Lower Conditioned Pain Modulation Research Articles

Conditioned Pain Modulation Differences in Central and Peripheral Burning Mouth Syndrome (BMS) Patients.

To evaluate conditioned pain modulation (CPM) in burning mouth syndrome (BMS) patients with different pain mechanisms. Twenty BMS patients (52.0 ± 6.8 years, 17 women and 3 men) and age- and gender-matched 22 healthy controls were enrolled in this randomised controlled trial. The patients received an active lingual nerve block (lidocaine) and a placebo injection (saline) randomly with an interval of 1 week in a double-blinded manner. Patients evaluated their pain intensity on a 0- to 10-cm visual analogue scale (VAS) before and after each injection, with or without CPM. Based on the anaesthesia effect, BMS patients were divided into two groups with presumed different pain mechanisms; a 'central subgroup (n = 11)' with pain relief less than 1 cm and 'peripheral subgroup (n = 9)' with pain relief more than 1 cm on the VAS. Mechanical pain threshold (MPT) and wind-up ratio (WUR) were investigated at two oral mucosa regions: the region with most intense symptoms and a control region for the patient group; tongue and buccal region for the control group. CPM was induced by immersing the left hand into cold water. A moderate level of pain (around five on the VAS) was obtained by adjusting the water temperature. MPT and WUR were measured twice for all the participants with and without CPM, which was analysed and presented as relative change in MPT and WUR. Differences between groups were analysed using two-way ANOVA. Differences within group between tests were assessed by paired t-test. At baseline, there were no significant group differences for MPT or WUR between BMS patients and healthy controls (p ≥ 0.156). The mean bath temperature to evoke moderate pain for the BMS group was significantly lower than that for the healthy control group (8.9°C vs. 11.9°C, p = 0.003). The CPM evoked an inhibitory modulation in 18.2%-44.4% of BMS patients, while for the healthy group, the ratio was 68.2%-81.8%. Central BMS patients had smaller CPM effects than healthy participants at the painful site and control site, which indicated a decreased CPM function (p ≤ 0.034). Peripheral BMS patients had lower CPM effects than healthy participants only at the painful site (p = 0.037). The present findings documented impairment of central nociceptive inhibition processing in BMS patients which was more extensive in central BMS than peripheral BMS. These findings add to the suggestion that BMS may a heterogeneous pain condition with at least two different phenotypes.

Pain profiles and variability in temporal summation of pain and conditioned pain modulation in pain-free individuals and patients with low back pain, osteoarthritis, and fibromyalgia.

Pain profiles (e.g. pro- and anti-nociceptive) can be developed using quantitative sensory testing (QST) but substantial variability exists. This study describes the variability in temporal summation of pain (TSP) and conditioned pain modulation (CPM) in chronic musculoskeletal pain patients, proposes cut-off values, and explores the association with clinical pain intensity. This is a secondary analysis in which TSP and CPM were assessed using cuff algometry in pain-free subjects (n = 69), and patients with chronic low back pain (cLBP, n = 267), osteoarthritis (n = 134), and fibromyalgia (n = 101). Using TSP and CPM from the pain-free subjects as a reference, four distinct pain profiles TSP (low/high) and CPM (low/high) were created, and differences in clinical pain between pain profiles were explored. Individual data revealed large inter-person variability. High TSP and low CPM were found in fibromyalgia (p < 0.01) and osteoarthritis (p < 0.01) but not cLBP when compared to pain-free subjects. The proportion of patients classified into the distinct pain profiles was significantly different (p < 0.001) with the largest proportion in the high TSP and low CPM group in fibromyalgia (52.5%) and osteoarthritis (41.4%). Clinical pain was not significantly different comparing the pain profiles, and no significant correlations were observed between clinical pain and TSP or CPM. These results demonstrated substantial inter-person variability in TSP and CPM in patients with different chronic pain conditions and pain-free subjects. The proportion of patients with a pro-nociceptive profile appears larger in fibromyalgia and osteoarthritis, but we found no association to clinical pain. This analysis shows that there is variability when assessing TSP and CPM in both pain-free subjects and patients with chronic pain. A cut-off for determining when a person is pain-sensitive is proposed, and data based on this cut-off approach suggest that significantly more patients with osteoarthritis and fibromyalgia are pain-sensitive (i.e. higher TSP and lower CPM) compared to pain-free subjects. This analysis does not find an association between pain sensitivity and clinical pain.

Disruptive compensatory mechanisms in fibromyalgia syndrome and their association with pharmacological agents.

Fibromyalgia syndrome (FMS) is a chronic disorder characterized commonly by widespread musculoskeletal pain and fatigue, predominantly affecting women, with its complexity often leading to underdiagnosis and complicating treatment effectiveness. Transcranial magnetic stimulation (TMS) metrics are potential markers to optimize FMS treatments; however, evidence is limited. Our study aimed to explore the relationship between cortical excitability and inhibition, assessed through TMS markers, and clinical characteristics in patients with FMS. This presented cross-sectional study employed baseline data from a clinical trial with 108 FMS patients, mostly female (88.8%), and mean age of 47.3 years old (SD = 12.06). Our analysis showed that decreased short-intracortical inhibition (SICI) was associated with gabapentinoids use, nicotine history, and increased fatigue levels, suggesting its connection with compensatory mechanisms for non-painful FMS features. Increased motor intracortical facilitation (ICF) was linked with greater pain severity and shorter FMS duration, implying its relationship with a reorganization of sensorimotor pathways due to chronic pain. Additionally, higher resting motor threshold (rMT) was associated with less effective pain modulation (lower conditioned pain modulation [CPM]), indicating a disruption of pain compensatory mechanism. Given the role of SICI in indexing homeostatic brain mechanisms and its association with fatigue, a hallmark characteristic of FMS-induced behavioral changes, these results suggest that FMS likely has a deleterious effect on brain inhibitory function, thus providing a potential novel insight for FMS mechanisms. In addition, it seems that this compensatory mechanism's disruption is enhanced by pharmacological agents such as gabapentioids and nicotine.

Pain Is Modulated Differently Between Females with and without Patellofemoral Pain: Factors Related to Sensitization.

Patellofemoral pain (PFP) has poor long-term recovery outcomes. Central sensitization describes central nervous system changes altering pain modulation, which can complicate recovery (poorer prognosis, worse function). Signs of central sensitization include amplified pain facilitation, pain hypersensitivity, and impaired pain inhibition, which can be measured with temporal summation of pain (TSP), pressure pain thresholds (PPTs) and conditioned pain modulation (CPM), respectively. Sex differences exist for these test responses, but female-only PFP investigations of sensitization are uncommon. Understanding pain modulation in females with PFP could improve treatment protocols. To determine whether females with PFP exhibit signs of central sensitization (greater TSP, lower PPTs, reduced CPM) compared to pain-free females. Cross-sectional Setting: Laboratory Patients or Other Participants: Thirty-three females [(20 PFP, 13 pain-free); Age: PFP 29.2 ± 7 years, pain-free 28 ± 7 years; Height: PFP 166.7 ± 5.9cm, pain-free 166 ± 9.5cm, Mass: PFP 66.7 ± 9.6kg, pain-free 69.3 ± 7.5kg). TSP was assessed with ten punctate stimuli applied to the knee and calculated by the difference in pain intensity between beginning and end responses. PPTs were tested at four sites [3 for local hypersensitivity (knee), 1 for widespread hypersensitivity (hand)]. CPM was conducted by comparing PPTs during two conditions (baseline, ice immersion). CPM response was defined as the percent difference between conditions. Between-group differences in TSP response were analyzed with a Welch's test. Separate Welch's tests analyzed group comparisons of PPTs and CPM responses at four sites. Females with PFP exhibited greater TSP response (P=0.019) and lower CPM response at patella center (P=0.010) and hand sites (P=0.007) than pain-free females. PPT group differences were not observed at any site (P>0.0125). Females with PFP modulate pain differently than pain-free females. Clinicians should recognize signs of central sensitization and their potential impact on treatment options.

Correlations of The Central Sensitization Inventory, conditioned pain modulation, cognitions and psychological factors in individuals with chronic neck pain: A cross-sectional study.

Chronic neck pain (CNP) is a global public health problem, with high prevalence and absenteeism rates. Central sensitization (CS) as a basis for chronic pain may play an essential role in its development and progression. It is often comorbid with low conditioned pain modulation (CPM) effects, cognitions, and psychological problems. The purposes of this study were to (1) explore the relationship between pain-related cognitions and psychological factors, CPM effects, and the central sensitization inventory (CSI) scores; and (2) determine whether cognitions and psychological factors can predict CSI scores and CPM effects in individuals with CNP. Fifty-four individuals with CNP were recruited for this cross-sectional study. The following outcome measures were evaluated: The CSI (screening tool) was compared with the cold pressor test (CPT), which was the psychophysical test used to assess the CPM; neck pain intensity using the visual analogue scale (VAS), as well as pain-related cognitions (including kinesiophobia and pain catastrophization) and psychological states (including anxiety and depression) using self-report questionnaires. CSI score was not associated with the CPM effect (r = 0.257, p > 0.05), and no cognitions or psychological factors were associated with CPM (p > 0.05), but CSI score was moderately positively correlated with kinesiophobia (r = 0.554, p < 0.01), lowly positively correlated with pain catastrophization (r = 0.332, p = 0.017) and anxiety (r = 0.492, p < 0.01), but not depression (r = 0.207, p = 0.132). Multiple linear regression analysis showed that kinesiophobia (B = 1.308, p < 0.01) and anxiety (B = 1.806, p = 0.02) were significant positive predictors of CSI score. The findings confirm some of our hypotheses. Accordingly, the findings inferred that the CSI does not seem to respond to CPM effect in patients with CNP effectively. In addition, CSI score was associated with cognitions and psychological factors, of which kinesiophobia and anxiety were effective predictors. In clinical practice, pain-related cognitions and psychological factors should be fully considered to manage neck pain efficiently.

Augmented Central Pain Processing Occurs after Osteoporotic Vertebral Compression Fractures and Is Associated with Residual Back Pain after Percutaneous Vertebroplasty.

A retrospective analysis. To investigate the occurrence of central sensitization (CS) in patients with osteoporotic vertebral compression fractures (OVCFs) and identify the association between CS and residual back pain (RBP). RBP is a vexing complication that affects 6.3%-17.0% of patients with OVCFs who underwent percutaneous vertebroplasty (PVP). Given the negative effect of RBP on patients' psychological and physiological statuses, efforts to preoperatively select patients who are at risk for RBP development have a high priority to offer additional treatment and minimize this complication. Preoperatively, all 160 patients with OVCFs underwent pressure-pain threshold (PPT), temporal summation (TS), conditioned pain modulation (CPM), and imaging assessments. Pain intensity and pain-related disability were evaluated before and after PVP. Preoperatively, patients with OVCFs had lower PPTs in both local pain and pain-free areas and lower CPM and higher TS in pain-free areas than healthy participants (p<0.05). Unlike patients with acute fractures, patients with subacute/chronic OVCFs showed higher TS with or without lower CPM in the pain-free area compared with healthy participants (p<0.05). Postoperatively, RBP occurred in 17 of 160 patients (10.6%). All preoperative covariates with significant differences between the RBP and non-RBP groups were subjected to multivariate logistic regression, showing that intravertebral vacuum cleft, posterior fascia edema, numeric rating pain scale scores for low back pain at rest, and TS were independently associated with RBP (p<0.05). Augmented central pain processing may occur in patients with OVCFs, even in the subacute stage, and this preexisting CS may be associated with RBP. Preoperative assessment of TS in pain-free areas may provide additional information for identifying patients who may be at risk of RBP development, which may be beneficial for preventing this complication.

Altered central pain processing in patients with degenerative lumbar diseases and its association with low physical activity levels after lumbar spinal surgeries: a retrospective cohort analysis.

To investigate the occurrence of altered central pain modulation in patients with degenerative lumbar diseases (DLDs) and to analyze its association with physical activity (PA) 3years after lumbar decompression and fusion. Preoperative assessments of pressure pain thresholds (PPTs), temporal summation (TS), conditioned pain modulation (CPM) and pain were, respectively, recorded in 304 patients. These patients further underwent International Physical Activity Questionnaire (IPAQ) and both pain-related and psychological assessments 3years post-operation. Preoperatively, the patients had lower PPTs in both local pain and pain-free areas and lower CPM and higher TS in pain-free areas than healthy subjects (P < 0.05). Postoperatively, 53.9% (164/304) patients showed PA below healthy-related thresholds (< 600 MET min/w). Low PA group showed a greater postoperative weight gain and bone loss and a higher postoperative prevalence of both moderate anxiety and marginal depression than high PA group (P < 0.05). All covariates with differences between the high and low PA groups were subjected to multivariate logistic regression, and long preoperative disease duration, low preoperative PPT in pain-free area, high preoperative TS, revision surgery, severe postoperative low back pain and significant postoperative pain catastrophizing thought were independently associated with low postoperative PA (P < 0.05). This study supports the existence of central sensitization (CS) caused by abnormal central pain modulation in DLDs. Pre-existing CS in these patients may be associated with low PA after lumbar surgeries, and this low-activity lifestyle may predispose patients to multiple adverse health outcomes. Preoperative dynamic quantitative sensory testing may provide information for the identification of at-risk patients.

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.

Motor corticospinal excitability abnormalities differ between distinct chronic low back pain syndromes

ObjectivesIt is not known whether cortical plastic changes reported in low-back pain (LBP) are present in all etiologies of LBP. Here we report on the assessment of patients with three LBP conditions: non-specific-LBP (ns-LBP), failed back surgery syndrome (FBSS), and sciatica (Sc). MethodsPatients underwent a standardized assessment of clinical pain, conditioned pain modulation (CPM), and measures of motor evoked potential (MEPs)-based motor corticospinal excitability (CE) by transcranial magnetic stimulation, including short interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Comparisons were also made with normative data from sex- and age-matched healthy volunteers. Results60 patients (42 women, 55.1±9.1 years old) with LBP were included (20 in each group). Pain intensity was higher in patients with neuropathic pain [FBSS (6.8±1.3), and Sc (6.4±1.4)] than in those with ns-LBP (4.7±1.0, P<0.001). The same was shown for pain interference (5.9±2.0, 5.9±1.8, 3.2±1.9, P<0.001), disability (16.4±3.3, 16.3±4.3, 10.4±4.3, P<0.001), and catastrophism (31.1±12.3, 33.0±10.4, 17.4±10.7, P<0.001) scores for FBSS, Sc, and ns-LBP groups, respectively. Patients with neuropathic pain (FBSS, Sc) had lower CPM (-14.8±1.9, -14.1±16.7, respectively) compared to ns-LBP (-25.4±16.6; P<0.02). 80.0% of the FBSS group had defective ICF compared to the other two groups (52.5% for ns-LBP, P=0.025 and 52.5% for Sc, P=0.046). MEPs (140%-rest motor threshold) were low in 50.0% of patients in the FBSS group compared to 20.0% of ns-LBP (P=0.018) and 15.0% of Sc (P=0.001) groups. Higher MEPs were correlated with mood scores (r=0.489), and with lower neuropathic pain symptom scores(r=-0.415) in FBSS. ConclusionsDifferent types of LBP were associated with different clinical, CPM and CE profiles, which were not uniquely related to the presence of neuropathic pain. These results highlight the need to further characterize patients with LBP in psychophysics and cortical neurophysiology studies.

Pain-related cognitions and emotional distress are not associated with conditioned pain modulation: an explorative analysis of 1142 participants with acute, subacute, and chronic pain.

Reduced conditioned pain modulation (CPM) and psychological distress co-occur frequently in many pain conditions. This study explored whether common negative pain cognitions and emotional factors were related to lower CPM in individuals across the spectrum from acute to chronic pain. Previously collected data on the CPM effect, pain-related cognitions (fear of movement, pain catastrophizing), and emotional distress (depression, anxiety) through questionnaires from 1142 individuals with acute, subacute, or chronic pain were used. The presence of negative psychological factors was dichotomized according to cutoff values for questionnaires. Associations between the presence of each negative psychological factor and the amplitude of pain reduction in the CPM paradigm was explored with Generalized Linear Models adjusted for sex, age, body mass index, and pain duration. A secondary analysis explored the cumulative effect of psychological factors on CPM. When dichotomized according to cutoff scores, 20% of participants were classified with anxiety, 19% with depression, 36% with pain catastrophizing, and 48% with fear of movement. The presence of any negative psychological factor or the cumulative sum of negative psychological factors was associated with lower CPM (individual factor: β between -0.15 and 0.11, P ≥ 0.08; total: β between -0.27 and -0.12, P ≥ 0.06). Despite the common observation of psychological factors and reduced CPM in musculoskeletal pain, these data challenge the assumption of a linear relationship between these variables across individuals with acute, subacute, and chronic pain. Arguably, there was a nonsignificant tendency for associations in nonexpected directions, which should be studied in a more homogenous population.

The OPRM1 gene and interactions with the 5-HT1a gene regulate conditioned pain modulation in fibromyalgia patients and healthy controls.

Fibromyalgia (FM) patients have dysfunctional endogenous pain modulation, where opioid and serotonergic signaling is implicated. The aim of this study was to investigate whether genetic variants in the genes coding for major structures in the opioid and serotonergic systems can affect pain modulation in FM patients and healthy controls (HC). Conditioned pain modulation (CPM), evaluating the effects of ischemic pain on pressure pain sensitivity, was performed in 82 FM patients and 43 HC. All subjects were genotyped for relevant functional polymorphisms in the genes coding for the μ-opioid receptor (OPRM1, rs1799971), the serotonin transporter (5-HTT, 5-HTTLPR/rs25531) and the serotonin 1a receptor (5-HT1a, rs6295). Results showed the OPRM1 G-allele was associated with decreased CPM. A significant gene-to-gene interaction was found between the OPRM1 and the 5-HT1a gene. Reduced CPM scores were seen particularly in individuals with the OPRM1 G*/5-HT1a CC genotype, indicating that the 5-HT1a CC genotype seems to have an inhibiting effect on CPM if an individual has the OPRM1 G-genotype. Thus, regardless of pain phenotype, the OPRM1 G-allele independently as well as with an interaction with the 5-HT1a gene influenced pain modulation. FM patients had lower CPM than HC but no group differences were found regarding the genetic effects on CPM, indicating that the results reflect more general mechanisms influencing pain modulatory processes rather than underlying the dysfunction of CPM in FM. In conclusion, a genetic variant known to alter the expression of, and binding to, the my-opioid receptor reduced a subject's ability to activate descending pain inhibition. Also, the results suggest a genetically inferred gene-to-gene interaction between the main opioid receptor and a serotonergic structure essential for 5-HT transmission to modulate pain inhibition. The results in this study highlight the importance of studying joint synergistic and antagonistic effects of neurotransmittor systems in regard to pain modulation.

Chronic postoperative pain after total knee arthroplasty: The potential contributions of synovitis, pain sensitization and pain catastrophizing-An explorative study.

BackgroundA subset of osteoarthritis patients will experience chronic postoperative pain after total knee arthroplasty (TKA), but the source of pain is unclear. The aim of this exploratory study was to assess patients with and without postoperative pain after TKA using magnetic resonance imaging (MRI), quantitative sensory testing (QST), clinical assessment of pain and assessments of catastrophizing thoughts.MethodsForty‐six patients completed the 6‐month postoperative assessment. MRI findings were scored according to the MRI Osteoarthritis Knee Score recommendation for Hoffa synovitis, effusion size and bone marrow lesions. QST included assessment of pressure pain thresholds (PPTs), temporal summation of pain (TSP) and conditioned pain modulation (CPM). Pain catastrophizing was assessed using the Pain Catastrophizing Scale (PCS). Clinical pain assessment was conducted using a visual analogue scale (VAS, 0–10 cm), and groups of moderate‐to‐severe (VAS > 3) and none‐to‐mild postoperative pain (VAS ≤ 3) were identified.ResultsPatients with moderate‐to‐severe postoperative pain (N = 15) demonstrated higher grades of Hoffa synovitis (p < 0.001) and effusion size (p < 0.001), lower PPTs (p = 0.039), higher TSP (p = 0.001) and lower CPM (p = 0.014) when compared with patients with none‐to‐mild postoperative pain (N = 31). No significant difference was found in PCS scores between the two groups. Multiple linear regression models found synovitis (p = 0.036), effusion size (p = 0.003), TSP (p = 0.013) and PCS (p < 0.001) as independent parameters contributing to the postoperative pain intensity.ConclusionThese exploratory findings could indicate that chronic postoperative pain after TKA is a combination of joint‐related synovitis and effusion, sensitization of central pain mechanisms and potentially pain catastrophizing thoughts, but larger studies are needed to confirm this.SignificanceThe end‐stage treatment of knee osteoarthritis is total knee arthroplasty. Some patients experience chronic postoperative pain after total knee arthroplasty, but the mechanism for chronic postoperative pain is widely unknown. The current study indicates that higher levels postoperative of synovitis and effusion, higher temporal summation of pain and higher pain catastrophizing scores could be associated with higher chronic postoperative pain.

Specific Electroencephalographic Signatures for Pain and Descending Pain Inhibitory System in Spinal Cord Injury.

The pain related to spinal cord injury (SCI) is difficult to treat, and it is associated with significant morbidity. One aspect to improve therapeutics is to explore markers of pain and its correlates in SCI. In this cross-sectional neurophysiological analysis of a randomized, double-blind controlled trial, 39 patients with SCI were included. We analyzed conditioned pain modulation (CPM) efficiency as the index of the descending pain inhibitory system, EEG variables, and clinical pain levels as measured by the Visual Analogue Scale. Regression analyses were performed to assess the relationship among EEG variables, pain levels, and CPM. We included 39 SCI patients, 74% reported SCI-related pain. We found that (1) less alpha and beta power are related to pain presence, (2) less alpha and beta power are associated with higher pain levels among patients with pain, (3) patients with pain have decreased peak alpha-theta frequency compared to no-pain group, (4) more relative theta power are related to the presence of low CPM efficiency, (5) higher relative theta power is associated with lower CPM efficiency. Our results confirm and provide additional data on the relationship between decreased alpha and beta frequencies and higher pain levels. One important finding, though, was a specific and different EEG signature for the descending inhibitory pain system, as we showed that increased theta EEG power is related to decreased CPM efficiency; suggesting that, although low CPM efficiency plays a major role in pain in these participants, it does seem to be associated with a specific oscillatory brain rhythm different from clinical pain. These findings have significant implications for future research on EEG-based biomarkers of pain in post-SCI and new interventions as neurofeedback to manage pain in this population.

The Combination of Preoperative Pain, Conditioned Pain Modulation, and Pain Catastrophizing Predicts Postoperative Pain 12 Months After Total Knee Arthroplasty.

Approximately 20% of knee osteoarthritis patients undergoing total knee arthroplasty (TKA) report chronic postoperative pain. Studies suggest that preoperative variables such as impaired descending pain control, catastrophizing, function, and neuropathic pain-like symptoms may predict postoperative pain 12months after TKA, but the combined prediction value of these factors has not been tested. The current prospective cohort study aimed to combine preoperative risk factors to investigate the predictive value for postoperative pain 12months after TKA. Prospective cohort with follow-up 12months after surgery. A consecutive sample of 131 knee osteoarthritis patients undergoing TKA. Pain intensity, Pain Catastrophizing Scale (PCS) scores, PainDETECT Questionnaire scores, conditioned pain modulation (CPM), and Oxford Knee Score (OKS) were obtained before and 12months after TKA. TKA improved pain (P < 0.001), PCS scores (P < 0.001), PainDETECT Questionnaire scores (P < 0.001), and OKSs (P < 0.001). Preoperative pain correlated with preoperative PCS scores (r = 0.38, P < 0.001), PainDETECT scores (r = 0.53, P < 0.001), and OKSs (r = -0.25, P = 0.001). Preoperative PainDETECT scores were associated with preoperative PCS scores (r = 0.53, P < 0.001) and OKSs (r = -0.25, P = 0.002). Higher postoperative pain was correlated with high preoperative pain (r = 0.424, P < 0.001), PCS scores (r = 0.33, P < 0.001), PainDETECT scores (r = 0.298, P = 0.001), and lower CPM (r = -0.18, P = 0.04). The combination of preoperative pain, PCS score, and CPM explained 20.5% of variance in follow-up pain. PCS scores had a significant effect on pain trajectory when accounting for patient variance (t = 14.41, P < 0.0005). The combination of high preoperative clinical pain intensity, high levels of pain catastrophizing thoughts, and impaired CPM may predict long-term postoperative pain 12months after surgery.

Risk factors of pain, physical function, and health-related quality of life in elderly people with knee osteoarthritis: A cross-sectional study

Data on the precise mechanisms of the complex interactions of factors related to clinical impact of knee osteoarthritis (KOA) in the elderly population remain limited. To find predictors that explain pain intensity, physical function, and quality of life in elderly KOA subjects, we performed a cross-sectional analysis of the baseline data from a randomized trial. The trial included 104 subjects (aged ≥60) with KOA pain and dysfunctional endogenous pain-inhibitory system activity assessed by conditioned pain modulation (CPM). Three multiple linear regression models were performed to understand the independent predictors of Brief Pain Inventory (BPI), WOMAC function subscale (WOMACFunc), and SF-12 physical subscale (SF12-PCS). Model 1 showed that BPI pain score was predicted by low CPM response, high von-Frey light touch threshold, worse radiological severity as indexed by Kellgren-Lawrence grade (KL), high von-Frey punctate pain intensity and high levels of anxiety (adjusted R2 = 27.1%, F (6,95) = 7.27, P < 0.0001). In model 2, von-Frey light touch threshold, KL, depressive symptoms indexed by Beck Depression Inventory (BDI), level of sleepiness and pain pressure threshold were risk factors for SF12-PCS (adjusted R2 = 31.9%, F (5,96) = 10.5, P < 0.0001). Finally, model 3 showed that WOMACFunc was predicted by BDI, KL and BPI (adjusted R2 = 41%, F (3,98) = 24.42, P < 0.0001). Our data provides an interesting framework to understand the predictors of KOA pain in the elderly and highlights how its related outcomes are affected by disease-specific factors, somatosensory dysfunction and emotional factors.

Association of Dysregulated Central Pain Processing and Response to Disease-Modifying Antirheumatic Drug Therapy in Rheumatoid Arthritis.

To determine the association between dysregulated central pain processing and treatment response in rheumatoid arthritis (RA). One hundred eighty-two participants with active RA were followed up for 12 weeks after starting a disease-modifying antirheumatic drug (DMARD). To assess central pain processing, participants underwent quantitative sensory testing (QST), including assessment of pressure pain thresholds (PPTs) at the trapezius muscles, temporal summation, and conditioned pain modulation (CPM). QST measures were categorized as high central dysregulation versus low central dysregulation. The association between baseline central dysregulation and treatment response, as defined by the European League Against Rheumatism (EULAR) response criteria, was assessed using multiple logistic regression adjusted for demographic characteristics, RA-related variables, and psychosocial variables. A good EULAR response was achieved in fewer participants with high CPM dysregulation than participants with low CPM dysregulation (22.5% versus 40.3%; P = 0.01). A similar trend, though not significant, was noted when central dysregulation was assessed with PPT and temporal summation. The adjusted odds ratios (ORs) for the association between high central dysregulation and good EULAR response were 0.59 for PPTs (95% confidence interval [95% CI] 0.28-1.23), 0.60 for temporal summation (95% CI 0.27-1.34), and 0.40 for CPM (95% CI 0.19-0.83). In a model examining the combined effects of dysregulated temporal summation and CPM, dysregulation of both measures was associated with lower odds of achieving a good EULAR response (OR 0.23 [95% CI 0.07-0.73]). Low CPM was significantly associated with lower odds of achieving a good EULAR response, suggesting that inefficient descending inhibitory mechanisms may be a potential treatment target for further study.

A Subgroup of Chronic Low Back Pain Patients With Central Sensitization.

Our knowledge of central sensitization (CS) in chronic low back pain (CLBP) is limited. 2011 fibromyalgia criteria and severity scales (2011 FM survey) have been used to determine FM positive as a surrogate of CS. The major features of CS including widespread hyperalgesia and dysfunction of the descending inhibitory pathways can be identified by pressure pain threshold (PPT) and conditioned pain modulation (CPM) tests. The purpose of the study was to examine neurophysiological characteristics and psychosocial symptoms in a subgroup of FM-positive CLBP compared with FM-negative CLBP patients. A total of 46 participants with CLBP and 22 pain-free controls completed outcome measures of the 2011 FM survey, PPT and CPM tests, and psychosocial questionnaires. Differences between FM-positive and FM-negative CLBP participants on these measures and correlations were analyzed. The 2011 FM survey identified 22 (48%) participants with CLBP as FM positive. FM-positive CLBP participants showed lower PPT values of the thumbnail (P=0.011) and lower back (P=0.003), lower CPM values of the thumbnail (P=0.002), and more severe pain catastrophizing, anxiety, and depression symptoms (P<0.05) than FM-negative CLBP participants. The 2011 FM scores were significantly correlated with the PPT and CPM values of the thumbnail and with psychosocial symptoms (P<0.001). Our findings suggest a subgroup of CLBP patients exhibiting with signs and symptoms of CS. Associations between subjective and objective CS measures indicate that the 2011 FM survey can be utilized to identify the presence of CS in CLBP in clinical practice.

Conditioned Pain Modulation (CPM) is Reduced in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of CPM and the Role of Psychological Factors.

This systematic review summarises evidence assessing endogenous pain inhibition in people with irritable bowel syndrome (IBS) compared with healthy controls using conditioned pain modulation (CPM) and offset analgesia (OA). Evidence regarding the role of psychological variables is also examined. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Four electronic databases were searched to retrieve studies assessing CPM or OA in adults diagnosed with IBS according to the ROME II/III criteria. Standardized mean differences were calculated for each study and a random effects model was used for meta-analysis. Eleven studies were included, 5 of which reported results on the relationship between CPM and psychological variables. None of the studies assessed OA. The risk of bias assessment found a lack of assessor blinding in all studies. The pooled effect estimate was 0.90 (95% CI, 0.40-1.40) indicating a significantly lower CPM effect in people with IBS compared with controls. This effect was reduced to 0.51 when 1 outlier was excluded from the analysis. In addition, reduced CPM responses were significantly correlated with higher anxiety (r=0.17 to 0.64), stress (r=0.63), and pain catastrophizing (r=0.38) in people with IBS; however, the evidence available was limited and the strength of these associations variable. Depression was not found to be associated with CPM in these IBS cohorts. The results of this review suggest that people with IBS, as a group, demonstrate reduced pain inhibition measured by CPM. The preliminary evidence about the association between psychological factors and CPM warrants further investigations.

Individual Variation in Pain Sensitivity and Conditioned Pain Modulation in Acute Low Back Pain: Effect of Stimulus Type, Sleep, and Psychological and Lifestyle Factors

Generalized hyperalgesia and impaired pain modulation are reported in chronic low back pain (LBP). Few studies have tested whether these features are present in the acute phase. This study aimed to test for differences in pain presentation in early-acute LBP and evaluate the potential contribution of other factors to variation in sensitivity. Individuals within 2 weeks of onset of acute LBP (n = 126) and pain-free controls (n = 74) completed questionnaires related to their pain, disability, behavior, and psychological status before undergoing conditioned pain modulation (CPM) and pain threshold (heat, cold, and pressure) testing at the back and forearm/thumb. LBP participants were more sensitive to heat and cold at both sites and pressure at the back than controls, without differences in CPM. Only those with high-pain (numeric rating scale ≥4) were more sensitive to heat at the forearm and pressure at the back. Four subgroups with distinct features were identified: “high sensitivity,” “low CPM efficacy,” “high sensitivity/low CPM efficacy,” and “low sensitivity/high CPM efficacy.” Various factors such as sleep and alcohol were associated with each pain measure. Results provide evidence for generalized hyperalgesia in many, but not all, individuals during acute LBP, with variation accounted for by several factors. Specific pain phenotypes provide candidate features to test in longitudinal studies of LBP outcome. PerspectiveSensory changes indicative of increased/decreased central processing of pain and nociceptive input presented differently between individuals with acute LBP and were related to factors such as sleep and alcohol. This may underlie variation in outcome and suggest potential for early identification of individuals with poor long-term outcome.

Beyond weakness: Characterization of pain, sensory profile and conditioned pain modulation in patients with motor neuron disease: A controlled study.

Motor neuron diseases (MND) represent a group of disorders that evolve with inexorable muscle weakness and medical management is based on symptom control. However, deeper characterization of non-motor symptoms in these patients have been rarely reported. This cross-sectional study aimed to describe non-motor symptoms in MND and their impact on quality of life and functional status, with a focus on pain and sensory changes. Eighty patients (31 females, 55.7±12.9years old) with MND underwent a neurological examination, pain, mood, catastrophizing and psychophysics assessments [quantitative sensory testing (QST) and conditioned pain modulation (CPM)], and were compared to sex- and age-matched healthy controls (HC). Chronic pain was present in 46% of patients (VAS=5.18±2.0). Pain of musculoskeletal origin occurred in 40.5% and was mainly located in the head/neck (51%) and lower back (35%). Neuropathic pain was not present in this sample. Compared to HC, MND patients had a lower cold detection threshold (p<0.002), and significantly lower CPM scores (4.9±0.2% vs. 22.1±0.2%, p=0.012). QST/CPM results did not differ between MND patients with and without pain. Pain intensity was statistically correlated with anxiety, depression and catastrophism, and spasticity scores were inversely correlated with CPM (ρ=-0.30, p=0.026). Pain is frequently reported by patients with MNDs. Somatosensory and CPM changes exist in MNDs and may be related to the neurodegenerative nature of the disease. Further studies should investigate the most appropriate treatment strategies for these patients. We report a comprehensive evaluation of pain and sensory abnormalities in motor neuron disease (MND) patients. We assessed the different pain syndromes present in MND with validated tools, and described the QST and conditioned pain modulation profiles in a controlled design.