Weak Relationships Between Psychological Factors and Experimental Pain Outcomes in Pain-Free Individuals: An Aggregate Analysis of 8 Studies.

Although psychological factors such as anxiety, depression, and pain catastrophizing are known to influence pain outcomes in chronic pain populations, there are mixed results regarding whether they influence experimental pain outcomes in pain-free individuals. The objectives of this study were to determine the associations between psychological factors and experimental pain outcomes in pain-free adolescents and adults. Relationships between anxiety, depression, and pain catastrophizing and experimental pain outcomes across 8 different studies (total N = 595) were examined in different populations of pain-free adult and adolescent participants. Analyses were conducted with and without controlling for sex, age, and race. Studies were analyzed separately and as part of an aggregate analysis. Individual study analyses resulted in 136 regression models. Of these, only 8 models revealed a significant association between psychological factors and pain outcomes. The significant results were small and likely due to Type 1 error. Controlling for demographic factors had minimal effect on the results. The aggregate analyses revealed weak relationships between anxiety and pressure pain threshold (Fisher's z = -.10 [-.19, -.01]), anxiety and cold pain intensity ratings (Fisher's z = .18 [.04, .32]), and pain catastrophizing and pressure pain threshold (Fisher's z = -.14 [-.26, -.02]). Sample size calculations based on the aggregate analyses indicated that several hundred participants would be required to detect true relationships between these psychological factors and pain measures. The overall negative findings suggest that in pain-free individuals, anxiety, depression, and pain catastrophizing are not meaningfully related to experimental pain outcomes. PERSPECTIVE: Psychological variables have been shown to predict pain outcomes in chronic pain populations but these relationships may not generalize to pain-free populations. An analysis of 595 pain-free individuals across 8 studies in our lab revealed that anxiety, depression, and pain catastrophizing were not meaningfully related to experimental pain outcomes.

Pain sensitivity does not differ between obese and healthy weight individuals.

INTRODUCTION: There is emerging evidence suggesting a relationship between obesity and chronic pain. OBJECTIVES: The aim of this study was to determine whether pain-free obese individuals display altered pain responses to acute noxious stimuli, thus raising the possibility of greater pain sensitivity and potential susceptibility for chronic pain development. METHODS: Psychophysical and anthropometric data were collected from 38 individuals with an obese body mass index (BMI) classification (BMI ≥ 30) and 41 age/sex-matched individuals of a healthy BMI (BMI < 24.9). Because BMI may be an inaccurate index of obesity, additional anthropometric parameters of central adiposity and percent body fat were examined. Pain responses to suprathreshold noxious heat and cold stimuli were examined. Subjects provided pain intensity and unpleasantness ratings to noxious heat (49°C) applied at varying durations and locations (ventral forearm/lower leg). Cold pain ratings, thresholds, and tolerances were obtained after immersion of the hand in a cold-water bath (0-2°C). Between-group differences in pain responses, as well as relationships between pain responses and obesity parameters, were examined. Importantly, confounds that may influence pain such as anxiety, depression, impulsivity, sleepiness, and quality of life were assessed. RESULTS: No between-group differences in pain sensitivity to noxious heat and cold stimuli were found. No relationships were found between central adiposity or body fat (percentage or distribution) and pain responses to noxious heat or cold stimuli. CONCLUSIONS: Obesity has minimal influence on pain sensitivity. Accordingly, it is unlikely that obesity alone increases susceptibility for chronic pain development through amplification of nociceptive processes.

During vigilance to painful stimuli: slower response rate is related to high trait anxiety, whereas faster response rate is related to high state anxiety.

A pathological increase in vigilance, or hypervigilance, may be related to pain intensity in some clinical pain syndromes and may result from attention bias to salient stimuli mediated by anxiety. During a continuous performance task where subjects discriminated painful target stimuli from painful nontargets, we measured detected targets (hits), nondetected targets (misses), nondetected nontargets (correct rejections), and detected nontargets (false alarms). Using signal detection theory, we calculated response bias, the tendency to endorse a stimulus as a target, and discriminability, the ability to discriminate a target from nontarget. Owing to the relatively slow rate of stimulus presentation, our primary hypothesis was that sustained performance would result in a more conservative response bias reflecting a lower response rate over time on task. We found a more conservative response bias with time on task and no change in discriminability. We predicted that greater state and trait anxiety would lead to a more liberal response bias. A multivariable model provided partial support for our prediction; high trait anxiety related to a more conservative response bias (lower response rate), whereas high state anxiety related to a more liberal bias. This inverse relationship of state and trait anxiety is consistent with reports of effects of state and trait anxiety on reaction times to threatening stimuli. In sum, we report that sustained attention to painful stimuli was associated with a decrease in the tendency of the subject to respond to any stimulus over time on task, whereas the ability to discriminate target from nontarget remains unchanged.NEW & NOTEWORTHY During a series of painful stimuli requiring subjects to respond to targets, we separated response willingness from ability to discriminate targets from nontargets. Response willingness declined during the task, with no change in subjects' ability to discriminate, consistent with previous vigilance studies. High trait anxious subjects were less willing to respond and showed slower reaction times to hits than low anxious subjects. This study reveals an important role of trait anxiety in pain vigilance.

Missed targets, reaction times, and arousal are related to trait anxiety and attention to pain during an experimental vigilance task with a painful target.

Although hypervigilance may play a role in some clinical pain syndromes, experimental vigilance toward painful stimuli has been studied infrequently. We evaluated vigilance toward pain by using a continuous performance task (CPT), in which subjects responded to moderately intense painful target stimuli, occurring in a train of mildly painful nontargets. We assessed nondetected targets (misses), reaction times (RTs), and psychological activation (tense arousal). During time on task in CPTs of other sensory modalities, there is an increase in misses and RTs (vigilance decrement). We hypothesized that our CPT would influence vigilance performance related to pain, anxiety, and limitation of attentional resources. The results showed a decrement in vigilance over time as misses increased, although RTs were unchanged. While mind-wandering did not influence vigilance performance, intrinsic attention to pain drove both hit RTs and number of misses. This resulted in pain-focused subjects performing worse on the CPT pain task with slower RTs and more misses per block. During the CPT, the change in stimulus salience was related to the change in pain intensity, while pain unpleasantness correlated with tense arousal. CPT performance during experimental vigilance to pain and psychological activation were related to trait anxiety, as measured by the Spielberger State-Trait Anxiety Inventory and neuroticism, as measured by the NEO five factor inventory. Trait anxiety and neuroticism may play important roles in an individual's predisposition to dwell on pain and interpret pain as threatening.NEW & NOTEWORTHY Subjects detected moderately painful target stimuli in a train of mildly painful nontarget stimuli, which resulted in vigilance performance metrics including missed targets, reaction times, and psychological activation. These performance metrics were related to intrinsic attention to pain and trait anxiety. Subjects with high trait anxiety and neuroticism scores, with a predisposition to attend to pain, had greater tense arousal and poorer vigilance performance, which may be important psychological aspects of vigilance to pain.

Brain moderators supporting the relationship between depressive mood and pain.

Pain and depressive mood commonly exhibit a comorbid relationship. Yet, the brain mechanisms that moderate the relationship between dysphoric mood and pain remain unknown. An exploratory analysis of functional magnetic resonance imaging, behavioral, and psychophysical data was collected from a previous study in 76 healthy, nondepressed, and pain-free individuals. Participants completed the Beck Depression Inventory-II (BDI), a measure of negative mood/depressive symptomology, and provided pain intensity and pain unpleasantness ratings in response to noxious heat (49°C) during perfusion-based, arterial spin-labeled functional magnetic resonance imaging. Moderation analyses were conducted to determine neural mechanisms involved in facilitating the hypothesized relationship between depressive mood and pain sensitivity. Higher BDI-II scores were positively associated with pain intensity (R = 0.10; P = 0.006) and pain unpleasantness (R = 0.12; P = 0.003) ratings. There was a high correlation between pain intensity and unpleasantness ratings (r = 0.94; P < 0.001); thus, brain moderation analyses were focused on pain intensity ratings. Individuals with higher levels of depressive mood exhibited heightened sensitivity to experimental pain. Greater activation in regions supporting the evaluation of pain (ventrolateral prefrontal cortex; anterior insula) and sensory-discrimination (secondary somatosensory cortex; posterior insula) moderated the relationship between higher BDI-II scores and pain intensity ratings. This study demonstrates that executive-level and sensory-discriminative brain mechanisms play a multimodal role in facilitating the bidirectional relationship between negative mood and pain.

Neural mechanisms supporting the relationship between dispositional mindfulness and pain.

Interindividual differences in pain sensitivity vary as a function of interactions between sensory, cognitive-affective, and dispositional factors. Trait mindfulness, characterized as the innate capacity to nonreactively sustain attention to the present moment, is a psychological construct that is associated with lower clinical pain outcomes. Yet, the neural mechanisms supporting dispositional mindfulness are unknown. In an exploratory data analysis obtained during a study comparing mindfulness to placebo analgesia, we sought to determine whether dispositional mindfulness is associated with lower pain sensitivity. We also aimed to identify the brain mechanisms supporting the postulated inverse relationship between trait mindfulness and pain in response to noxious stimulation. We hypothesized that trait mindfulness would be associated with lower pain and greater deactivation of the default mode network. Seventy-six meditation-naive and healthy volunteers completed the Freiburg Mindfulness Inventory and were administered innocuous (35°C) and noxious stimulation (49°C) during perfusion-based functional magnetic resonance imaging. Higher Freiburg Mindfulness Inventory ratings were associated with lower pain intensity (P = 0.005) and pain unpleasantness ratings (P = 0.005). Whole brain analyses revealed that higher dispositional mindfulness was associated with greater deactivation of a brain region extending from the precuneus to posterior cingulate cortex during noxious heat. These novel findings demonstrate that mindful individuals feel less pain and evoke greater deactivation of brain regions supporting the engagement sensory, cognitive, and affective appraisals. We propose that mindfulness and the posterior cingulate cortex should be considered as important mechanistic targets for pain therapies.

Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia.

Mindfulness meditation reduces pain in experimental and clinical settings. However, it remains unknown whether mindfulness meditation engages pain-relieving mechanisms other than those associated with the placebo effect (e.g., conditioning, psychosocial context, beliefs). To determine whether the analgesic mechanisms of mindfulness meditation are different from placebo, we randomly assigned 75 healthy, human volunteers to 4 d of the following: (1) mindfulness meditation, (2) placebo conditioning, (3) sham mindfulness meditation, or (4) book-listening control intervention. We assessed intervention efficacy using psychophysical evaluation of experimental pain and functional neuroimaging. Importantly, all cognitive manipulations (i.e., mindfulness meditation, placebo conditioning, sham mindfulness meditation) significantly attenuated pain intensity and unpleasantness ratings when compared to rest and the control condition (p < 0.05). Mindfulness meditation reduced pain intensity (p = 0.032) and pain unpleasantness (p < 0.001) ratings more than placebo analgesia. Mindfulness meditation also reduced pain intensity (p = 0.030) and pain unpleasantness (p = 0.043) ratings more than sham mindfulness meditation. Mindfulness-meditation-related pain relief was associated with greater activation in brain regions associated with the cognitive modulation of pain, including the orbitofrontal, subgenual anterior cingulate, and anterior insular cortex. In contrast, placebo analgesia was associated with activation of the dorsolateral prefrontal cortex and deactivation of sensory processing regions (secondary somatosensory cortex). Sham mindfulness meditation-induced analgesia was not correlated with significant neural activity, but rather by greater reductions in respiration rate. This study is the first to demonstrate that mindfulness-related pain relief is mechanistically distinct from placebo analgesia. The elucidation of this distinction confirms the existence of multiple, cognitively driven, supraspinal mechanisms for pain modulation. SIGNIFICANCE STATEMENT: Recent findings have demonstrated that mindfulness meditation significantly reduces pain. Given that the "gold standard" for evaluating the efficacy of behavioral interventions is based on appropriate placebo comparisons, it is imperative that we establish whether there is an effect supporting meditation-related pain relief above and beyond the effects of placebo. Here, we provide novel evidence demonstrating that mindfulness meditation produces greater pain relief and employs distinct neural mechanisms than placebo cream and sham mindfulness meditation. Specifically, mindfulness meditation-induced pain relief activated higher-order brain regions, including the orbitofrontal and cingulate cortices. In contrast, placebo analgesia was associated with decreased pain-related brain activation. These findings demonstrate that mindfulness meditation reduces pain through unique mechanisms and may foster greater acceptance of meditation as an adjunct pain therapy.

Voxel-based morphometry and arterial spin labeling fMRI reveal neuropathic and neuroplastic features of brain processing of itch in end-stage renal disease.

Pruritus of end-stage renal disease (ESRD) is a multifactorial symptom of complex etiology not yet fully understood. In this study we have investigated the cerebral perfusion patterns at rest in ESRD patients on hemodialysis, compared with those in healthy volunteers. We have also studied the brain responses evoked by experimental itch induction in ESRD, after stimulating the two distinct histamine and cowhage itch pathways, and compared them with the responses evoked in healthy volunteers. To identify potential structural alterations in ESRD patients compared with a group of age-matched healthy volunteers, we calculated the density of gray matter for the entire brain using a voxel-based morphometric analysis. Our results indicated that gray matter density was significantly reduced in ESRD patients in the frontal, parietal, temporal, and occipital cortices, as well as in the S1, precuneus, and insula, whereas the brain stem, hippocampus, amygdala, midcingulate cortex, and nucleus accumbens displayed an increased gray matter density. Functionally, we found a significantly higher brain perfusion at baseline associated with ESRD pruritus in the anterior cingulate, insula, claustrum, hippocampus, and nucleus accumbens. The brain responses evoked by cowhage itch, which are mediated by protease-activated receptors (PAR2), displayed significant differences compared with responses in healthy individuals and were correlated with perceived itch intensity in a dual, complex manner. The inverse correlations in particular suggested that a negative feedback mechanism modulated itch intensity, when elicited in a preexistent chronic itch background.

Pain sensitivity is inversely related to regional grey matter density in the brain.

Pain is a highly personal experience that varies substantially among individuals. In search of an anatomical correlate of pain sensitivity, we used voxel-based morphometry to investigate the relationship between grey matter density across the whole brain and interindividual differences in pain sensitivity in 116 healthy volunteers (62 women, 54 men). Structural magnetic resonance imaging (MRI) and psychophysical data from 10 previous functional MRI studies were used. Age, sex, unpleasantness ratings, scanner sequence, and sensory testing location were added to the model as covariates. Regression analysis of grey matter density across the whole brain and thermal pain intensity ratings at 49°C revealed a significant inverse relationship between pain sensitivity and grey matter density in bilateral regions of the posterior cingulate cortex, precuneus, intraparietal sulcus, and inferior parietal lobule. Unilateral regions of the left primary somatosensory cortex also exhibited this inverse relationship. No regions showed a positive relationship to pain sensitivity. These structural variations occurred in areas associated with the default mode network, attentional direction and shifting, as well as somatosensory processing. These findings underscore the potential importance of processes related to default mode thought and attention in shaping individual differences in pain sensitivity and indicate that pain sensitivity can potentially be predicted on the basis of brain structure.