Efficient Conditioned Pain Modulation Research Articles

The effects of neighborhood disadvantage and adverse childhood experiences on conditioned pain modulation in adults with chronic low back pain

Chronic low back pain (cLBP) remains a major health crisis worldwide. Current conceptualizations of cLBP utilize the biopsychosocial model, yet research on social factors remains limited. Adverse childhood experiences (ACEs) are a risk factor for a variety of chronic health problems, including cLBP. However, the extent to which socioeconomic context might influence associations between ACEs and cLBP remains unclear. Socioeconomic factors such as healthcare access and living conditions, which cluster at the neighborhood level, may affect how ACEs relate to cLBP in adulthood. This study examined (1) the relationship between ACEs and conditioned pain modulation (CPM), and (2) the moderating effect of area-level deprivation index (ADI) in a sample of community-dwelling adults with cLBP. 183 adults with cLBP (53% female, 62.8% non-Hispanic Black) reported on ACEs, ADI, sociodemographics, and completed experimental testing of conditioned pain modulation (CPM). Greater ACEs were associated with a less efficient CPM response for individuals residing in low neighborhood deprivation (p < 0.01). ACEs were not significantly associated with CPM for those residing in average (p = 0.31) or high deprivation (p = 0.15). Our findings suggest that a history of ACEs is associated with diminished ability to inhibit pain, especially among individuals living in less deprived neighborhoods. The association between ACEs and CPM was weakest for the portion of our sample residing in neighborhoods with the most deprivation. People from disadvantaged backgrounds may experience numerous psychosocial stressors that hinder CPM, making it difficult to assess the specific impact of ACEs on CPM. Trial registrationThis study utilized baseline data collected as part of a parent trial titled “Examining Racial and SocioEconomic Disparities in Chronic Low Back Pain” (ERASED - ClinicalTrials.gov ID: NCT03338192). PerspectiveThis study demonstrates that early life adversity is associated with abnormal endogenous pain modulation, particularly for participants who live in neighborhoods characterized by less deprivation.

Psychological Factors Modulate Quantitative Sensory Testing Measures in Fibromyalgia Patients: A Systematic Review and Meta-Regression Analysis.

Considering the growing evidence that psychological variables might contribute to fibromyalgia syndrome (FMS), our study aims to understand the impact of psychological factors in quantitative sensory testing (QST) in FMS patients by performing a systematic review with meta-analysis. A systematic search was carried out in PubMed/MEDLINE, EMBASE, Web of Science, and PsycINFO databases for records up until January 2024. We included 20 studies ( n = 1623, 16 randomized controlled trials, and 4 nonrandomized controlled trials) with low or moderate risk of bias included. From nonrandomized evidence, our meta-analysis found a baseline relationship between anxiety, depression, and pain catastrophizing and QST measures in FMS patients. Higher pain catastrophizing levels were associated with less efficient conditioned pain modulation. Higher anxiety and depression were associated with lower pain threshold (PT). Randomized evidence showed a statistically significant increase in PT after fibromyalgia treatments (effect size = 0.29, 95% confidence interval = 0.03-0.56). The effect was not influenced by treatment type. Moreover, we found that only anxiety levels before treatment negatively influenced the PT improvements after treatment. FMS patients with higher anxiety levels at baseline showed a smaller increase in PT after the intervention. Depression factor was not significant in either changes in anxiety or depression. Baseline anxiety levels should be monitored as possible confounders of QST measurements. Understanding how psychological factors and QST are related in FMS patients is critical for improving the syndrome's management and treatment.Protocol Registration: CRD42023429397.

Vagal tone, pain sensitivity and exercise-induced hypoalgesia: The effect of physical activity level.

Vagal activity has analgesic effects that are attributed to exercise-induced hypoalgesia (EIH). High vagal tone and low pain sensitivity are reported in individuals who routinely exercise yet, their association is unclear. Furthermore, it is unknown if the heightened vagal tone following high physical activity predicts and intensifies EIH. Fifty-one healthy participants (27 low-moderately physically active; 27 females) underwent a resting-state electrocardiogram followed by heart rate variability analysis. Pain measurements, including pressure (PPT) and heat (HPT) pain thresholds, ratings of tonic heat pain (THP) and conditioned pain modulation (CPM) paradigm, were conducted pre- and post-exercise on a cycle ergometer. The highly active group demonstrated higher vagal tone compared to the low-moderately active (root mean square of successive differences between R-R intervals: 63.96.92 vs. 34.78 ms, p = 0.018; percentage of successive R-R intervals that exceed 50 ms: 24.41 vs. 11.52%, p = 0.012). Based on repeated-measure ANOVA, the highly active group showed higher PPT at pre-exercise, compared to the low-moderately active group (382 kPa vs. 327 kPa; p = 0.007). Post-exercise, both groups demonstrated EIH, increased HPT (p = 0.013) and decreased THP ratings (p < 0.001). Linear regression revealed that only in the low-moderately active group, higher vagal tone was associated with more efficient pre-exercise CPM and a greater reduction in THP ratings post-exercise (p ≤ 0.01). Highly active individuals demonstrate greater vagal tone and lower pain sensitivity but no greater EIH. Vagal tone moderates pain inhibition efficiency and EIH only in low-moderately active individuals. These findings suggest that physical activity level moderates the vagal-pain association via the endogenous analgesia system. Highly physically active individuals exhibit greater vagal tone and reduced sensitivity to experimental pain, yet they do not benefit more from exercise-induced hypoalgesia (EIH) compared to low-moderately active individuals. Moreover, low-moderately active individuals with greater vagal tone exhibited more efficient endogenous pain inhibition and greater EIH, suggestive of the moderation effect of physical activity level on vagal-pain associations.

Somatosensory and psychosocial profile of migraine patients: A cross-sectional study

BackgroundMigraine is a chronic neurological disorder that involves the brain, characterized by a series of abnormal neuronal networks interacting at different levels of the central and peripheral nervous system. Furthermore, it is known that psychosocial features contribute to the exacerbation and chronicity of symptoms. ObjectiveTo compare the somatosensory and psychosocial profiles of migraine patients with a control group. MethodsWe conducted a cross-sectional study comparing the somatosensory and psychosocial profiles of patients with migraine and healthy volunteers. A total of 52 women were included. For the somatosensory profile, Mechanical Detection Threshold (MDT), Pressure Pain Threshold (PPT), Temporal Summation (TS), and Conditioned Pain Modulation (CPM) in the trigeminal and extra-trigeminal areas were evaluated. Psychosocial profiles were assessed using questionnaires, the Central Sensitization Inventory, the Generalized Anxiety Disorders, the Pain Catastrophizing Scale, and the Tampa Scale of Kinesiophobia. Mann-Whitney U test was used to compare differences in the profiles between groups. The significance level was set at 5%. ResultsMigraine patients showed a loss of somatosensory function in the trigeminal area for MDT (p = 0.019, r = 0.34 and p = 0.011, r = 0.37 for the ophthalmic nerve and masseter muscle respectively), lower PPT in trigeminal and extra-trigeminal areas (p < 0.001, r=>0.60) and less efficient CPM (p < 0.001, r=>0.60). No statistically significant differences were found in the TS (p=>0.05). Statistically significant differences were found in all psychosocial variables (p = <0.001 r=>0.60). ConclusionMigraine patients showed loss of somatosensory function, lower pressure pain threshold, and an inhibitory pro-nociceptive profile with high scores on central sensitization and fear of movement compared to the control group.

Botulinum toxin-A effects on pain, somatosensory and psychosocial features of patients with refractory masticatory myofascial pain: a randomized double-blind clinical trial

The antinociceptive effect of BoNT-A have been well documented in animal studies; however, results of few but well-designed randomized placebo-controlled clinical trials about BoNT-A efficacy in masticatory myofascial pain (MFP) are inconsistent. Therefore, the present randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy of BoNT-A in patients with refractory MFP. Twenty-eight patients with pain reduction of less than 30% despite conservative treatment and with an average pain intensity of > 50 mm on the visual analogue scale (VAS) participated. Patients were randomly assigned to receive a total of 80 U of BoNT-A or saline solution (SS) injected into the masseter and anterior temporalis muscles. Pain intensity (VAS), quantitative sensory testing (QST), conditioned pain modulation (CPM), and psychosocial status were examined. Follow-up was performed at 1 and 6 months. For repeated-measure comparisons between evaluation times, Friedman test with Bonferroni correction was used for pain and somatosensory variables and the Wilcoxon test for the psychosocial variables. The Mann–Whitney test was used for all comparisons between groups. The BoNT-A group had a significant decrease in pain intensity at follow-ups compared with the SS group (p < 0.001). QST assessment revealed higher pressure pain threshold values in the masseter muscle for BoNT-A group compared to SS (p < 0.03) at all follow-ups. No differences were found for mechanical pain threshold and wind-up ratio values (p > 0.05) in the entire study. The BoNT-A group presented the most efficient CPM effect (p < 0.03) only at the 1 month follow-up in the masseter muscle. There was a significant time effect for BoNT-A in all psychosocial variables (p < 0.05) and a drug effect in the Central Sensitization Inventory (p < 0.01), Pittsburgh Sleep Quality Index (p < 0.004), and Healthy Survey 36 (p < 0.05) at 6 months follow-up. The study demonstrates that a single injection-session of BoNT-A has positive effects on the hall pain spectrum of patients with refractory masticatory myofascial pain.

Biopsychosocial contributors to irritability in individuals with shoulder or low back pain

ABSTRACT Objectives Irritability is a foundational clinical reasoning concept in rehabilitation to evaluate reactivity of the examination and treatment. While originally theorized to reflect tissue damage, a large body of evidence supports pain is a biopsychosocial experience impacted by pain sensitivity and psychological factors. Therefore, the purpose of this study was to examine biopsychosocial contributors to irritability. Methods 40 patients with shoulder (n = 20) and low back (n = 20) pain underwent Quantitative Sensory Testing (QST) (Pressure Pain Threshold, Heat Pain Threshold, Conditioned Pain Modulation, Temporal Summation), completed pain-related psychological questionnaires, an Exercise-Induced Hypoalgesia protocol, and standardized irritability assessment based on Clinical Practice Guidelines. Participants were then categorized as irritable or not irritable based on Maitland’s criteria and by irritability level based on Clinical Practice Guidelines. An independent samples t-test examined for differences in QST and psychological factors by irritability category. A MANOVA examined for differences in QST and psychological factors by irritability level (high, moderate, low). Results Significantly lower heat and pressure pain thresholds at multiple locations (p < 0.05), as well as less efficient conditioned pain modulation (p = 0.02), were demonstrated in individuals categorized as irritable. Heat and pressure pain thresholds were also significantly lower in patients with high irritability compared to other levels. Significantly higher depression and anger, as well as lower self-efficacy, were reported in individuals with an irritable presentation. Discussion/Conclusion Biopsychosocial factors, including widespread hyperalgesia and elevated psychological factors, may contribute to an irritable presentation.

Examination of Conditioned Pain Modulation in Myofascial TMD With Consideration of Temporal Summation

Research on myofascial temporomandibular disorder (mTMD) has often focused on potential dysfunction in endogenous pain modulation. However, studies on the specific inhibitory and facilitatory components of endogenous pain modulation using conditioned pain modulation (CPM) and temporal summation of second pain (TSSP) have shown mixed results. This study aimed to 1) examine whether women with mTMD demonstrated efficient CPM compared to controls; 2) explore the association between independent measures of CPM and TSSP in women with mTMD relative to controls; and 3) determine whether resulting modulatory profiles differentially predicted pain intensity among cases. All participants were recruited from dental clinics. Cases were women who met the research diagnostic criteria for mTMD. Controls did not have facial pain on exam and were selected to be sociodemographically similar to cases. CPM and TSSP were assessed via independent psychophysical protocols. CPM was examined in linear mixed models predicting pain thresholds adjusted for age and stratified by TSSP. Mean CPM was estimated at a 2.2 (SD = 2.8) degree increase in pain thresholds (P ≤ .001), similar in cases and controls (P = .67). CPM was less efficient in cases with enhanced TSSP (P = .031), but not in controls. Although the double-pronociceptive profile of both low CPM and high TSSP trended higher among cases than controls, it did not predict higher levels of pain intensity among cases. This study does not support deficient inhibitory endogenous pain modulation in mTMD, but results suggest that inhibitory and facilitatory pain modulation should be examined concomitantly in the study of endogenous pain modulation. PerspectiveThis manuscript presents a novel examination of inhibitory modulation by the level of facilitatory modulation in mTMD. The findings and approach may prove useful for mechanistic researchers studying endogenous pain modulation and clinical researchers seeking to jointly examine conditioned pain modulation and temporal summation in future research on chronic pain.

Clusters of facilitatory and inhibitory conditioned pain modulation responses in a large sample of children, adolescents, and young adults with chronic pain.

When investigating the role of facilitatory and inhibitory pain mechanisms such as conditioned pain modulation (CPM) and temporal summation of pain (TSP), it is important to take both into consideration in a single experimental model to provide the most information on subgroups of patients. Therefore, the objective of this study was to identify subgroups in a large population of pediatric patients with chronic pain based on their facilitatory and inhibitory pain mechanisms and compare them with control subjects. Five hundred twenty-one female subjects and 147 male subjects between 8 and 21 years old underwent a CPM assessment using a 2-minute tonic noxious heat stimulation as the test stimulus and a 2-minute cold-pressor task (CPT) (12°C) as the conditioning stimulus. The best partition of clusters of patients was 3 clusters accounting for 27.15% of the total variation in the data. Cluster 1 (n = 271) was best characterized by high pain intensity during the CPT, lack of TSP during the test stimuli, and efficient inhibitory CPM. Cluster 2 (n = 186) was best characterized by low pain intensity during the CPT, lack of TSP during the test stimuli, and efficient inhibitory CPM. Cluster 3 (n = 151) was best characterized by high pain intensity during the CPT, presence of TSP during the test stimuli, and inefficient inhibitory CPM. A single thermal CPM experimental design can identify combinations of facilitatory and inhibitory pain modulation responses. Findings from the current study add to the literature by describing different clinical phenotypes of central pain mechanisms of youth with chronic pain.

Association between systemic inflammation and experimental pain sensitivity in subjects with pain and painless neuropathy after traumatic nerve injuries.

Peripheral neuropathies that occur secondary to nerve injuries may be painful or painless, and including a low-grade inflammation and pro-inflammatory cytokines associated with both regeneration and damage of peripheral nerve cells and fibers. Currently, there are no validated methods that can distinguished between neuropathic pain and painless neuropathy. The aim of this study was to search for proinflammatory and anti-inflammatory proteins associated with pain and experimental pain sensitivity in subjects with surgeon-verified nerve injuries in the upper extremities. One hundred and thirty-one subjects [69 with neuropathic pain, NP; 62 with painless neuropathy, nP] underwent a conditioned pain modulation (CPM) test that included a cold pressor task (CPT) conducted with the non-injured hand submerged in cold water (4°C) until pain was intolerable. CPM was assessed by pain ratings to pressure stimuli before and after applying the CPT. Efficient CPM effect was defined as the ability of the individual's CS to inhibit at least 29% of pain (eCPM). The subjects were assigned to one of two subgroups: pain sensitive (PS) and pain tolerant (PT) after the time they could tolerate their hand in cold water (PS<40s and PT=60s) . Plasma samples were analyzed for 92 proteins incorporated in the inflammation panel using multiplex Protein Extension Array Technology (PEA). Differentially expressed proteins were investigated using both univariate and multivariate analysis (principal component analysis-PCA and orthogonal partial least-squares discriminant analysis-OPLS-DA). Significant differences in all protein levels were found between PS and PT subgroups (CV-ANOVA p<0.001), but not between NP and nP groups (p=0.09) or between inefficient CPM (iCPM) and eCPM (p=0.53) subgroups. Several top proteins associated with NP could be detected using multivariate regression analysis such as stromelysin 2 (MMPs), interleukin-2 receptor subunit beta (IL2RB), chemokine (C-X-C motif) ligand 3 (CXCL3), fibroblast growth factor 5 (FGF5), chemokine (C-C motif) ligand 28 (CCL28), CCL25, CCL11, hepatocyte growth factor (HGF), interleukin 4 (IL4), IL13. After adjusting for multiple testing, none of these proteins correlated significantly with pain. Higher levels of CCL20 (p=0.049) and CUB domain-containing protein (CDCP-1; p=0.047) were found to correlate significantly with cold pain sensitivity. CDCP-1 was highly associated with both PS and iCPM (p=0.042). No significant alterations in systemic proteins were found comparing subjects with neuropathic pain and painless neuropathy. An expression of predominant proinflammatory proteins was associated with experimental cold pain sensitivity in both subjects with pain and painless neuropathy. One these proteins, CDC-1 acted as "molecular fingerprint" overlapping both CPM and CPT. This observation might have implications for the study of pain in general and should be addressed in more detail in future experiments.

Central nervous system monoaminergic activity in hip osteoarthritis patients with disabling pain: associations with pain severity and central sensitization.

Monoaminergic activity modulates nociceptive transmission in the central nervous system (CNS). Although pain is the most disabling symptom of osteoarthritis (OA), limited knowledge exists regarding the CNS mechanisms that amplify pain and drive sensitization processes in humans. The main objective of this study was to evaluate associations between cerebrospinal fluid (CSF) monoamine metabolites, pain severity, and central sensitization in patients with OA undergoing total hip arthroplasty (THA). Patients with OA (n = 52) and pain-free controls (n = 30) provided CSF samples for measurement of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), noradrenaline (3-methoxy-4-hydroxyphenylglycol [HMPG]), and dopamine (homovanillic acid [HVA]) monoamine metabolites. Patients with OA completed longitudinal evaluation of pain using clinical measures and quantitative sensory testing. Patients with OA had higher HMPG levels when compared with controls (P = 0.036). Within patients with OA undergoing THA, higher 5-HIAA and HVA levels were consistently associated with higher preoperative pain severity. Higher concentrations of 5-HIAA and HVA were also associated with lower conditioned pain modulation levels, whereas higher HMPG levels were linked to more efficient conditioned pain modulation. Patients with higher levels of CSF HVA exhibited increased pressure pain sensitivity (arm pressure pain detection threshold < 250 kPa vs ≥ 250 kPa, P = 0.042). Higher preoperative levels of CSF 5-HIAA predicted poorer pain control 6 months postoperatively (brief pain inventory pain severity; adjusted β = 0.010, 95% CI 0.001-0.019). In OA patients with disabling pain, higher CSF levels of serotonin and dopamine metabolites are associated with increased pain severity and central sensitization. Increased noradrenergic activity may be associated with more efficient pain inhibitory capacity.

Conditioned pain modulation is more efficient in patients with painful diabetic polyneuropathy than those with nonpainful diabetic polyneuropathy.

Endogenous pain modulation, as tested by the conditioned pain modulation (CPM) protocol, is typically less efficient in patients with chronic pain compared with healthy controls. We aimed to assess whether CPM is less efficient in patients with painful diabetic polyneuropathy (DPN) compared with those with nonpainful DPN. Characterization of the differences in central pain processing between these 2 groups might provide a central nervous system explanation to the presence or absence of pain in diabetic neuropathy in addition to the peripheral one. Two hundred seventy-one patients with DPN underwent CPM testing and clinical assessment, including quantitative sensory testing. Two modalities of the test stimuli (heat and pressure) conditioned to cold noxious water were assessed and compared between patients with painful and nonpainful DPN. No significant difference was found between the groups for pressure pain CPM; however, patients with painful DPN demonstrated unexpectedly more efficient CPMHEAT (-7.4 ± 1.0 vs -2.3 ± 1.6; P = 0.008). Efficient CPMHEAT was associated with higher clinical pain experienced in the 24 hours before testing (r = -0.15; P = 0.029) and greater loss of mechanical sensation (r = -0.135; P = 0.042). Moreover, patients who had mechanical hypoesthesia demonstrated more efficient CPMHEAT (P = 0.005). More efficient CPM among patients with painful DPN might result from not only central changes in pain modulation but also from altered sensory messages coming from tested affected body sites. This calls for the use of intact sites for proper assessment of pain modulation in patients with neuropathy.

A psychophysical study comparing massage to conditioned pain modulation: A single blind randomized controlled trial in healthy participants

IntroductionPain-inducing massage results in greater pain inhibition than pain free massage, suggesting a mechanism dependent on conditioned pain modulation (CPM). The purpose of this study was to test the hypothesis that pain inducing massage produces similar magnitude of reduction in pain sensitivity as a cold pressor task and that baseline conditioned pain modulation efficiency predicts pain inducing massage related hypoalgesia. MethodsSixty healthy participants were randomly assigned to receive either pain inducing massage to the neck, cold pressor task to the hand, or pain free massage to the neck. Participants also underwent pre and immediate post-intervention quantitative sensory testing. A repeated measures ANCOVA determined between group differences in pain sensitivity changes. ResultsPain inducing massage used as a conditioning stimulus resulted in comparable experimental pain sensitivity changes as a cold pressor task (p > 0.05). Pain intensity during the intervention demonstrated a weak correlation (r = 0.20, p = 0.12) with changes in pain sensitivity at a remote site. Individuals with an efficient CPM at baseline who received the pain inducing massage displayed greater increases in pressure pain threshold compared to individuals with a less efficient CPM indicating the potential benefit of treatment stratification by mechanism. ConclusionAlthough pain inducing massage resulted in less self-reported pain than a cold pressor task, both resulted in similar magnitude of the CPM response, suggesting shared underlying mechanisms. Understanding mechanisms of interventions can move us closer to mechanistic based treatments for pain which is consistent with a personalized medicine approach to care.

Prolonged time of after-sensation after experimental pain stimuli despite efficient conditioned pain modulation in patients with chronic neuropathic pain after traumatic nerve injuries in upper extremity.

As yet, there is limited research that can identify factors that differentiate between painful and nonpainful neuropathies after traumatic nerve injury. The aim of this study was to compare subjects with pain and without pain, all after operative nerve repair in the upper extremities. Subjects in both groups (pain, n = 69; painless, n = 62) underwent clinical assessment of sensory nerve function and psychophysical tests: quantitative sensory testing and conditioned pain modulation (CPM). Conditioned pain modulation was assessed by pain ratings to 120 seconds pressure stimuli administered before and after a 60 seconds noxious 4°C cold conditioning stimulus (CS). Time of recovery (time off) of pain intensity from peak VASmaxc after CS was recorded. Questionnaires about the quality of life (RAND-36) and disability of the extremity (QuickDash) were completed. There were no significant differences between groups for CPM (P = 0.19). Time off was 42 seconds in subjects with pain in comparison with 28 seconds in those without pain (P < 0.0001). Compared with individuals reporting no pain, participants with neuropathic pain after nerve injuries had 1.8 times the odds of recovering later after CS, gain of function findings at sensory examination (P < 0.0001), lower scores of the physical component of RAND-36 (P < 0.0001), and increase arm disability (P < 0.0001). Hyperesthesia to cold pain stimulation (P = 0.03) and lowered pain pressure threshold (P = 0.01) were found in the pain group. Recovery after the pain induced by cold CS indicates changes in central processing of pain and provides a potential measurement of endogenous pain modulation in individuals with chronic neuropathic pain.

Clinical variables associated with the presence of articular pain in patients with temporomandibular joint clicking.

To study and estimate the impact of clinical, somatosensory, and psychosocial variables associated with the concomitant presence of temporomandibular joint (TMJ) pain in patients with TMJ clicking. Ninety-three individuals composed the sample: patients with painful TMJ clicking (n = 47) and patients with painless TMJ clicking (n = 46). Four categories of data were evaluated: clinical features (gender, maximal interincisal distance (MID), side of complaint, age); bruxism (sleep bruxism (SB), awake bruxism (AB)); somatosensory (mechanical pain threshold (MPT), wind-up ratio (WUR), pressure pain threshold (PPT), conditioned pain modulation (CPM)); and psychosocial (Pittsburgh Sleep Quality Index (PSQI), pain vigilance and awareness questionnaire (PVAQ), Pain Catastrophizing Scale (PCS), Tampa Scale for Kinesiophobia for Temporomandibular Disorders (TSK/TMD), Oral Behaviors (OBs)). Female gender, AB, WUR, CPM, PSQI, PCS, and OBs significantly (p < 0.05) increased the chance of the concomitant presence of TMJ pain in patients with TMJ clicking. On the other hand, MID, MPT, and PPT significantly (p < 0.05) decreased this chance. The other variables had no association. It can be concluded that being a woman, having AB, hyperalgesia in WUR, less efficient CPM, poor sleep quality, pain catastrophizing, and harmful OBs significantly increased the chance of the concomitant presence of TMJ pain in patients with TMJ clicking. In the opposite, high figures of MID, MPT, and PPT decreased the chance. Most patients with TMJ clicking usually postpone seeking treatment until the clicking truly disturbs or there is a concomitant presence of TMJ pain. Understanding the variables associated with this concomitance can be important in clinical practice.

Somatosensory and psychosocial profile of patients with painful temporomandibular joint clicking

Determining the somatosensory and psychosocial profile of patients with painful temporomandibular joint (TMJ) clicking can help to understand the pain mechanisms in cases of TMJ clicking. To characterise the somatosensory and psychosocial profile of patients with painful TMJ clicking when compared to patients with painless TMJ clicking and healthy control group. Somatosensory and psychosocial functions were assessed in 90 individuals: patients with painful TMJ clicking (n=30); patients with painless TMJ clicking (n=30); and healthy controls (n=30). Somatosensory profile included: mechanical pain threshold (MPT); wind-up ratio (WUR); pressure pain threshold (PPT); and conditioned pain modulation (CPM). Psychosocial profile included some questionnaires: Pittsburgh Sleep Quality Index (PSQI); Pain Vigilance-Awareness Questionnaire (PVAQ); Pain Catastrophizing Scale (PCS); Tampa Scale for Kinesiophobia (TSK); Perceived Stress (PSS); and State-Trait Anxiety Inventory (STAI). All variables were compared among all groups. Higher values of MPT and WUR; lower PPT; less efficient CPM; and higher scores of PSQI, PVAQ, PCS, and TSK were found in patients with painful TMJ clicking when compared to the other two groups (P<.001). Patients with painless TMJ clicking showed lower PPT and higher scores of PVAQ and TKS than the healthy control group. PSS and STAI data had no differences. Patients with painful TMJ clicking had abnormalities in the somatosensory profile, with a significant somatosensory gain of function (more sensitive) to mechanical pain tests and less efficient CPM. Poor sleep quality along with higher levels of hypervigilance, pain catastrophising, and kinesiophobia were features of psychosocial profile of these patients.

Identification of neural and psychophysical predictors of headache reduction after cognitive behavioral therapy in adolescents with migraine.

Cognitive behavioral therapy (CBT) is a psychological intervention that involves development of coping strategies to reduce the experience of pain. Although CBT is a promising intervention to reduce headache days in patients with migraine, it may not be effective for all patients. Thus, there is a need to identify markers that could predict which patients will respond to CBT. We aimed to determine whether baseline brain function and amygdalar connectivity, assessed by functional magnetic resonance imaging, or pain modulation capacities, assessed by the conditioned pain modulation (CPM) response, can predict a reduction in headache days after CBT in adolescents with migraine. Patients with migraine (n = 20; age range 10-17 years) completed 8 weekly CBT sessions. The CPM response was examined in the trapezius and the leg. Headache days significantly decreased after CBT (P < 0.001). Greater functional connectivity before CBT between the right amygdala and frontal gyrus, anterior cingulate cortex, and precentral gyrus was related to greater headache reduction after CBT. Greater reduction in headache days after CBT was related with less efficient CPM response before CBT at the trapezius (r = -0.492, P = 0.028) but not at the leg. This study found that headache reduction after CBT was related to right amygdala connectivity with frontal and sensorimotor regions at baseline as well as baseline pain modulation capacities. These findings suggest that individual differences in brain function and pain modulation can be associated with clinical improvements and help with determination of CBT responsiveness.

Exercise-induced Hypoalgesia Is Impaired in Chronic Whiplash-associated Disorders (WAD) With Both Aerobic and Isometric Exercise.

Exercise-induced hypoalgesia (EIH) can be impaired in patients with chronic pain and may be dependent on exercise type. Factors predictive of EIH are not known. This study aimed to: (1) compare EIH in participants with chronic whiplash-associated disorders (WAD) to asymptomatic controls, (2) determine if EIH differs between aerobic and isometric exercise, (3) determine predictors of EIH. A pre-post study investigated the effect of single sessions of submaximal aerobic treadmill walking and isometric knee extension on EIH in 40 participants with chronic WAD and 30 controls. Pressure pain thresholds were measured at the hand, cervical spine, and tibialis anterior. Pain intensity, reported previous week physical activity, temporal summation, and conditioned pain modulation (CPM) were measured at baseline. Participants with WAD demonstrated impaired EIH. Although, the WAD participants demonstrated a partial EIH response (EIH induced at the hand during exercise), no EIH response was found immediately after exercise. There was no difference in EIH between exercise types. In the WAD group, moderate physical activity levels predicted EIH at the hand and high physical activity levels predicted impaired EIH at the neck. More efficient CPM predicted EIH at the hand and less efficient CPM predicted impaired EIH at the neck. These associations were found for isometric exercise only. Individuals with chronic WAD have impaired EIH with both aerobic and isometric exercise. Higher levels of physical activity and less efficient CPM may be associated with impaired EIH. This may have implications for exercise prescription in this patient group.

The Endogenous Analgesia Signature in the Resting Brain of Healthy Adults and Migraineurs

Altered pain modulation and resting state functional connectivity (rsFC) were found to be related to migraine pathology and clinical manifestation. We examined how pain modulation psychophysical measures are related to resting-state networks and rsFC between bottom-up and top-down pain modulation areas. Thirty-two episodic migraineurs and 23 age-matched healthy individuals underwent temporal summation of pain (TSOP) and conditioned pain modulation (CPM) tests, followed by a resting-state imaging scan. No differences in temporal summation of pain and CPM were found between groups. However, in healthy individuals, more efficient CPM was correlated with 1) stronger rsFCs of the posterior cingulate cortex, with the ventromedial prefrontal cortex and with the pregenual anterior cingulate cortex; 2) weaker rsFC of the anterior insula with the angular gyrus. Conversely, in migraineurs, the association between CPM and rsFC was altered. Our results suggest that the functional connectivity within the default mode network (DMN) components and the functional coupling between the DMN and pain inhibitory brain areas is linked with pain inhibition efficiency. In migraineurs, this interplay is changed, yet enables normal pain inhibition. Our findings shed light on potential functional adaptation of the DMN and its role in pain inhibition in health and migraine. PerspectiveThis article establishes evidence for the relationship between the resting-state brain and individual responses in psychophysical pain modulation tests, in both migraine and healthy individuals. The results emphasize the significant role of the default mode network in maintaining pain inhibition efficiency in health and in the presence of chronic pain.

Pain inhibitory mechanisms and response to weak analgesics in patients with knee osteoarthritis.

Conditioned pain modulation (CPM) and offset analgesia are different features of descending pain inhibition. This study investigated CPM, offset analgesia and clinical pain measures in patients with knee osteoarthritis (KOA) before and after treatment with the combination of a non-steroidal anti-inflammatory drug (NSAIDs) plus acetaminophen. Forty-two patients with KOA received Ibuprofen 1.2g/daily and acetaminophen 3.0g/daily for three weeks. Before administration, CPM magnitude was assessed as the difference between cuff pain detection (cPDT) with and without a conditioning stimulus (evoked by tourniquet pain). Offset analgesia was assessed as the pain intensities evoked by a constant 46°C for 30-s stimulus compared to an offset analgesia paradigm of 46°C for 5-s, 47°C for 5-s and 46°C for 20-s. The worst pain within the last 24-hr and pain during activity were assessed before and after treatment. Clinical pain significantly decreased after treatment (p<0.001) and less efficient CPM before treatment was associated with weaker analgesic effect (R=0.354, p=0.043). No significant modulation of CPM or offset analgesia was found for the treatment. This study found that less efficient CPM is associated with reduced analgesic effect of NSAIDs plus acetaminophen in patients with KOA whereas the treatment did not modulate CPM nor offset analgesia magnitude. This study demonstrated that conditioned pain modulation is correlated with the response to a standard pharmaceutical interventions treating osteoarthritis pain. Furthermore, we demonstrated that a decrease in clinical pain intensity is not associated with a normalization of conditioned pain modulation or offset analgesia, which questions if restoring these descending pain inhibitory mechanisms are pain intensity driven.

Changes in peripheral and central sensitization in patients undergoing occipital nerve stimulation.

Central sensitization and impaired conditioned pain modulation (CPM) response have been reported to contribute to migraine progression. Migraine patients can present with allodynia possibly attributed to increased sensitivity of peripheral ends of nociceptors with both peripheral and central sensitization. Occipital nerve stimulation (ONS) works by stimulating the distal branches of C1, C2 and C3 possibly altering the nociceptive traffic to the trigemino-cervical complex, brainstem and supranuclear connections. This observational study explores peripheral and central sensitization in patients undergoing percutaneous ONS. Following local regulatory approval, 13 patients undergoing ONS with dual Octrode 90 cm leads and rechargeable implantable pulse generator (IPG) (St Jude) were recruited to have quantitative sensory testing (QST) pre- and post-procedure 2 weeks, 1, 3, 6 and 12 months. Patients with intractable migraine demonstrated impaired CPM (mean baseline pressure pain thresholds (PPTs): 61.98 kPa vs 48.01 kPa cuff inflated) prior to ONS, reverting to an efficient CPM response within 2 weeks following ONS implant (68.9 kPa vs 104.5 kPa cuff inflated) and continuing positively over the next 12 months. In contrast, no statistical difference was observed in PPTs. This is the first reported observation highlighting the effects on central sensitization following ONS. A consistent and sustained improvement in CPM was observed in contrast to PPT's where there was no difference. Normalisation of the CPM response following ONS indicates that the treatment may reduce central sensitization in the migraine population.