Assessment of exercise-induced hypoalgesia in chronic low back pain and potential associations with psychological factors and central sensitization symptoms: A case-control study.

INTRODUCTION: Exercise is the most recommended treatment for chronic low back pain (CLBP) and is effective in reducing pain, but the mechanisms underlying its effects remain poorly understood. Exercise-induced hypoalgesia (EIH) may play a role and is thought to be driven by central pain modulation mechanisms. However, EIH appears to be disrupted in many chronic pain conditions and its presence in people with CLBP remains unclear. As people suffering from chronic pain often exhibit psychological factors and central sensitization symptoms influencing pain perception, EIH might be associated with these factors. OBJECTIVE: The aim of this study is to compare the level of EIH between participants with and without CLBP following back and wrist exercises and to assess the associations between EIH, psychological factors, and symptoms of central sensitization (using the central sensitization inventory - CSI) in CLBP. METHOD: Twenty-eight participants with CLBP and 23 without pain were recruited. Pressure pain thresholds (PPT) were measured at 4 sites (2 bony sites = capitate, S1|2 muscle sites = wrist flexors, lumbar erector spinae) before and after each of two exercises (wrist flexion and lumbar extension). Exercise-induced hypoalgesia was defined as percent change in PPT from pre- to post-exercise. Participants with CLBP also completed questionnaires to measure psychological factors (e.g., kinesiophobia, catastrophizing, anxiety, and self-efficacy) and symptoms of central sensitization (CSI), and correlations with EIH were calculated. RESULTS: After wrist exercise, EIH measured at the muscle sites was lower in the CLBP group compared with the pain-free group (p = 0.047) but no differences were found at bony sites (p = 0.49). No significant differences for EIH were observed following back exercise at muscle sites (p = 0.14) or at bony sites (p = 0.65). Exercise-induced hypoalgesia was not correlated with any psychological factors or with the CSI score. CONCLUSION: The lower EIH following wrist exercises may represent an alteration in pain modulation control in CLBP. However, psychological factors and central sensitization symptoms may not explain the differences observed.

The role of negative emotions in sex differences in pain sensitivity.

Pain perception varies widely among individuals due to the varying degrees of biological, psychological, and social factors. Notably, sex differences in pain sensitivity have been consistently observed in various experimental and clinical investigations. However, the neuropsychological mechanism underlying sex differences in pain sensitivity remains unclear. To address this issue, we quantified pain sensitivity (i.e., pain threshold and tolerance) using the cold pressure test and negative emotions (i.e., pain-related fear, pain-related anxiety, trait anxiety, and depression) using well-established questionnaires and collected magnetic resonance imaging (MRI) data (i.e., high-resolution T1 structural images and resting-state functional images) from 450 healthy subjects. We observed that, as compared to males, females exhibited lower pain threshold and tolerance. Notably, sex differences in pain sensitivity were mediated by pain-related fear and anxiety. Specifically, pain-related fear and anxiety were the complementary mediators of the relationship between sex and pain threshold, and they were the indirect-only mediators of the relationship between sex and pain tolerance. Besides, structural MRI data revealed that the amygdala subnuclei (i.e., the lateral and basal nuclei in the left hemisphere) volumes were the complementary mediators of the relationship between sex and pain-related fear, which further influenced pain sensitivity. Altogether, our results provided a comprehensive picture of how negative emotions (especially pain-related negative emotions) and related brain structures (especially the amygdala) contribute to sex differences in pain sensitivity. These results deepen our understanding of the neuropsychological underpinnings of sex differences in pain sensitivity, which is important to tailor a personalized method for treating pain according to sex and the level of pain-related negative emotions for patients with painful conditions.

I expect what you expect: An electrophysiological study on social expectation of pain.

Expectations and motor reactions related to pain are mainly acquired through personal experiences. Contingent negative variation (CNV) has been shown to be an informative electrophysiological measure of this pain anticipation. Expectations can also arise while observing others in painful conditions. However, it still remains unclear what are the neural correlates of this phenomenon and how the observation of others in pain can subsequently change our personal pain perception as well as our motor reaction to pain. Using CNV as a measure of expectation, this study aims to assess whether expectations formed through observation change the observer's own experience of pain and reaction to pain. A new cooperative task was designed where one participant, the model, received an electrical stimulation while another, the observer, watched the experiment and both were asked to stop the stimulation as fast as possible. Crucially, in a successive session, participants inverted their roles so that models became observers and vice versa. CNV was recorded in both participants simultaneously by means of two synchronized electroencephalograms. Results showed that CNV area did not differ between models and observers and reaction times were significantly faster in observers compared to models. Moreover, observers' pain perception was correlated to models' pain perception as well as to observers' empathy scores. These data show how expectations, perceptions as well as reactions related to pain are crucially affected not only by observation but by personal attitudes toward others and all these changes can be clearly described through CNV.

The CPM Effect: Functional Assessment of the Diffuse Noxious Inhibitory Control in Humans.

The diffuse noxious inhibitory control, which has been investigated extensively in animals, consists of the inhibitory modulation of pain pathways after heterotopic noxious stimulation. The subnucleus reticularis dorsalis, which lies in the caudal part of the medulla, together with its descending projections to the wide-dynamic-range neurones, is responsible for the diffuse noxious inhibitory control. Many studies have investigated the diffuse noxious inhibitory control phenomenon in humans. However, owing to the complexity of the effect of descending modulation on human pain perception, expert opinion has recommended the term "conditioned pain modulation" to describe the psychophysical paradigm in which a heterotopic noxious stimulus is used to affect pain pathways in humans. In this narrative review, we present the current knowledge on the mechanisms underlying the diffuse noxious inhibitory control in animals and show how this phenomenon can be investigated in humans by using the conditioned pain modulation paradigm. We also demonstrate the relevance of conditioned pain modulation to the pathophysiology of pain.

Assessment of experimental orofacial pain, pleasantness and unpleasantness via standardized psychophysical testing.

BACKGROUND: Somatosensory assessment within the orofacial region may be performed using highly standardized quantitative sensory testing (QST). However, the function of the C-tactile (CT) afferent, a nerve fibre linked to the perception of pleasant touch, is usually not evaluated. Furthermore, the perception of unpleasantness is also rarely assessed, a dimension not only limited to a painful experience. Therefore, the primary aim was to apply standardized QST stimuli as well as standardized pleasant stimuli and evaluate their potential capacity for evocation of perceived pain, pleasant and unpleasant sensations in the facial region. METHODS: Twenty-one female participants underwent QST as per the protocol derived from the German Research Network on Neuropathic Pain. For the first time, two modified protocols were used to investigate stimuli for perceived pleasantness and unpleasantness. RESULTS: Thermal stimuli provided separate thresholds for each sensation. From certain mechanical stimuli (e.g., vibration), overlap between the perceived sensations of pleasantness and unpleasantness was identified. It was not possible to evoke only an unpleasant sensation without a painful contribution, and both these sensations increased significantly when utilizing an increasing pinprick force (p < 0.011). Between dynamic stimuli, the brush was rated as significantly more pleasant than the cotton wool tip (p = 0.015). A quadratic model provided the best fit for velocity against mean pleasantness ratings (R2  = 0.62 ± 0.08), supporting previous CT afferent literature to some extent. CONCLUSION: Stimuli were generally not isolated to one sensation, highlighting the multidimensional construct of stimulus perception and the need for scales to capture this. SIGNIFICANCE: The battery of QST tests from the DFNS protocol has been modified to investigate pleasant and unpleasant sensations. This allows the evaluation of psychophysical properties across standardized dimensions to provide a thorough view of somatosensory function and to better understand the affective spectrum of somatosensory function.

Assessment of intra- and inter-regional interrelations between GABA+, Glx and BOLD during pain perception in the human brain - A combined 1H fMRS and fMRI study.

To explore brain activity and the related neurochemical processes, current research focuses increasingly on the combined acquisition of 1H MR spectra and fMRI data to investigate potential associations between local metabolite resting state levels and stimulus-induced BOLD signal changes. In this study, whole-brain fMRI measurements and localized functional 1H MEGA-PRESS MRS scans were conducted at 3T in healthy subjects prior to and during acute pain stimulation to quantify resting state GABA+/tCr and Glx/tCr levels in the insular cortex together with their stimulus-induced changes and to explore associations between these neurochemical parameters with intra-regional but also inter-regional BOLD responses. Inter-regionally, a significant negative correlation between the BOLD signal of a cluster in the supplementary motor area with overlap to the mid-cingulate cortex (R = -0.56, p = 0.004) and the insular resting state GABA+/tCr was obtained. Furthermore, pain induced insular ΔGlx was significantly positively associated with the BOLD signal in the left superior frontal gyrus, left and right inferior frontal gyrus, left inferior parietal lobe, left superior temporal gyrus, left anterior insula and right posterior insula, with R values ranging from 0.59 to 0.73 (p < 0.005). No intra-regional association was observed between BOLD and metabolite measures. These findings point toward interactions between metabolite levels and stimulus-induced BOLD responses in brain regions belonging to the pain processing network. The combination of fMRS and fMRI provides a powerful tool to improve our understanding about the complex system of neurochemical processes and brain activity within brain networks.

Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia.

Value information about a drug, such as the price tag, can strongly affect its therapeutic effect. We discovered that value information influences adverse treatment outcomes in humans even in the absence of an active substance. Labeling an inert treatment as expensive medication led to stronger nocebo hyperalgesia than labeling it as cheap medication. This effect was mediated by neural interactions between cortex, brainstem, and spinal cord. In particular, activity in the prefrontal cortex mediated the effect of value on nocebo hyperalgesia. Value furthermore modulated coupling between prefrontal areas, brainstem, and spinal cord, which might represent a flexible mechanism through which higher-cognitive representations, such as value, can modulate early pain processing.

Feelings of Clinician-Patient Similarity and Trust Influence Pain: Evidence From Simulated Clinical Interactions.

Pain is influenced by many factors other than external sources of tissue damage. Among these, the clinician-patient relationship is particularly important for pain diagnosis and treatment. However, the effects of the clinician-patient relationship on pain remain underexamined. We tested the hypothesis that patients who believe they share core beliefs and values with their clinician will report less pain than patients who do not. We also measured feelings of perceived clinician-patient similarity and trust to see if these interpersonal factors influenced pain. We did so by experimentally manipulating perceptions of similarity between participants playing the role of clinicians and participants playing the role of patients in simulated clinical interactions. Participants were placed in 2 groups on the basis of their responses to a questionnaire about their personal beliefs and values, and painful thermal stimulation was used as an analog of a painful medical procedure. We found that patients reported feeling more similarity and trust toward their clinician when they were paired with clinicians from their own group. In turn, patients' positive feelings of similarity and trust toward their clinicians-but not clinicians' feelings toward patients or whether the clinician and patient were from the same group-predicted lower pain ratings. Finally, the most anxious patients exhibited the strongest relationship between their feelings about their clinicians and their pain report. These findings increase our understanding of context-driven pain modulation and suggest that interventions aimed at increasing patients' feelings of similarity to and trust in health care providers may help reduce the pain experienced during medical care. PERSPECTIVE: We present novel evidence that the clinician-patient relationship can affect the pain experienced during medical care. We found that "patients" in simulated clinical interactions who reported feeling more similarity and trust toward their "clinicians" reported less pain, suggesting that increasing feelings of clinician-patient similarity and trust may reduce pain disparities.

Distinct temporal filtering mechanisms are engaged during dynamic increases and decreases of noxious stimulus intensity.

Physical stimuli are subject to pronounced temporal filtering during afferent processing such that changes occurring at certain rates are amplified and others are diminished. Temporal filtering of nociceptive information remains poorly understood. However, the phenomenon of offset analgesia, where a disproportional drop in perceived pain intensity is caused by a slight drop in noxious heat stimulation, indicates potent temporal filtering in the pain pathways. To develop a better understanding of how dynamic changes in a physical stimulus are constructed into an experience of pain, a transfer function between the skin temperature and the perceived pain intensity was modeled. Ten seconds of temperature-controlled near-infrared (970 nm) laser stimulations above the pain threshold with a 1°C increment, decrement, or constant temperature were applied to the dorsum of the hand of healthy human volunteers. The skin temperature was assessed by an infrared camera. Offset analgesia was evoked by laser heat stimulation. The estimated transfer functions showed shorter latencies when the temperature was increased by 1°C (0.53 seconds [0.52-0.54 seconds]) than when decreased by 1°C (1.15 seconds [1.12-1.18 seconds]) and smaller gains (increase: 0.89 [0.82-0.97]; decrease: 2.61 [1.91-3.31]). The maximal gain was observed at rates around 0.06 Hz. These results show that temperature changes occurring around 0.06 Hz are best perceived and that a temperature decrease is associated with a larger but slower change in pain perception than a comparable temperature increase. These psychophysical findings confirm the existence of differential mechanisms involved in temporal filtering of dynamic increases and decreases in noxious stimulus intensity.

Assessment of quadriceps muscle inactivation with a new electrical stimulation paradigm.

INTRODUCTION: In this study we evaluated the validity of garment-based quadriceps stimulation (GQS) for assessment of muscle inactivation in comparison with femoral nerve stimulation (FNS). METHODS: Inactivation estimates (superimposed doublet torque), self-reported discomfort, and twitch and doublet contractile properties were compared between GQS and FNS in 15 healthy subjects. RESULTS: Superimposed doublet torque was significantly lower for GQS than for FNS at 20% and 40% maximum voluntary contraction (MVC) (P < 0.01), but not at 60%, 80%, and 100% MVC. Discomfort scores were systematically lower for GQS than for FNS (P < 0.05). Resting twitch and doublet peak torque were lower for GQS, and time to peak torque was shorter for GQS than for FNS (P < 0.01). CONCLUSIONS: GQS can be used with confidence for straightforward evaluation of quadriceps muscle inactivation, whereas its validity for assessment of contractile properties remains to be determined.

Is experimentally induced pain associated with socioeconomic status? Do poor people hurt more?

BACKGROUND: The association of pain and socioeconomic status is widely reported, yet much less clearly understood. The aim of this study was to investigate the association of experimentally induced pain threshold and tolerance with socioeconomic status. MATERIAL/METHODS: The study sample consisted of 319 adult subjects from the population of the island of Vis, Croatia, which was previously shown to have a high level of social homogeneity. A manual dolorimeter was used to measure mechanical pressure pain threshold (least stimulus intensity) and pain tolerance (maximum tolerance stimulus intensity) on both hands. Pain tolerance interval was defined as the difference between pain tolerance and threshold. Years of schooling and material status were used as socioeconomic estimates. RESULTS: Both of the socioeconomic estimates were significantly correlated with pain threshold, tolerance, and tolerance interval (P<0.001). The mixed modeling analysis, controlled for the effects of age, gender, and 4 psychological variables, indicated that education was not a significant predictor in any of the 3 models. However, lower material status was significantly associated with lower pain tolerance (P=0.038) and narrower pain tolerance interval (P=0.032), but not with pain threshold (P=0.506). The overall percentages of explained variance were lower in the tolerance interval model (20.2%) than in pain tolerance (23.1%) and threshold (33.1%), suggesting the increasing share of other confounding variables in pain tolerance and even more so in tolerance interval model. CONCLUSIONS: These results suggest a significant association between experimentally induced pain tolerance and tolerance interval with material status, suggesting that poor people indeed do hurt more.

The sources of pain in osteoarthritis: a pathophysiological review.

The pain of osteoarthritis (OA) has multifaceted etiologies within and outside the joint. It is believed to be driven by both nociceptive and neuropathic mechanisms, as well as abnormal excitability in the pain pathways of the peripheral and central nervous system. Inflammation in the joint triggers a cascade of events that leads to peripheral sensitization, increased sensitivity of nociceptive primary afferent neurons, and hyperexcitability of the nociceptive neurons in the central nervous system. Pain receptors have been found in the synovium, ligaments, capsule, subchondral bone and surrounding tissues, with the exception of articular cartilage. The bone-related causes of pain in OA include subchondral microfractures, bone stretching with elevation of the periosteum due to osteophyte growth, bone remodeling and repair, bone marrow lesions, and bone angina caused by decreased blood flow and increased intra-osseous pressure. Central factors alter pain processing by setting the gain in such a way that, when a peripheral input is present, it is processed against a background of central factors that can enhance or diminish the experience of pain. As a complex phenomenon with a strong subjective component, pain can also be influenced by the nature of the underlying disease, personal predisposition (biological and psychological), and environmental and psychosocial factors. This review examines the current literature regarding the sources and mechanisms of pain in OA.

A prospective longitudinal controlled assessment of pain experience and oral health-related quality of life in adolescents undergoing fixed appliance treatment.

OBJECTIVE: To compare subjective pain experience and oral health-related quality of life (OH-QoL) in treated and untreated subjects over the first 3 months of fixed appliance therapy. SETTING AND SAMPLE POPULATION: The Department of Orthodontics, School of Medicine and Dentistry. One hundred and twenty-four subjects aged between 11 and 14 years either commencing or awaiting fixed appliance treatment. MATERIAL & METHODS: A prospective controlled longitudinal study design was applied to subjects, over a 3-month observation period, following the placement of fixed appliances. Socio-economic status, OH-QoL, pain experience and analgesic consumption were recorded on questionnaires at baseline (T0), 6 weeks (T1) and 3 months (T2). RESULTS: Oral symptoms and functional limitation domains of OH-QoL were found to worsen, during the follow-up period, in the test group (p = 0.001 and p = 0.002, respectively). In the treated group, pain intensity declined significantly on days 3 and 2 at T1 and T2, respectively (p < 0.001). Analgesia was required during both periods in a total of 13 participants (24.5%) undergoing orthodontic treatment. CONCLUSION: Based on this prospective controlled study, the initial stages of fixed appliance treatment results in subjective pain experience, with subsequent reduction, and a significant impact on oral symptoms and functional limitation domains of OH-QoL.

Assessment of data acquisition parameters, and analysis techniques for noise reduction in spinal cord fMRI data.

PURPOSE: The purpose of this work is to characterize the noise in spinal cord functional MRI, assess current methods aimed at reducing noise, and optimize imaging parameters. METHODS: Functional MRI data were acquired at multiple echo times and the contrast-to-noise ratio (CNR) was calculated. Independently, the repetition time was systematically varied with and without parallel imaging, to maximize BOLD sensitivity and minimize type I errors. Noise in the images was characterized by examining the frequency spectrum, and investigating whether autocorrelations exist. The efficacy of several physiological noise reduction methods in both null (no stimuli) and task (thermal pain paradigm) data was also assessed. Finally, our previous normalization methods were extended. RESULTS: The echo time with the highest functional CNR at 3 Tesla is at roughly 75msec. Parallel imaging reduced the variance and the presence of autocorrelations, however the BOLD response in task data was more robust in data acquired without parallel imaging. Model-free based approaches further increased the detection of active voxels in the task data. Finally, inter-subject registration was improved. CONCLUSIONS: Results from this study provide a rigorous characterization of the properties of the noise and assessment of data acquisition and analysis methods for spinal cord and brainstem fMRI.

The pain and movement reasoning model: introduction to a simple tool for integrated pain assessment.

Pain is no longer considered to be simply the transmission of nociception, but rather an output subsequent to the complex interactions of homeostatic systems. Manual therapists' clinical reasoning needs to incorporate this complexity in order to develop individualised effective treatment plans. Pain classification strategies attempting to assist clinical reasoning traditionally define multiple types of pain - nociceptive, neuropathic, centrally sensitised - potentially fitting elements of the pain experience to linear independent systems, rather than embracing the multiple dimensions. It is our contention that pain should not be classified unidimensionally. In all pain states consideration should be given to the combined influence of physiological, cognitive, emotional and social inputs, all of which have the potential to influence nociception. The Pain and Movement Reasoning Model presented in this paper attempts to capture the complexity of the human pain experience by integrating these multiple dimensions into a decision making process. Three categories have been created to facilitate this - central modulation, regional influences, and local stimulation. The Model allows for the identification of a predominant element to become the focus of treatment but also for the identification of changes to clinical presentation, where new treatment targets can emerge.

What imaging teaches us about pain.

Pain diminishes the quality of life for many people, although it also may be a vital teacher or a warning message to be heeded. How humans process pain is a complicated, individualized process affected by genetics, personality, life experiences, and straightforward physiological processes. Imaging provides investigators with insight into this complicated phenomenon, and it promises to continue to help experts understand not only how pain is processed, but also why chronic pain develops in some people but not others, how we might better manage pain, and how pain may have played a key role in human evolution.

Assessment of pain and anxiety following surgical placement of dental implants.

PURPOSE: To investigate the change in 89 patients' pain and anxiety following implant surgery and to evaluate the correlation among anxiety, pain, and influencing factors. MATERIALS AND METHODS: Eighty-nine patients were included in this study. Subjective factors influencing pain perception included anxiety from the overall dental treatment (scored on the Dental Anxiety Scale [DAS]) and anxiety relative to the time from implant surgery. Objective factors were sex, age, and implant location and number. Patients completed questionnaires just before surgery (T0), immediately after surgery (T1), 1 day after surgery (T2), and 1 week after surgery (T3). RESULTS: The average pain perception was highest at T2, followed by T1 and T3. Pain perception at T1 was significantly higher in women and for a larger number of implant placements. Pain perception at T2 was significantly higher in women and when DAS and anxiety scores were high. The pain score at T3 was significantly higher in women and when anxiety scores were high. The results from multiple linear regression analysis showed that pain perception was significantly higher at T1 in women and for a larger number of implant placements, and at T3 when the dental anxiety score was high. CONCLUSION: Within the limitations of this study, a patient's anxiety represented by dental anxiety score and state of anxiety scores affected pain intensity 1 day after implant surgery. Sex and the number of implants affected pain intensity immediately after implant surgery. Patients who have high pain intensity 1 week after implant surgery showed high pain intensity at each time point.

Salivary alpha-amylase: a new non-invasive biomarker for assessment of pain perception in epileptic children.

The aim of this study was to evaluate pain perception in epileptic children during an invasive procedure as the collection of venous blood through salivary alpha-amylase (sAA) activity determination, and to compare it with that of healthy children. In the study 23 children, 12 with epilepsy and 11 healthy controls were enrolled. From all children of both groups, one sample of saliva was collected through a non-invasive device, 15 min before (t 0), during (t 1), and 15 min later (t 2) blood withdrawal, and sAA activity was then determined through a kinetic-colorimetric assay. A statistically significant difference (p < 0.001) was found at t 2 between the sAA activity in the two groups, suggesting that epileptic children have an increased sensitization to pain, while at t 0 the difference was at the limit of statistical significance and at t 1 no statistically significant difference was found indicating that in both groups the venipuncture equally induced a state of stress. Our data suggest that sAA activity could represent a new objective and non-invasive biomarker for the assessment of pain perception in epileptic children.

[Chronic pain: medico-biologic and sotsio-economic aspects].

In this article the role of neurobiological, psychological and social factors in pathogenesis of chronic pain is analyzed. The chronic pain is considered not as a symptom of damage of tissue and as independent illness due to non-adequate neuroplasticity of systems involved into regulation of pain sensitivity. The major role in development and maintenance of chronic pain is devoted to the primary genetically determined and/or secondary disturbance of interaction between nociceptive and antinociceptive systems at various levels--from peripheral neuron to central structures--that provides pain perception and painful behaviour development.