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Variability in pain sensitivity arises not only from the differences in peripheral sensory receptors but also from the differences in central nervous system (CNS) pain inhibition and facilitation mechanisms. Temporal summation of pain (TSP) is an experimental protocol commonly used in human studies of pain facilitation but is susceptible to confounding when elicited with the skin-contact thermode, which adds the responses of touch-related Aβ low-threshold mechanoreceptors to nociceptive receptors. In the present study, we evaluate an alternative method involving the use of a contactless cutaneous laser for TSP assessment. We show that repetitive laser stimulations with a one second inter-stimulus interval evoked reliable TSP responses in a significant proportion of healthy subjects (N = 36). Female subjects (N = 18) reported greater TSP responses than male subjects confirming earlier studies of sex differences in central nociceptive excitability. Furthermore, repetitive laser stimulations during TSP induction elicited increased time-frequency electroencephalography (EEG) responses. The present study demonstrates that repetitive laser stimulation may be an alternative to skin-contact methods for TSP assessment in patients and healthy controls. PERSPECTIVE: Temporal summation of pain (TSP) is an experimental protocol commonly used in human studies of pain facilitation. We show that contactless cutaneous laser stimulation is a reliable alternative to the skin contact approaches during TSP assessment., (Copyright © 2023 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Pain is a dynamic experience subject to substantial individual differences. Intensive longitudinal designs best capture the dynamical ebb and flow of the pain experience across time and settings. Thanks to the development of innovative and efficient data collection technologies, conducting an intensive longitudinal pain study has become increasingly feasible. However, the majority of longitudinal studies have tended to examine average level of pain as a predictor or as an outcome, while conceptualizing intraindividual pain variation as noise, error, or a nuisance factor. Such an approach may miss the opportunity to understand how fluctuations in pain over time are associated with pain processing, coping, other indices of adjustment, and treatment response. The present review introduces the 4 most frequently used intraindividual variability indices: the intraindividual SD/variance, autocorrelation, the mean square of successive difference, and probability of acute change. In addition, we discuss recent development in dynamic structural equation modeling in a nontechnical manner. We also consider some notable methodological issues, present a real-world example of intraindividual variability analysis, and offer suggestions for future research. Finally, we provide statistical software syntax for calculating the aforementioned intraindividual pain variability indices so that researchers can easily apply them in their research. We believe that investigating intraindividual variability of pain will provide a new perspective for understanding the complex mechanisms underlying pain coping and adjustment, as well as for enhancing efforts in precision pain medicine. Audio accompanying this abstract is available online as supplemental digital content at http://links.lww.com/PAIN/A817.

Objective: The purpose of this study was to examine the interaction of daily concurrent positive interpersonal events (PIE) and negative interpersonal events (NIE) on the daily experience of negative affect and fatigue in a sample of men and women with rheumatoid arthritis. Two hypotheses were made. The blunting hypothesis predicted that NIE would nullify the beneficial influence of PIE on outcome measures, and the buffering hypothesis predicted that PIE would offset the adverse influence of NIE., Design: Participants completed up to 30 consecutive daily diaries. Multilevel modeling was used to examine the day-to-day dependencies among study variables., Main Outcome Measures: The primary outcomes were daily negative affect and fatigue., Results: In support of the blunting hypothesis, on days when NIE were diminished, PIE were associated with a greater reduction in fatigue. In contrast, consistent with the buffering hypothesis, on days when PIE were elevated, NIE were associated with a lesser increase in negative affect., Conclusion: The examination of concurrent PIE and NIE provides a unique perspective on the role of interpersonal events in affective and physiological outcomes, beyond that which can be gained from the examination of either type of event in isolation., (PsycINFO Database Record (c) 2010 APA, all rights reserved.)

This research examined whether cognitive behavioral therapy and mindfulness interventions that target responses to chronic stress, pain, and depression reduce pain and improve the quality of everyday life for adults with rheumatoid arthritis (RA). The 144 RA participants were clustered into groups of 6-10 participants and randomly assigned to 1 of 3 treatments: cognitive behavioral therapy for pain (P); mindfulness meditation and emotion regulation therapy (M); or education-only group (E), which served as an attention placebo control. The authors took a multimethod approach, employing daily diaries and laboratory assessment of pain and mitogen-stimulated levels of interleukin-6 (IL-6), a proinflammatory cytokine. Participants receiving P showed the greatest Pre to Post improvement in self-reported pain control and reductions in the IL-6; both P and M groups showed more improvement in coping efficacy than did the E group. The relative value of the treatments varied as a function of depression history. RA patients with recurrent depression benefited most from M across several measures, including negative and positive affect and physicians' ratings of joint tenderness, indicating that the emotion regulation aspects of that treatment were most beneficial to those with chronic depressive features., ((c) 2008 APA, all rights reserved)

The match/mismatch model of pain prediction was tested with a group of rheumatoid arthritis patients (N = 227) in a natural setting. Daily diary measures of pain prediction and pain experience were obtained over 30 days. Results revealed a greater number of underpredictors (N = 147) than over predictors (N = 58) in our sample, with a minority (N = 22) overpredicting and underpredicting with equal frequency. Further, people modified their predictions to a greater degree after an over prediction than they did after an under prediction. As expected, anxious participants were less accurate and more prone to over predicting their pain than their less anxious counterparts. In contrast, participants who reported low levels of daily pessimism were more likely than their more pessimistic counterparts to under predict their pain. The findings suggest that people continued to under predict their pain despite repeated disconfirmations and that low levels of pessimism may have accounted for this pattern.

Among individuals with rheumatoid arthritis (RA), stress-associated disease flare can severely impact well-being. Psychological factors such as personal mastery may buffer an individual from the negative effects of those flares. We tested the hypothesis that a high sense of personal mastery would prospectively predict stress reactivity. Measures of pain,perceived stress, fatigue, and mean arterial pressure (MAP) were collected before, during, and after two interpersonal stressors conducted on 73 individuals with RA. Factor analysis of the personal mastery scale yielded two independent factors: a 5-item "fatalism" component and a 2-item "control" component. Individuals with high fatalism scores reported overall greater joint pain at baseline and those scoring high on control exhibited lower MAP, and reported less stress and fatigue at baseline. After controlling for baseline differences, those high in control exhibited greater MAP increase during stress, and less drop in pain when compared to those low in control. These results suggest that individuals high in control may be more susceptible to the effects of acute stress; however, the overall beneficial aspects of high control outweigh the acute negative effects. Personal mastery may play a role in the experience of pain, stress, and fatigue for people with RA.

AbstractSleep loss heightens pain sensitivity, but the pathways underlying this association are not known. Given that experimental sleep disruption induces increases in cellular inflammation as well as selective loss of slow wave, N3 sleep, this study examined whether these mechanisms contribute to pain sensitivity following sleep loss in healthy adults. This assessor-blinded, cross-over sleep condition, single-site, randomized clinical trial enrolled 95 healthy adults (mean [SD] age, 27.8 [6.4]; female, 44 [53.7%]). The 2 sleep conditions were 2 nights of undisturbed sleep (US) and 2 nights of sleep disruption or forced awakening (FA, 8 pseudorandomly distributed awakenings and 200 minutes wake time during the 8-hour sleep opportunity), administered in a cross-over design after 2 weeks of washout and in a random order (FA-US; US-FA). Primary outcome was heat pain threshold (hPTH). Sleep architecture was assessed by polysomnography, and morning levels of cellular inflammation were evaluated by Toll-like receptor-4 stimulated monocyte intracellular proinflammatory cytokine production. As compared with US, FA was associated with decreases in the amount of slow wave or N3 sleep ( P < 0.001), increases in Toll-like receptor-4 stimulated production of interleukin-6 and tumor necrosis factor-α ( P = 0.03), and decreases in hPTH ( P = 0.02). A comprehensive causal mediation analysis found that FA had an indirect effect on hPTH by decreases in N3 sleep and subsequent increases in inflammation (estimate=-0.15; 95% confidence interval, -0.30 to -0.03; P < 0.05) with the proportion mediated 34.9%. Differential loss of slow wave, N3 sleep, and increases in cellular inflammation are important drivers of pain sensitivity after sleep disruption.Clinical Trials Registration: NCT01794689.

Chronic pain is prevalent in older adults. Treatment, especially with opioids, is often ineffective and poses considerable negative consequences in this population. To improve treatment, it is important to understand why older adults are at a heightened risk for developing chronic pain. Insomnia is a major modifiable risk factor for chronic pain that is ubiquitous among older adults. Insomnia can also lead to heightened systemic inflammation and affective disturbance, both of which may further exacerbate pain conditions in older adults. Endotoxin exposure can be used as an experimental model of systemic inflammation and affective disturbance. The current study aims to understand how insomnia status and endotoxin-induced changes in inflammation and affect (increased negative affect and decreased positive affect) may interact to impact pain facilitatory and inhibitory processes in older adults. Longitudinal data will also assess how pain processing, affective, and inflammatory responses to endotoxin may predict the development of pain and/or depressive symptoms. The current study is a randomized, double-blinded, placebo-controlled, mechanistic clinical trial in men and women, with and without insomnia, aged 50 years and older. Participants were randomized to either 0.8ng/kg endotoxin injection or saline placebo injection. Daily diaries were used to collect variables related to sleep, mood, and pain at two-week intervals during baseline and 3-, 6-, 9-, and 12-months post-injection. Primary outcomes during the experimental phase include conditioned pain modulation, temporal summation, and affective pain modulation ∼5.5 hours after injection. Primary outcomes for longitudinal assessments are self-reported pain intensity and depressive symptoms. The current study uses endotoxin as an experimental model for pain. In doing so, it aims to extend the current literature by: (1) including older adults, (2) investigating insomnia as a potential risk factor for chronic pain, (3) evaluating the role of endotoxin-induced affective disturbances on pain sensitivity, and (4) assessing sex differences in endotoxin-induced hyperalgesia. Clinicaltrials.gov: NCT03256760. Trial sponsor: NIH R01AG057750-01.

The nucleus accumbens (NAc) has been implicated in sleep, reward, and pain modulation, but the relationship between these functional roles is unclear. This study aimed to determine whether NAc function at the onset and offset of a noxious thermal stimulus is enhanced by rewarding music, and whether that effect is reversed by experimental sleep disruption. Twenty-one healthy subjects underwent functional magnetic resonance imaging scans on 2 separate days after both uninterrupted sleep and experimental sleep disruption. During functional magnetic resonance imaging scans, participants experienced noxious stimulation while listening to individualized rewarding or neutral music. Behavioral results revealed that rewarding music significantly reduced pain intensity compared with neutral music, and disrupted sleep was associated with decreased pain intensity in the context of listening to music. In whole-brain family-wise error cluster-corrected analysis, the NAc was activated at pain onset, but not during tonic pain or at pain offset. Sleep disruption attenuated NAc activation at pain onset and during tonic pain. Rewarding music altered NAc connectivity with key nodes of the corticostriatal circuits during pain onset. Sleep disruption increased reward-related connectivity between the NAc and the anterior midcingulate cortex at pain onset. This study thus indicates that experimental sleep disruption modulates NAc function during the onset of pain in a manner that may be conditional on the presence of competing reward-related stimuli. These findings point to potential mechanisms for the interaction between sleep, reward, and pain, and suggest that sleep disruption affects both the detection and processing of aversive stimuli that may have important implications for chronic pain.

Ample behavioral and neurobiological evidence links sleep and affective functioning. Recent self-report evidence suggests that the affective problems associated with sleep loss may be stronger for positive versus negative affective state and that those effects may be mediated by changes in electroencepholographically measured slow wave sleep (SWS). In the present study, we extend those preliminary findings using multiple measures of affective functioning. In a within-subject randomized crossover experiment, we tested the effects of one night of sleep continuity disruption via forced awakenings (FA) compared to one night of uninterrupted sleep (US) on three measures of positive and negative affective functioning: self-reported affective state, affective pain modulation, and affect-biased attention. The study was set in an inpatient clinical research suite. Healthy, good sleeping adults (N = 45) were included. Results indicated that a single night of sleep continuity disruption attenuated positive affective state via FA-induced reductions in SWS. Additionally, sleep continuity disruption attenuated the inhibition of pain by positive affect as well as attention bias to positive affective stimuli. Negative affective state, negative affective pain facilitation, nor negative attention bias were altered by sleep continuity disruption. The present findings, observed across multiple measures of affective function, suggest that sleep continuity disruption has a stronger influence on the positive affective system relative to the negative affective affective system.

Chronic opioid therapy is a common treatment regimen for patients with sickle cell disease (SCD), a chronically painful recessive hemoglobinopathy. The collective risk profile of chronic opioid therapy necessitates an understanding of which pain-related factors, such as affect and pain catastrophizing, are associated with the ebbs and flows of opioid use in daily life, a topic that has received very little attention among patients with any type of chronically painful condition, including SCD. We therefore investigated the variability of day-to-day patterns of short- and long-acting opioid use and their associations with pain and pain-related cognitive and affective processes in daily life among patients with SCD using a nightly electronic diary (N = 45). Opioid use was self-reported and converted into oral morphine equivalents for analysis, which was conducted with mixed effects modeling. Results indicated that greater pain and pain catastrophizing were associated with greater use of short-acting opioids, and negative affect was associated with greater use of long-acting opioids. Additionally, the association of pain and short-acting opioid use was moderated by pain catastrophizing, showing that opioid use was elevated when patients catastrophized about their pain, even if they reported low levels of pain. These findings suggest that monitoring pain-related cognitive and affective variables may be a useful approach to understanding risk for problematic opioid use in patients with daily pain.Perspective: The present study shows that pain and pain-related cognitive and affective variables are associated with daily variation in prescription opioid use in SCD. The findings may have broad implications for tracking and defining risk for prescription opioid misuse in patients with daily pain. [ABSTRACT FROM AUTHOR]

Background and aims Sex differences in clinical pain severity and response to experimental pain are commonly reported, with women generally showing greater vulnerability. Affect, including state (a single rating) and stable (average daily ratings over two weeks) positive affect and negative affect has also been found to impact pain sensitivity and severity, and research suggests that affect may modulate pain differentially as a function of sex. The current study aimed to examine sex as a moderator of the relationships between affect and pain-related outcomes among participants with knee osteoarthritis (KOA). Methods One hundred and seventy-nine participants (59 men) with KOA completed electronic diaries assessing clinical pain, positive affect, and negative affect. A subset of participants ( n = 120) underwent quantitative sensory testing, from which a single index of central sensitization to pain was derived. We used multiple regression models to test for the interactive effects of sex and affect (positive versus negative and stable versus state) on pain-related outcomes. We used mixed effects models to test for the moderating effects of sex on the relationships between state affect and pain over time. Results Sex differences in affect and pain were identified, with men reporting significantly higher stable positive affect and lower central sensitization to pain indexed by quantitative sensory testing, as well as marginally lower KOA-specific clinical pain compared to women. Moreover, there was an interaction between stable positive affect and sex on KOA-specific clinical pain and average daily non-specific pain ratings. Post hoc analyses revealed that men showed trends towards an inverse relationship between stable positive affect and pain outcomes, while women showed no relationship between positive affect and pain. There was also a significant interaction between sex and stable negative affect and sex on KOA-specific pain such that men showed a significantly stronger positive relationship between stable negative affect and KOA-specific pain than women. Sex did not interact with state affect on pain outcomes. Conclusions Findings suggest that men may be particularly sensitive to the effects of stable positive affect and negative affect on clinical pain. Future work with larger samples is needed in order to identify potential mechanisms driving the sex-specific effects of affect on pain. Implications The current study provides novel data that suggesting that the association of positive affect, negative affect, and pain are different in men versus women with KOA. Further understanding of the difference in affective expression between men and women may lead to the development of novel therapeutic interventions and help to identify additional modifiable factors in the prevention and management of pain. [ABSTRACT FROM AUTHOR]

Unlabelled: Generalized dysfunction of the nociceptive system has been hypothesized to be an important pathophysiologic process underlying temporomandibular disorder (TMD) pain. Studies have not identified sensitization to painful stimuli administered prospectively across consecutive days among participants with TMD with chronic pain. We attempted to isolate an empirically derived laboratory-based marker of sustained mechanical pain sensitization. We examined whether this index accounted for variance in prospective assessments of clinical TMD pain. Participants were women with a clinical diagnosis of chronic TMD (n = 30) and healthy female controls (n = 30). Pain thresholds were assessed using digital algometry 4 times at 12-hour intervals over 48 consecutive hours and clinical TMD pain via follow-up telephone assessments. Sustained mechanical pain sensitization, defined by statistically significant linear decrements in pressure pain thresholds across the consecutive testing sessions, discriminated chronic TMD and control participants. An index of sustained sensitization at the masseter accounted for unique variance in clinical TMD pain over the subsequent 3-month assessment period, even controlling for mean pain threshold and baseline pain severity. These preliminary findings highlight discriminant and predictive validity characteristics of a novel marker of protracted pain sensitization among women with chronic TMD pain.Perspective: A laboratory-based and empirically defined marker of sustained mechanical pain sensitization over the course of days with acceptable discriminant and predictive validity was identified. This marker may represent a clinically useful marker of chronic TMD pain in women. [ABSTRACT FROM AUTHOR]

This analysis examined the influence of quantifiable parameters of daily sleep continuity, primarily sleep duration and sleep fragmentation, on daily pain in adults with sickle cell disease. Seventy-five adults with sickle cell disease completed baseline psychosocial measures and daily morning (sleep) and evening (pain) diaries over a 3-month period. Mixed-effect modeling was used to examine daily between- and within-subjects effects of sleep continuity parameters on pain, as well as the synergistic effect of sleep fragmentation and sleep duration on pain. Results revealed that nights of shorter sleep duration and time in bed, increased fragmentation, and less efficient sleep (relative to one's own mean) were followed by days of greater pain severity. Further, the analgesic benefit of longer sleep duration was attenuated when sleep fragmentation was elevated. These results suggest that both the separate and combined effects of sleep duration and fragmentation should be considered in evaluating pain in adults with sickle cell disease. Perspective Subjective parameters of sleep continuity (eg, sleep duration, fragmentation, and efficiency) predict clinical pain in individuals with sickle cell disease. Additionally, sleep duration should not be considered in isolation, and its association with pain may be qualified by sleep fragmentation. Research and practice should include assessments of both when addressing pain severity. [ABSTRACT FROM AUTHOR]

Background: Patients with painful knee osteoarthritis (OA) demonstrate hyperalgesia and altered pain-modulatory responses. While some prior work has demonstrated cross-sectional associations between laboratory and clinical pain measures, it is unknown whether individual variability in quantitative sensory testing (QST) responses at baseline can prospectively predict analgesic treatment responses. Method Patients with knee OA (n = 35) were compared on QST responses to a demographically-matched pain-free control group (n = 39), after which patients completed a month-long treatment study of diclofenac sodium topical gel (1 %), applied up to 4 times daily. Results: OA patients demonstrated reduced pain thresholds at multiple anatomic sites, as well as reduced conditioned pain modulation (CPM) and enhanced temporal summation of pain. The most pain-sensitive patients tended to report the most intense and neuropathic OA pain. Following diclofenac treatment, the knee OA cohort showed a roughly 30 % improvement in pain, regardless of the presence or absence of neuropathic symptoms. Baseline CPM scores, an index of endogenous pain-inhibitory capacity, were prospectively associated with treatment-related changes in clinical pain. Specifically, participants with higher CPM at baseline (i.e., better functioning endogenous pain-inhibitory systems) showed more reduction in pain at the end of treatment (p < .05). Conclusions: These results support prior findings of amplified pain sensitivity and reduced pain-inhibition in OA patients. Moreover, the moderate to strong associations between laboratory-based measures of pain sensitivity and indices of clinical pain highlight the clinical relevance of QST in this sample. Finally, the prospective association between CPM and diclofenac response suggests that QST-based phenotyping may have utility in explaining inter-patient variability in long-term analgesic treatment outcomes. Trial registration ClinicalTrials.Gov Identifier: NCT01383954. Registered June 22, 2011.

The article presents a study if genes influences the dynamics of pain and affect in fibromyalgia (FM). Forty-six female patients with FM were assessed daily of positive affect and pain. Results show that there is ample reason to further investigate the contribution of catecholamine and opioid systems and their genomic variance to the vaguely understood condition of FM.

Dynamical systems modeling was used to analyze fluctuations in the pain prediction process of people with rheumatoid arthritis. 170 people diagnosed with rheumatoid arthritis completed 29 consecutive days of diaries. Difference scores between pain predictions and next-day pain experience ratings provided a time series of pain prediction accuracy. Pain prediction accuracy oscillated over time. The oscillation amplitude was larger at the start of the diary than at the end, which indicates damping toward more accurate predictions. State-level psychological characteristics moderated the damping pattern such that the oscillations for patients with lower negative affect and higher pain control damped more quickly than the oscillations for their counterparts. Those findings suggest that low negative affect and high pain control generally contributed to a more accurate pain prediction process in the chronically ill. Positive affect did not differentiate the damping pattern but, within each oscillation cycle, patients with higher positive affect spent more time making inaccurate predictions than their counterparts. The current analyses highlight the need to account for change in data through dynamical modeling, which cannot be fully observed through traditional statistical techniques. [ABSTRACT FROM AUTHOR]