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.

Anatomical and functional correlates of persistent pain in Parkinson's disease.

BACKGROUND: The pathophysiology of pain in Parkinson's disease (PD) is still poorly understood, although it is conceivable that supraspinal mechanisms may be responsible for pain generation and maintenance. METHODS: We examined brain functional and anatomical changes associated with persistent pain in 40 PD patients, 20 with persistent pain and 20 without pain. We also examined 15 pain-free healthy participants of similar age, gender, and cognitive state as a control group. We assessed pain by the King's Parkinson's Pain Scale, the Visual Analogue Scale for pain, and the Leeds Assessment for Neuropathic Symptoms and Sign. All patients underwent structural, diffusion tensor imaging, and resting-state functional MRI. We compared clinical characteristics, whole-brain cortical thickness, subcortical volumes, diffusion tensor imaging scalar measures, and functional connectivity by network based statistics. RESULTS: The group with PD and persistent pain showed significant thinning in the bilateral temporal pole, left-medial orbitofrontal cortex, bilateral superior and left-inferior parietal areas, pars orbicularis, and right superior frontal, posterior cingulated, and precentral cortex. There were no significant subcortical volume and white matter differences between PD subgroups. Functional MRI showed a decrease of brain activity in the left frontal inferior orbital in PD patients with persistent pain, with greater activity bilaterally in the cerebellum and in the right inferior temporal areas. Only PD patients with persistent pain showed an accumbens-hippocampus disconnection without white matter and subcortical alterations. CONCLUSIONS: We showed that persistent pain in PD is associated with supraspinal structural and functional changes. We also highlighted the contribution of frontal, prefrontal, and insular areas in nociceptive modulation and accumbens-hippocampus disconnection. © 2016 International Parkinson and Movement Disorder Society.

The moral experience of the patient with chronic pain: bridging the gap between first and third person ethics.

BACKGROUND: There has been a widespread call for an ethics in the management of patients with chronic pain which is patient centered and takes into account the lived experience of the patient. It has been argued in literature that current "duty" or principlist-based models of ethics (so-called 3rd person ethics) have not adequately addressed the needs of either patients or practitioners in this area. METHOD: Two strands of literature within phenomenology were reviewed: the literature of interpretative phenomenological analysis and the study of the lived experience of the person with chronic pain; and the contribution of phenomenology in neo-Aristotelian virtue ethics (1st person ethics). FINDINGS: Patients experience chronic pain in existential and moral terms in addition to their biomedical issues, facing dilemmas in understanding their own self-identity and in attempting to recover a sense of moral worth and agency. DISCUSSION: We outline a patient-centered ethics to underpin contemporary collaborative, multimodal approaches in the management of chronic pain. We firstly describe an agency-oriented, neo-Aristotelian 1st person ethics and then outline a hermeneutic relationship with extant "duty-based," 3rd person bioethics. The utility of the ethics model we propose (the ethical reasoning bridge) lies in its capacity for developing a sense of moral agency for both practitioner and patient, resonating with the current emphasis of seeking active engagement of patients in management.

Alterations in resting-state regional cerebral blood flow demonstrate ongoing pain in osteoarthritis: An arterial spin-labeled magnetic resonance imaging study.

OBJECTIVE: Increasing evidence suggests a central nervous system (CNS) component underpinning persistent pain disease states. This study was undertaken to determine regional cerebral blood flow (rCBF) changes representing ongoing pain experienced by patients with painful osteoarthritis (OA) of the carpometacarpal (CMC) joint and to examine rCBF variability across sessions. We used pulsed continuous arterial spin labeling (pCASL), a perfusion magnetic resonance imaging (MRI) technique. METHODS: The study included 16 patients with CMC OA and 17 matched controls. Two pCASL scans and numerical rating scale (NRS) estimates of ongoing pain were acquired in each of two identical sessions. Voxelwise general linear model analyses were performed to determine rCBF differences between OA and control groups, rCBF differences between sessions within each group, and whether sessionwise rCBF differences were related to variability in perceived ongoing pain. RESULTS: In the OA group, rCBF increases representing ongoing pain were identified in the primary and secondary somatosensory, insula, and cingulate cortices; thalamus; amygdala; hippocampus; and dorsal midbrain/pontine tegmentum, including the periaqueductal gray/nucleus cuneiformis. Sessionwise rCBF differences in the OA group in the postcentral, rostral/subgenual cingulate, mid/anterior insula, prefrontal, and premotor cortices were related to changes in perceived ongoing pain. No significant sessionwise rCBF differences were observed in controls. CONCLUSION: This is the first quantitative endogenous perfusion MRI study of the cerebral representation of ongoing, persistent pain due to OA. Observed rCBF changes potentially indicate dysregulated CNS appraisal and modulation of pain, most likely the maladaptive neuroplastic sequelae of living with painful OA. Understanding the neural basis of ongoing pain is likely to be important in developing novel treatment strategies.

Identifying consistent biomechanical parameters across rising-to-walk subtasks to inform rehabilitation in practice: A systematic literature review.

BACKGROUND: The best approach to rehabilitate the control of everyday whole-body movement (e.g. rise-to-walk) after pathology remains unclear in part because the associated controlled performance variables are not known. Rise-to-walk can be performed fluidly (sit-to-walk) or non-fluidly (sit-to-stand, proceeded by gait-initiation). Biomechanical variables that remain consistent in health regardless of how rise-to walk is performed represent controlled performance variable candidates which could monitor rehabilitative change. RESEARCH QUESTION: To determine if any biomechanical parameters remain consistent across rising-to-walk (RTW) subtasks (sit-to-stand, gait-initiation, and sit-to-walk) in healthy adults for purposes of movement control assessment in clinical practice. METHODS: Data sources included Medline, Cinahl, and Scopus databases, and the grey literature. Study selection was based on eligibility criteria and must have reported spatiotemporal, kinematic and/or kinetic biomechanical parameters featuring >1 RTW subtask. Data extraction and synthesis; standardised-mean-differences (SMDs) were calculated (pooled if replicated in >1 study) for each parameter. Consistency was determined if SMD95 %CIs included the zero-effect line. RESULTS: Nine studies (n = 99) were included (40 ±â€¯7.5yrs). Seven parameters were replicated in >1 study and subjected to meta-analysis (fixed-effect model). Two were consistent between sit-to-stand and sit-to-walk: flexion-momentum time (M(95 %CI) = 0.055(-0.423 to 0.533); p = 0.823) and peak whole-body-centre-of-mass vertical velocity (M(95 %CI)= -0.415(-0.898 to 0.069); p = 0.093); and centre-of-pressure to whole-body-centre-of-mass distance at toe-off (M(95 %CI)= -0.137(-0.712 to 0.439); p = 0.642) between gait-initiation and sit-to-walk. Another 20 parameters were consistent based on single-study SMDs. SIGNIFICANCE: Consistent parameters might exist across RTW subtasks. However, the evidence is based on few studies with small samples and variable RTW protocols. Future studies designed to confirm consistency using a standardised RTW protocol are needed.

Gait-initiation onset estimation during sit-to-walk: Recommended methods suitable for healthy individuals and ambulatory community-dwelling stroke survivors.

BACKGROUND: Gait-initiation onset (GI-onset) during sit-to-walk (STW) is commonly defined by mediolateral ground-reaction-force (xGRF) rising and crossing a threshold pre-determined from sit-to-stand peak xGRF. However, after stroke this method [xGRFthresh] lacks validity due to impaired STW performance. Instead, methodologies based upon instance of swing-limb maximum-vertical-GRF [vGRFmaxSWING], maximum-xGRF [xGRFmax], and swing-limb heel-off [firstHEELoff] can be applied, although their validity is unclear. Therefore, we determined these methodologies' validity by revealing the shortest transition-time (seat-off-GI-onset), their utility in routinely estimating GI-onset, and whether they exhibited satisfactory intra-subject reliability. METHODS: Twenty community-dwelling stroke (60 (SD 14) years), and twenty-one age-matched healthy volunteers (63 (13) years) performed 5 standardised STW trials with 2 force-plates and optical motion-tracking. Transition-time differences across-methods were assessed using Friedman tests with post-hoc pairwise-comparisons. Within-method single-measure intra-subject reliability was determined using ICC3,1 and standard errors of measurement (SEMs). RESULTS: In the healthy group, median xGRFthresh transition-time was significantly shorter than xGRFmax (0.183s). In both the healthy and stroke groups, xGRFthresh transition-times (0.027s, 0.695s respectively) and vGRFmaxSWING (0.080s, 0.522s) were significantly shorter than firstHEELoff (0.293s, 1.085s) (p<0.001 in all cases). GI-onset failed to be estimated in 48% of stroke trials using xGRFthresh. Intra-subject variability was relatively high but was comparable across all estimation methods. CONCLUSION: The firstHEELoff method yielded significantly longer transition-times. The xGRFthresh method failed to routinely produce an estimation of GI-onset estimation. Thus, with all methods exhibiting low, yet comparable intra-subject repeatability, averaged xGRFmax or vGRFmaxSWING repeated-measures are recommended to estimate GI-onset for both healthy and community-dwelling stroke individuals.

Psychosocial Risk Factors and the Association With Carpal Tunnel Syndrome: A Systematic Review.

BACKGROUND: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy of the upper limb. Research has shown that associative factors for CTS include occupational and biomechanical elements, sex, and age. To date, no systematic review has been undertaken to determine specifically whether there are any psychosocial risk factors in developing CTS. The objective is to determine whether psychosocial factors are associated with and/or predict the development of CTS. METHODS: A systematic review was conducted including searches of PubMed (MEDLINE), EMBASE, and CINAHL from inception to May 30, 2017. Quantitative studies must have investigated a minimum of 1 or more psychosocial factors-cognitive, affective, behavioral, vocational, or interpersonal processes (eg, social support)-and include a point or risk estimate. One reviewer conducted the search and 2 reviewers independently assessed eligibility and completed methodological quality assessment using a modified Downs and Black checklist. Data were analyzed narratively. RESULTS: Six moderate- to high-quality studies were included in the final review. Five studies reported a positive association between psychosocial factors and CTS, where psychosocial factors were more in those who reported CTS. One study reported no positive or negative association with CTS development. Four studies reported a negative association between psychosocial factors and CTS, where psychosocial factors were less in those who reported CTS. CONCLUSIONS: There is limited evidence for a positive association between psychosocial factors and CTS. However, this was not a consistent finding across all included studies. Further research is indicated in standardizing CTS diagnostic criteria and investigating other working environments.

Physical activity participation and the association with work-related upper quadrant disorders (WRUQDs): A systematic review.

BACKGROUND: Workers in various occupations often report work-related upper quadrant disorders (WRUQDs). Research has shown that associative factors for WRUQDs include psychosocial and environmental elements, gender and physical activity levels. To date, no review has investigated whether physical activity participation is associated with and/or predicts the development of WRUQDs, so the present study set out to determine this. METHODS: A systematic review was conducted including searches of PubMed (MEDLINE), EMBASE and CINAHL from inception to 31 March 2017. Quantitative studies, including any outcome measure of physical activity participation and its association with and/or prediction of WRUQDs, were included. One reviewer conducted the search and two reviewers independently assessed eligibility and completed methodological quality assessment using a modified Downs and Black checklist. Data were analysed narratively. RESULTS: Eight studies were eligible for inclusion in the final review. The quality of these ranged from moderate to high quality. Three studies reported no statistical difference between physical activity participation and the risk of developing WRUQD. Three studies reported a negative and one study a positive association between physical activity participation and WRUQDs. One study reported that little or no physical exercise participation was a risk factor for WRUQD. CONCLUSIONS: There is limited evidence for a negative association between physical activity participation and the development of WRUQDs. However, this was not a consistent finding across all studies included. Further research is indicated in standardizing diagnostic criteria and the measurement of physical activity participation in this patient population.

Factors associated with physical activity participation in adults with chronic cervical spine pain: a systematic review.

OBJECTIVE: To determine the factors associated with physical activity participation in adults with chronic cervical spine pain. METHODS: A systematic review was conducted including searches of PubMed (MEDLINE), EMBASE and CINAHL from inception to June 12th, 2016. Grey literature and reference checking was also undertaken. Quantitative studies including factors related to physical activity participation in adults with chronic cervical spine pain were included. Two independent authors conducted the searches, extracted data and completed methodological quality assessment. RESULTS: A total of seven studies met the selection criteria, however, four papers were finally included in the final review. A modified Downs and Black criteria was used to assess methodological quality, each study included was classed as moderate quality. A total of six factors were assessed against physical activity participation for people with chronic neck pain. These included: pain, fear of movement, smoking habits, socioeconomic status, gender, leisure and work time habits. A significant relationship was demonstrated between pain, leisure and work time habits and physical activity. Subjects were less likely to participate in physical activity if they were in pain. Subjects with neck pain were less likely to participate in physical activity in their leisure and work time. CONCLUSION: This review, based on a small number of heterogeneous studies demonstrated key factors that are likely to affect physical activity in people with chronic neck pain, most notably, pain levels, leisure and work habits. This review suggests that more in-depth, high quality studies are required to fully understand the impact of chronic pain on physical activity. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42015027970.

Parameters that remain consistent independent of pausing before gait-initiation during normal rise-to-walk behaviour delineated by sit-to-walk and sit-to-stand-and-walk.

BACKGROUND: Rising-to-walk is an everyday transitional movement task rarely employed in gait rehabilitation. Sit-to-walk (STW) and sit-to-stand-and-walk (STSW), where a pause separates sit-to-stand and gait-initiation (GI) represent extremes of rising-to-walk behaviour. Delayed GI can indicate pathological impairment but is also observed in healthy individuals. We hypothesise that healthy subjects express consistent biomechanical parameters, among others that differ, during successful rising-to-walk task performance regardless of behaviour. This study therefore sought to identify if any parameters are consistent between STW and STSW in health because they represent normal rise-to-walk performance independent of pause, and also because they represent candidate parameters sensitive enough to monitor change in pathology. METHODS: Ten healthy volunteers performed 5 trials of STW and STSW. Event timing, ground-reaction-forces (GRFs), whole-body-centre-of-mass (BCoM) displacement, and centre-of-pressure (CoP) to extrapolated BCoM (xCoM) distance (indicator of positional stability) up to the 3rd step were compared between-tasks with paired t-tests. For consistent parameters; agreement between-tasks was assessed using Bland-Altman analyses and minimal-detectable-change (MDC) calculations. RESULTS: Mean vertical GRFs, peak forward momentum and fluidity during rising; CoP-xCoM separation at seat-off, upright, GI-onset, and steps1-2; and forward BCoM velocity were all significantly greater in STW. In contrast, peak BCoM vertical momentum, flexion-momentum time, and 3rd step stability were consistent between tasks and yielded acceptable reliability. CONCLUSION: STW is a more challenging task due to the merging of rising with GI reflected by greater CoP-xCoM separation compared to STSW indicative of more positional instability. However, BCoM vertical momentum, flexion-momentum time, and step3 stability remained consistent in healthy individuals and are therefore candidates with which to monitor change in gait rehabilitation following pathology. Future studies should impose typical pause-durations observed in pathology upon healthy subjects to determine if the parameters we have identified remain consistent.

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.

Physical activity interventions are delivered consistently across hospitalized older adults but multimorbidity is associated with poorer rehabilitation outcomes: A population-based cohort study.

BACKGROUND: Older adults live with multimorbidity including frailty and cognitive impairment often requiring hospitalization. While physical activity interventions (PAIs) are a normal rehabilitative treatment, their clinical effect in hospitalized older adults is uncertain. OBJECTIVE: To observe PAI dosing characteristics and determine their impact on clinical performance parameters. DESIGN: A single-site prospective observational cohort study in an older persons' unit. SUBJECTS: Seventy-five older persons' unit patients ≥65 years. INTERVENTION: PAI; therapeutic contact between physiotherapy clinician and patient. MEASUREMENTS: Parameters included changes in activities-of-daily-living (Barthel Index), handgrip strength, balance confidence, and gait velocity, measured between admission and discharge (episode). Dosing characteristics were PAI temporal initiation, frequency, and duration. Frailty/cognition status was dichotomized independently per participant yielding 4 subgroups: frail/nonfrail and cognitively-impaired/cognitively-unimpaired. RESULTS: Median (interquartile range) PAI initiation occurred after 2 days (1-4), frequency was 0.4 PAIs per day (0.3-0.5), and PAI duration per episode was 3.75 hours (1.8-7.2). All clinical parameters improved significantly across episodes: grip strength median (interquartile range) change, 2.0 kg (0.0-2.3) (P < .01); Barthel Index, 5 (3-8) (P < .01); gait velocity, 0.06 m.∙s-1 (0.06-0.16) (P < .01); and balance confidence, -3 (-6 to -1) (P < .01). Physical activity intervention dosing remained consistent within subgroups. While several moderate to large associations between amount of PAIs and change in clinical parameters were observed, most were within unimpaired subgroups. CONCLUSIONS: PAI dosing is consistent. However, while clinical changes during hospital episodes are positive, more favourable responses to PAIs occur if patients are nonfrail/cognitively-unimpaired. Therefore, to deliver a personalized rehabilitation approach, adaptation of PAI dose based on patient presentation is desirable.

Sit-to-stand-and-walk from 120% Knee Height: A Novel Approach to Assess Dynamic Postural Control Independent of Lead-limb.

Individuals with sensorimotor pathology e.g., stroke have difficulty executing the common task of rising from sitting and initiating gait (sit-to-walk: STW). Thus, in clinical rehabilitation separation of sit-to-stand and gait initiation - termed sit-to-stand-and-walk (STSW) - is usual. However, a standardized STSW protocol with a clearly defined analytical approach suitable for pathological assessment has yet to be defined. Hence, a goal-orientated protocol is defined that is suitable for healthy and compromised individuals by requiring the rising phase to be initiated from 120% knee height with a wide base of support independent of lead limb. Optical capture of three-dimensional (3D) segmental movement trajectories, and force platforms to yield two-dimensional (2D) center-of-pressure (COP) trajectories permit tracking of the horizontal distance between COP and whole-body-center-of-mass (BCOM), the decrease of which increases positional stability but is proposed to represent poor dynamic postural control. BCOM-COP distance is expressed with and without normalization to subjects' leg length. Whilst COP-BCOM distances vary through STSW, normalized data at the key movement events of seat-off and initial toe-off (TO1) during steps 1 and 2 have low intra and inter subject variability in 5 repeated trials performed by 10 young healthy individuals. Thus, comparing COP-BCOM distance at key events during performance of an STSW paradigm between patients with upper motor neuron injury, or other compromised patient groups, and normative data in young healthy individuals is a novel methodology for evaluation of dynamic postural stability.

Sit-to-walk and sit-to-stand-and-walk task dynamics are maintained during rising at an elevated seat-height independent of lead-limb in healthy individuals.

INTRODUCTION: Sit-to-walk (STW) is a common transitional motor task not usually included in rehabilitation. Typically, sit-to-stand (STS), pause, then gait initiation (GI) before walking is used, which we term sit-to-stand-and-walk (STSW). Separation between centre-of-pressure (COP) and whole-body centre-of-mass (BCOM) during GI is associated with dynamic postural stability. Rising from seats higher than knee-height (KH) is more achievable for patients, but whether this and/or lead-limb significantly affects task dynamics is unclear. This study tested whether rising from seat-heights and lead-limb affects STW and STSW task dynamics in young healthy individuals. METHODS: Ten (5F) young (29±7.7 years) participants performed STW and STSW from a standardised position. Five trials of each task were completed at 100 and 120%KH leading with dominant and non-dominant legs. Four force-plates and optical motion capture delineated key movement events and phases with effect of seat-height and lead-limb determined by 2-way ANOVA within tasks. RESULTS: At 120%KH, lower peak vertical ground-reaction-forces (vGRFs) and vertical BCOM velocities were observed during rising irrespective of lead-limb. No other parameters differed between seat-heights or lead-limbs. During GI in STSW there was more lateral, and less posterior, COP excursion than expected. CONCLUSION: Reduction in vGRFs and velocity during rising at 120%KH is consistent with reduced effort in young healthy individuals and is likely therefore to be an appropriate seat-height for patients. Lead-limb had no effect upon STSW or STW parameters suggesting that normative data independent of lead-limb can be utilised to monitor motor rehabilitation should differences be observed in patients. STSW should be considered an independent movement transition.

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.