is different between those with and without chronic pain. Such a possibility has profound implications for the investigation and treatment of pain. The present investigation tested the application of this hypothesis to a heterogenous chronic pain population. METHODS: Individuals with chronic pain (36; 27F) and matched pain-free controls were recruited. Each participant was required to judge the distance to a series of target cones, to which they were to subsequently walk. In addition, at each distance, participants used Numerical Rating Scales to indicate their perceived effort and perceived pain associated with the distance presented. RESULTS: Our findings do not support the Economy of Action hypothesis: there were no significant differences in distance estimates between the chronic pain and pain-free groups (F1,60=0.927; P=0.340). In addition, we found no predictive relationship in the chronic pain group between anticipated pain and estimated distance (F1,154=0.122, P=0.727), nor anticipated effort (1.171, P=0.281) and estimated distance (F1,154=1.171, P=0.281). DISCUSSION: The application of the Economy of Action hypothesis and the notion of spatial perceptual scaling as a means to assess and treat the experience of chronic pain are not supported by the results of this study.

The close proximity of threat: altered distance perception in the anticipation of pain.

Pain is an experience that powerfully influences the way we interact with our environment. What is less clear is the influence that pain has on the way we perceive our environment. We investigated the effect that the anticipation of experimental pain (THREAT) and its relief (RELIEF) has on the visual perception of space. Eighteen (11F) healthy volunteers estimated the distance to alternating THREAT and RELIEF stimuli that were placed within reachable space. The results determined that the estimated distance to the THREAT stimulus was significantly underestimated in comparison to the RELIEF stimulus. We conclude that pain-evoking stimuli are perceived as closer to the body than otherwise identical pain-relieving stimuli, an important consideration when applied to our decisions and behaviors in relation to the experience of pain.

Cerebral analgesic response to nonsteroidal anti-inflammatory drug ibuprofen.

Nonopioid agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are the most commonly used class of analgesics. Increasing evidence suggests that cyclooxygenase (COX) inhibition at both peripheral and central sites can contribute to the antihyperalgesic effects of NSAIDs, with the predominant clinical effect being mediated centrally. In this study, we examined the cerebral response to ibuprofen in presurgical and postsurgical states and looked at the analgesic interaction between surgical state and treatment. We used an established clinical pain model involving third molar extraction, and quantitative arterial spin labelling (ASL) imaging to measure changes in tonic/ongoing neural activity. Concurrent to the ASL scans, we presented visual analogue scales inside the scanner to evaluate the subjective experience of pain. This novel methodology was incorporated into a randomized double-blind placebo-controlled design, with an open method of drug administration. We found that independent of its antinociceptive action, ibuprofen has no effect on regional cerebral blood flow under pain-free conditions (presurgery). However, in the postsurgical state, we observed increased activation of top-down modulatory circuits, which was accompanied by decreases in the areas engaged because of ongoing pain. Our findings demonstrate that ibuprofen has a measurable analgesic response in the human brain, with the subjective effects of pain relief reflected in two distinct brain networks. The observed activation of descending modulatory circuits warrants further investigation, as this may provide new insights into the inhibitory mechanisms of analgesia that might be exploited to improve safety and efficacy in pain management.

Pharmacologic modulation of hand pain in osteoarthritis: a double-blind placebo-controlled functional magnetic resonance imaging study using naproxen.

OBJECTIVE: In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging (fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC) joint. METHODS: A placebo-controlled, double-blind, 2-period crossover study was performed in 19 individuals with painful OA of the CMC joint of the right hand. Following placebo or naproxen treatment periods, a functionally relevant task was performed, and behavioral measures of the pain experience were collected in identical fMRI examinations. Voxelwise and a priori region of interest analyses were performed to detect between-period differences in brain activity. RESULTS: Significant reductions in brain activity following treatment with naproxen, compared to placebo, were observed in brain regions commonly associated with pain perception, including the bilateral primary somatosensory cortex, thalamus, and amygdala. Significant relationships between changes in perceived pain intensity and changes in brain activity were also observed in brain regions previously associated with pain intensity. CONCLUSION: This study demonstrates the sensitivity of fMRI to detect the mechanisms underlying treatments of known efficacy. The data illustrate the enticing potential of fMRI as an adjunct to self-report for detecting early signals of efficacy of novel therapies, both pharmacologic and nonpharmacologic, in small numbers of individuals with persistent pain.

Quantifying the test-retest reliability of cerebral blood flow measurements in a clinical model of on-going post-surgical pain: A study using pseudo-continuous arterial spin labelling.

Arterial spin labelling (ASL) is increasingly being applied to study the cerebral response to pain in both experimental human models and patients with persistent pain. Despite its advantages, scanning time and reliability remain important issues in the clinical applicability of ASL. Here we present the test-retest analysis of concurrent pseudo-continuous ASL (pCASL) and visual analogue scale (VAS), in a clinical model of on-going pain following third molar extraction (TME). Using ICC performance measures, we were able to quantify the reliability of the post-surgical pain state and ΔCBF (change in CBF), both at the group and individual case level. Within-subject, the inter- and intra-session reliability of the post-surgical pain state was ranked good-to-excellent (ICC > 0.6) across both pCASL and VAS modalities. The parameter ΔCBF (change in CBF between pre- and post-surgical states) performed reliably (ICC > 0.4), provided that a single baseline condition (or the mean of more than one baseline) was used for subtraction. Between-subjects, the pCASL measurements in the post-surgical pain state and ΔCBF were both characterised as reliable (ICC > 0.4). However, the subjective VAS pain ratings demonstrated a significant contribution of pain state variability, which suggests diminished utility for interindividual comparisons. These analyses indicate that the pCASL imaging technique has considerable potential for the comparison of within- and between-subjects differences associated with pain-induced state changes and baseline differences in regional CBF. They also suggest that differences in baseline perfusion and functional lateralisation characteristics may play an important role in the overall reliability of the estimated changes in CBF. Repeated measures designs have the important advantage that they provide good reliability for comparing condition effects because all sources of variability between subjects are excluded from the experimental error. The ability to elicit reliable neural correlates of on-going pain using quantitative perfusion imaging may help support the conclusions derived from subjective self-report.

Perceptual bias in pain: a switch looks closer when it will relieve pain than when it won't.

Pain is fundamental to survival, as are our perceptions of the environment. It is often assumed that we see our world as a read-out of the sensory information that we receive; yet despite the same physical makeup of our surroundings, individuals perceive differently. What if we "see" our world differently when we experience pain? Until now, the causal effect of experimental pain on the perception of an external stimulus has not been investigated. Eighteen (11 female) healthy volunteers participated in this randomised repeated-measures experiment, in which participants estimated the distance to a switch placed on the table in front of them. We varied whether or not the switch would instantly stop a stimulus, set to the participant's pain threshold, being delivered to their hand, and whether or not they were required to reach for the switch. The critical result was a strong interaction between reaching and pain [F(1,181)=4.8, P=0.03], such that when participants experienced pain and were required to reach for a switch that would turn off the experimental stimulus, they judged the distance to that switch to be closer, as compared to the other 3 conditions (mean of the true distance 92.6%, 95% confidence interval 89.7%-95.6%). The judged distance was smaller than estimates in the other 3 conditions (mean±SD difference >5.7%±2.1%, t(181) >3.5, P<0.01 for all 3 comparisons). We conclude that the perception of distance to an object is modulated by the behavioural relevance of the object to ongoing pain.

CCL2 is a key mediator of microglia activation in neuropathic pain states.

While neuroimmune interactions are increasingly recognized as important in nociceptive processing, the nature and functional significance of these interactions is not well defined. There are multiple reports that the activation of spinal microglia is a critical event in the generation of neuropathic pain behaviors but the mediators of this activation remain disputed. Here we show that the chemokine CCL2, produced by both damaged and undamaged primary sensory neurons in neuropathic pain states in rats, is released in an activity dependent manner from the central terminals of these fibres. We also demonstrate that intraspinal CCL2 in naïve rats leads to activation of spinal microglia and neuropathic pain-like behavior. An essential role for spinal CCL2 is demonstrated by the inhibition of neuropathic pain behavior and microglial activation by a specific neutralising antibody to CCL2 administered intrathecally. Thus, the neuronal expression of CCL2 provides a mechanism for immune activation, which in turn regulates the sensitivity of pain signaling systems in neuropathic pain states.

Pathophysiology of peripheral neuropathic pain: immune cells and molecules.

Damage to the peripheral nervous system often leads to chronic neuropathic pain characterized by spontaneous pain and an exaggerated response to painful and/or innocuous stimuli. This pain condition is extremely debilitating and usually difficult to treat. Although inflammatory and neuropathic pain syndromes are often considered distinct entities, emerging evidence belies this strict dichotomy. Inflammation is a well-characterized phenomenon, which involves a cascade of different immune cell types, such as mast cells, neutrophils, macrophages, and T lymphocytes. In addition, these cells release numerous compounds that contribute to pain. Recent evidence suggests that immune cells play a role in neuropathic pain in the periphery. In this review we identify the different immune cell types that contribute to neuropathic pain in the periphery and release factors that are crucial in this particular condition.