Trends in Patient Representation in Low Back Pain Pharmacological Randomized Clinical Trials, 2011 to 2020: A Systematic Review.

Low back pain (LBP) significantly affects global health, with associated detrimental outcomes such as physical impairment, emotional distress, and exacerbated mental health symptoms. This study evaluated the representation of marginalized groups, including racialized, gender minority, pregnant/lactating, and elderly individuals in randomized controlled trials for pharmacological interventions treating LBP from 2011 to 2020. We searched Embase, MEDLINE, and CINAHL in December 2021, and 139 studies were eligible. Most trials (n = 113, 81%) reported participant sex; however, no study collected data on sexual and gender minorities, and the majority (n = 99, 71%) excluded pregnant/lactating individuals. Most trials (n = 105, 76%) reported no data on participant race or ethnicity. We limited within-country analyses of race and ethnicity to US-based trials because US-based trials were more likely to report race and/or ethnicity (48%) compared to non-US-based trials (8%). Black participants were the only racialized group whose composition was comparable to US Census estimates. About half (n = 73, 53%) of all trials had an upper age limit for eligibility (range: 40-85 years old) and 24% (n = 33) excluded adults aged >65 years. Our findings confirm that trials for pharmacological LBP interventions underreport demographic data, and the trials that include this data have unrepresentative samples. There is an urgent need for more inclusive and representative patient samples to ensure generalizability and equitable benefits. Standardizing demographic data reporting and integrating community-based participatory research methods can help foster inclusive research practices. This review was registered with prospective register of systematic reviews (PROSPERO), ID 296017. PERSPECTIVE: This systematic review investigates patient representation in pharmacological-based clinical trials for low back pain, LBP, the most prevalent pain condition worldwide. Improvements in reporting demographic data and recruiting diverse participant populations-across different racialized, gender and sexual minority, and age groups-will help clinical research generalizability and provide equitable benefits.

How Pain-Related Facial Expressions Are Evaluated in Relation to Gender, Race, and Emotion.

Inequities in pain assessment are well-documented; however, the psychological mechanisms underlying such biases are poorly understood. We investigated potential perceptual biases in the judgments of faces displaying pain-related movements. Across five online studies, 956 adult participants viewed images of computer-generated faces ("targets") that varied in features related to race (Black and White) and gender (women and men). Target identity was manipulated across participants, and each target had equivalent facial movements that displayed varying intensities of movement in facial action-units related to pain (Studies 1-4) or pain and emotion (Study 5). On each trial, participants provided categorical judgments as to whether a target was in pain (Studies 1-4) or which expression the target displayed (Study 5) and then rated the perceived intensity of the expression. Meta-analyses of Studies 1-4 revealed that movement intensity was positively associated with both categorizing a trial as painful and perceived pain intensity. Target race and gender did not consistently affect pain-related judgments, contrary to well-documented clinical inequities. In Study 5, in which pain was equally likely relative to other emotions, pain was the least frequently selected emotion (5%). Our results suggest that perceivers can utilize facial movements to evaluate pain in other individuals, but perceiving pain may depend on contextual factors. Furthermore, assessments of computer-generated, pain-related facial movements online do not replicate sociocultural biases observed in the clinic. These findings provide a foundation for future studies comparing CGI and real images of pain and emphasize the need for further work on the relationship between pain and emotion. Supplementary Information: The online version contains supplementary material available at 10.1007/s42761-023-00181-6.

Instructions and experiential learning have similar impacts on pain and pain-related brain responses but produce dissociations in value-based reversal learning.

Recent data suggest that interactions between systems involved in higher order knowledge and associative learning drive responses during value-based learning. However, it is unknown how these systems impact subjective responses, such as pain. We tested how instructions and reversal learning influence pain and pain-evoked brain activation. Healthy volunteers (n=40) were either instructed about contingencies between cues and aversive outcomes or learned through experience in a paradigm where contingencies reversed three times. We measured predictive cue effects on pain and heat-evoked brain responses using functional magnetic resonance imaging. Predictive cues dynamically modulated pain perception as contingencies changed, regardless of whether participants received contingency instructions. Heat-evoked responses in the insula, anterior cingulate, and other regions updated as contingencies changed, and responses in the prefrontal cortex mediated dynamic cue effects on pain, whereas responses in the brainstem's rostroventral medulla (RVM) were shaped by initial contingencies throughout the task. Quantitative modeling revealed that expected value was shaped purely by instructions in the Instructed Group, whereas expected value updated dynamically in the Uninstructed Group as a function of error-based learning. These differences were accompanied by dissociations in the neural correlates of value-based learning in the rostral anterior cingulate, thalamus, and posterior insula, among other regions. These results show how predictions dynamically impact subjective pain. Moreover, imaging data delineate three types of networks involved in pain generation and value-based learning: those that respond to initial contingencies, those that update dynamically during feedback-driven learning as contingencies change, and those that are sensitive to instruction. Together, these findings provide multiple points of entry for therapies designs to impact pain.

Test-Retest Reliability of an Adaptive Thermal Pain Calibration Procedure in Healthy Volunteers.

Quantitative sensory testing (QST) allows researchers to evaluate associations between noxious stimuli and acute pain in clinical populations and healthy participants. Despite its widespread use, our understanding of QST's reliability is limited, as reliability studies have used small samples and restricted time windows. We examined the reliability of pain ratings in response to noxious thermal stimulation in 171 healthy volunteers (n = 99 female, n = 72 male) who completed QST on multiple visits ranging from 1 day to 952 days between visits. On each visit, participants underwent an adaptive pain calibration in which they experienced 24 heat trials and rated pain intensity after stimulus offset on a 0 to 10 Visual Analog Scale. We used linear regression to determine pain threshold, pain tolerance, and the correlation between temperature and pain for each session and examined the reliability of these measures. Threshold and tolerance were moderately reliable (Intra-class correlation = .66 and .67, respectively; P < .001), whereas temperature-pain correlations had low reliability (Intra-class correlation = .23). In addition, pain tolerance was significantly more reliable in female participants than male participants, and we observed similar trends for other pain sensitive measures. Our findings indicate that threshold and tolerance are largely consistent across visits, whereas sensitivity to changes in temperature vary over time and may be influenced by contextual factors. PERSPECTIVE: This article assesses the reliability of an adaptive thermal pain calibration procedure. We find that pain threshold and tolerance are moderately reliable whereas the correlation between pain rating and stimulus temperature has low reliability. Female participants were more reliable than male participants on all pain sensitivity measures.

Dispositional Mindfulness and Acute Heat Pain: Comparing Stimulus-Evoked Pain With Summary Pain Assessment.

OBJECTIVE: Dispositional mindfulness is associated with reduced pain in clinical and experimental settings. However, researchers have neglected the type of pain assessment, as dispositional mindfulness may have unique benefits for reduced pain sensitivity when relying on summary pain assessments, in contrast to assessing the pain of each noxious stimulus. Here, we test the association between dispositional mindfulness and pain using both trial-by-trial pain assessments and overall summary ratings after acute pain tasks. METHODS: One hundred thirty-one healthy adult volunteers (mean age = 29.09 [8.00] years, 55.7% female) underwent two experimental thermal pain paradigms. We tested whether dispositional mindfulness measured with the Mindful Attention Awareness Scale was related to a) heat-evoked pain sensitivity, as measured by pain threshold, pain tolerance, average pain, trial-by-trial ratings, and heat-evoked skin conductance response, and b) summary judgments of sensory and affective pain assessed using the McGill Pain Questionnaire (MPQ). RESULTS: Mindful Attention Awareness Scale ratings were associated with decreased pain on the MPQ sensory (B = -0.18, SE = 0.05, 95% confidence interval = -0.29 to -0.07, t = -3.28, p = .001) and affective (B = -0.11, SE = 0.03, 95% confidence interval = -0.18 to -0.05, t = -3.32, p = .001) dimensions but not with experimental thermal pain assessments, including threshold, tolerance, heat-evoked pain, or skin conductance response (p values ≥ .29). CONCLUSIONS: In this study, dispositional mindfulness mitigated acute thermal pain only when pain was assessed using the MPQ. These findings may reflect differences in immediate versus retrospective judgments or the type of pain assessed by each measure. Future research should examine regulation processes that may explain these differential analgesic benefits, such as attention, rumination, or reappraisal.

Expectations about pain and analgesic treatment are shaped by medical providers' facial appearances: Evidence from five online clinical simulation experiments.

RATIONALE: There is a robust link between patients' expectations and clinical outcomes, as evidenced by the placebo effect. Expectations depend in large part on the context surrounding treatment, including the patient-provider interaction. Prior work indicates that providers' behavior and characteristics, including warmth and competence, can shape patient outcomes. Yet humans rapidly form trait impressions of others before any in-person interaction. It is unknown whether these first impressions influence subsequent health care choices and expectations. OBJECTIVE: Our goal was to test whether trait impressions of hypothetical medical providers, based exclusively on facial images, influence the choice of medical providers and expectations about pain and analgesia following hypothetical painful medical procedures. METHOD: Across five online experiments, participants (total N = 1108) viewed and made judgments about hypothetical healthcare providers. Experiments 1-4 included computer-generated faces that varied in features associated with competence, while experiment 5 included real faces. We measured how apparent competence affected expectations about pain and anticipated analgesic use in all studies. We also measured warmth and similarity. RESULTS: Across five online studies, participants selected providers who appeared more competent, based on facial visual information alone. Further, providers' apparent competence predicted participants' expectations about post-procedural pain and medication use. Participants' perception of their similarity to providers also shaped expectations about pain and treatment outcomes. CONCLUSIONS: Results from our experimental simulations suggest that humans develop expectations about pain and health outcomes before even setting foot in the clinic, based exclusively on first impressions. These findings have strong implications for health care, as individuals increasingly rely on digital services to select healthcare providers and even receive treatment, a trend that is exacerbated as the world embraces telemedicine.

Ethnic Differences in Experimental Pain Responses Following a Paired Verbal Suggestion With Saline Infusion: A Quasiexperimental Study.

BACKGROUND: Ethnic differences in placebo and nocebo responses are an important, yet underresearched, patient factor that might contribute to treatment disparities. PURPOSE: The purpose of this study was to examine ethnic differences in pain trajectories following a verbal suggestion paired with a masked, inert substance (i.e., saline). METHODS: Using a quasiexperimental design, we examined differences between 21 non-Hispanic Black (NHB) participants and 20 non-Hispanic White (NHW) participants in capsaicin-related pain rating trajectories following a nondirectional verbal suggestion + saline infusion. All participants were told that the substance would "either increase pain sensation, decrease it, or leave it unchanged." A spline mixed model was used to quantify the interaction of ethnicity and time on ratings. RESULTS: There was a significant Ethnicity × Time interaction effect (ß = -0.28, p = .002); NHB individuals reported significantly greater increases in pain following, but not before, the verbal suggestion + saline infusion. Sensitivity analyses showed no change in primary results based on differences in education level, general pain sensitivity, or condition order. CONCLUSIONS: The present results showed ethnic differences in pain response trajectories following a verbal suggestion + saline infusion and suggest that future research rigorously examining possible ethnic differences in placebo/nocebo responses is warranted.

Confidence in subjective pain is predicted by reaction time during decision making.

Self-report is the gold standard for measuring pain. However, decisions about pain can vary substantially within and between individuals. We measured whether self-reported pain is accompanied by metacognition and variations in confidence, similar to perceptual decision-making in other modalities. Eighty healthy volunteers underwent acute thermal pain and provided pain ratings followed by confidence judgments on continuous visual analogue scales. We investigated whether eye fixations and reaction time during pain rating might serve as implicit markers of confidence. Confidence varied across trials and increased confidence was associated with faster pain rating reaction times. The association between confidence and fixations varied across individuals as a function of the reliability of individuals' association between temperature and pain. Taken together, this work indicates that individuals can provide metacognitive judgments of pain and extends research on confidence in perceptual decision-making to pain.

The Confidence Database.

Understanding how people rate their confidence is critical for the characterization of a wide range of perceptual, memory, motor and cognitive processes. To enable the continued exploration of these processes, we created a large database of confidence studies spanning a broad set of paradigms, participant populations and fields of study. The data from each study are structured in a common, easy-to-use format that can be easily imported and analysed using multiple software packages. Each dataset is accompanied by an explanation regarding the nature of the collected data. At the time of publication, the Confidence Database (which is available at https://osf.io/s46pr/) contained 145 datasets with data from more than 8,700 participants and almost 4 million trials. The database will remain open for new submissions indefinitely and is expected to continue to grow. Here we show the usefulness of this large collection of datasets in four different analyses that provide precise estimations of several foundational confidence-related effects.

Pain or nociception? Subjective experience mediates the effects of acute noxious heat on autonomic responses - corrected and republished.

Nociception reliably elicits an autonomic nervous system (ANS) response. Because pain and ANS circuitry interact on multiple spinal, subcortical, and cortical levels, it remains unclear whether autonomic responses are simply a reflexive product of noxious stimulation regardless of how stimulation is consciously perceived or whether the experience of pain mediates ANS responses to noxious stimulation. To test these alternative predictions, we examined the relative contribution of noxious stimulation and individual pain experience to ANS responses in healthy volunteers who underwent 1 or 2 pain assessment tasks. Participants received 8 seconds of thermal stimulation of varied temperatures and judged pain intensity on every trial. Skin conductance responses and pupil dilation responses to stimulation served as measures of the heat-evoked autonomic response. We used multilevel modelling to examine trial-by-trial relationships between heat, pain, and ANS response. Although both pain and noxious heat stimulation predicted skin conductance response and pupil dilation response in separate analyses, the individual pain experience statistically mediated effects of noxious heat on both outcomes. Furthermore, moderated mediation revealed that evidence for this process was stronger when stimulation was perceived as painful compared with when stimulation was perceived as nonpainful, although this difference emerged late, in the 4-second period after thermal stimulation. These findings suggest that pain appraisal regulates the heat-evoked autonomic response to noxious stimulation, documenting the flexibility of the autonomic pain response to adjust to perceived or actual changes in environmental affordances above and beyond nociceptive input.

Anticipatory Effects on Perceived Pain: Associations With Development and Anxiety.

OBJECTIVE: Naturalistic studies suggest that expectation of adverse experiences such as pain exerts particularly strong effects on anxious youth. In healthy adults, expectation influences the experience of pain. The current study uses experimental methods to compare the effects of expectation on pain among adults, healthy youth, and youth with an anxiety disorder. METHODS: Twenty-three healthy adults, 20 healthy youth, and 20 youth with an anxiety disorder underwent procedures in which auditory cues were paired with noxious thermal stimulation. Through instructed conditioning, one cue predicted low-pain stimulation and the other predicted high-pain stimulation. At test, each cue was additionally followed by a single temperature calibrated to elicit medium pain ratings. We compared cue-based expectancy effects on pain across the three groups, based on cue effects on pain elicited on medium heat trials. RESULTS: Across all groups, as expected, participants reported greater pain with increasing heat intensity (ß = 2.29, t(41) = 29.94, p < .001). Across all groups, the critical medium temperature trials were rated as more painful in the high- relative to low-expectancy condition (ß = 1.72, t(41) = 10.48, p < .001). However, no evidence of between-group differences or continuous associations with age or anxiety was observed. CONCLUSIONS: All participants showed strong effects of expectancy on pain. No influences of development or anxiety arose. Complex factors may influence associations among anxiety, development, and pain reports in naturalistic studies. Such factors may be identified using experiments that employ more complex, yet controlled manipulations of expectancy or assess neural correlates of expectancy.

Pain or nociception? Subjective experience mediates the effects of acute noxious heat on autonomic responses.

Nociception reliably elicits an autonomic nervous system (ANS) response. Because pain and ANS circuitry interact on multiple spinal, subcortical, and cortical levels, it remains unclear whether autonomic responses are simply a reflexive product of noxious stimulation regardless of how stimulation is consciously perceived or whether the experience of pain mediates ANS responses to noxious stimulation. To test these alternative predictions, we examined the relative contribution of noxious stimulation and individual pain experience to ANS responses in healthy volunteers who underwent 1 or 2 pain assessment tasks. Participants received 8 seconds of thermal stimulation of varied temperatures and judged pain intensity on every trial. Skin conductance responses and pupil dilation responses to stimulation served as measures of the heat-evoked autonomic response. We used multilevel modelling to examine trial-by-trial relationships between heat, pain, and ANS response. Although both pain and noxious heat stimulation predicted skin conductance response and pupil dilation response in separate analyses, the individual pain experience statistically mediated effects of noxious heat on both outcomes. Furthermore, moderated mediation revealed that evidence for this process was stronger when stimulation was perceived as painful compared with when stimulation was perceived as nonpainful. These findings suggest that pain appraisal regulates the heat-evoked autonomic response to noxious stimulation, documenting the flexibility of the autonomic pain response to adjust to perceived or actual changes in environmental affordances above and beyond nociceptive input.