BACKGROUND: Conditioned pain modulation (CPM) is a quantitative estimation of the capacity for endogenous pain modulation. Reduced CPM enables chronic painful event development or exacerbates pre-existing pain symptoms. Emerging reports indicate that patients with trigeminal neuralgia (TN) have dysregulated endogenous pain modulation. Transauricular vagus nerve stimulation (taVNS) is known to alleviate both acute and chronic pain symptoms. Its role in modulation or management of TN remains unknown. Here, we evaluated the taVNS efficacy in modulating CPM among TN patients. Conclusions from this investigation may facilitate establishment of novel non-invasive adjunctive approaches to treating TN patients.
METHODS: All research work was conducted at the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital). In all, we recruited 62 study participants, 31 TN patients and 31 healthy volunteers, for a 2-day experimental test. At the beginning of the experiment (Day 1), all subjects received 30 min of active taVNS. On Day 2, they received sham taVNS with the same duration and intensity. Meanwhile, technicians documented participant pressure pain thresholds (PPT) and CPM values at baseline, and at 15 and 30 min post-active or sham taVNS.
RESULTS: A 30-min active taVNS exposure substantially elevated the PPT and CPM effect (P < 0.05) among TN patients, and we also observed a notable rise in the PPT and CPM effect (P < 0.05) among healthy controls. Additionally, there were no serious adverse events from the administered treatment.
CONCLUSIONS: Exposure to 30 min of active taVNS strongly augmented the CPM effect and elevated the PPT among TN patients and healthy controls. These effects were not observed with sham stimulation. Despite the limitations inherent to survey studies, such as duration and compliance biases, we consider that taVNS is a promising, safe, and cost-effective therapy. In future investigations, we recommend assessment of long-term taVNS application and its effects on CPM and clinical pain.
BACKGROUND: ChiCTR2300078673 ( www.Chictr.org.cn ).

BACKGROUND: 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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.

BACKGROUND: Various exercises can attenuate pain perception in healthy individuals and may interact with the descending pain modulation in the central nervous system. However, the analgesic effects of exercise in patients with myofascial pain can be disrupted by the pathological changes during chronic pain conditions. Thus, the exercises targeted on the facilitation of the sensory-motor interaction may have a positive impact on the restoration of the descending pain modulation and the analgesia effects.
OBJECTIVE: This paper estimates the effect of proprioceptive neuromuscular facilitation (PNF) and resistance training on exercise-induced hypoalgesia (EIH) and conditioned pain modulation (CPM) among patients with myofascial pain syndrome.
METHODS: A total of 76 female patients with myofascial pain syndrome (aged 18-30 years), with the pain in the upper trapezius and a visual analog scale score of greater than 30/100 mm, were enrolled in the study. Participants were randomly assigned into 3 intervention groups, including isometric (n=18, 24%), isotonic (n=19, 25%), and PNF (n=20, 26%) exercises, as well as 1 control group (n=19, 25%) with no intervention. Pressure pain threshold and the CPM responses at the myofascial trigger point, arm, and leg sites were assessed before and after the exercise session. The effective EIH response was reflected in the improvement of pressure pain thresholds.
RESULTS: There was an increase in pressure pain thresholds and CPM responses at trigger point (P<.001 and P<.001), arm (P<.001 and P<.001), and leg sites (P<.001 and P=.03) in participants who performed PNF and isotonic exercise, while the isometric exercise only increased pressure pain thresholds at leg sites (P=.03). Compared with the control group, both the isotonic (P=.02) and PNF (P<.001) groups showed greater EIH responses at the trigger points. In comparison to the control group, only the PNF exercise (P=.01) significantly improved pressure pain thresholds and CPM responses at arm and leg sites compared to the control group.
CONCLUSIONS: PNF, isotonic, and isometric exercises could lead to local and global EIH effects. The improvement in CPM response following PNF and isotonic exercises suggested that the EIH mechanisms of different resistance exercises may be attributed to the enhancement of the endogenous pain modulation via the motor-sensory interaction from the additional eccentric and dynamic muscle contraction.
BACKGROUND: Chinese Clinical Trial Registry ChiCtr202111090819166165; https://tinyurl.com/2ab93p7n.

OBJECTIVE: To investigate the presence of altered central pain processing in patients with failed back surgery syndrome (FBSS) using quantitative sensory testing (QST).
METHODS: This study included 34 patients with FBSS, 102 patients post-lumbar surgery without low back pain (LBP), and 102 healthy subjects. All subjects underwent both pressure pain threshold (PPT) and conditioned pain modulation (CPM) in both local and remote pain-free areas, as well as temporal summation (TS) in a remote pain-free area. All patient subjects were assessed using the Pain Catastrophizing Scale (PCS), Beck Anxiety Inventory (BAI), Beck Depression Index (BDI), Numeric rating pain scale (NRS) and Oswestry Disability Index (ODI).
RESULTS: Compared with both control groups, FBSS patients showed a reduction in both PPT and CPM in both tested areas, along with increased TS in a pain-free area (P < 0.05). Furthermore, the patients with FBSS had a significantly higher prevalence of anxiety, depression and pain catastrophizing thoughts than the patient controls (P < 0.05). In the FBSS patients, there was a significant correlation between LBP at rest and both CPM and TS in the pain-free areas, and QST measurements were also associated with the ODI, PCS and BAI (P < 0.05).
CONCLUSIONS: These findings support the existence of augmented central pain processing in patients with FBSS, which may be caused by dysfunction of endogenous pain facilitation and inhibition. This central amplification of pain may contribute to both LBP intensity and disability in FBSS patients. Therefore, treatment efforts should take into account functional alterations in the central nervous system of FBSS patients.

UNASSIGNED: The effect of caffeine on acupuncture analgesia in humans is unclear. This study aimed to investigate whether caffeine-containing beverage intake influences the effect of electroacupuncture (EA) on static quantitative sensory testing (QST) and dynamic QST in healthy subjects.
UNASSIGNED: A total of 40 healthy subjects were enrolled and randomly assigned to receive coffee containing moderate doses of caffeine (coffee group) or non-caffeinated juice (juice group) for 4 weeks. The primary outcome measures were the pressure pain threshold (PPT), pressure pain tolerance (PPTo), and heat pain threshold (HPT) as static QST parameters. Numerical rating scales (NRS) of heat stimulus and nociceptive flexor reflex (RIII reflex), as parameters of dynamic QST, were also examined. EA stimulation with tolerance intensity was performed at ST36 (Zusanli)-GB34 (Yanglingquan) points at weeks 0, 2, and 4. PPT, PPTo, and HPT were detected pre- and post- EA. The NRS scores were examined pre-, during, and post-EA, and 1 min after EA was completed. The RIII reflex was examined pre- and 1-5 min post-EA.
UNASSIGNED: At week 0, both groups showed increased PPT and PPTo and decreased NRS scores of heat stimuli and RIII reflex after EA, but HPT was not affected. After 4 weeks, the effects of EA on PPT and PPTo were attenuated in the coffee group compared to the juice group, whereas the effect of EA on the NRS scores and RIII reflex were not influenced. There was no significant difference found at week 2 for these indications. EA also did not affect the HPT in both groups at week 4.
UNASSIGNED: Moderate caffeine intake reduced the effects of EA on PPT and PPTo in healthy subjects.

BACKGROUND: Postoperative axial pain (PAP), characterized by pain and/or stiffness around the posterior neck, periscapular areas and/or shoulder region, is a vexing complication affecting 5-60% of patients undergoing posterior cervical decompression. Given its relatively high frequency and negative impact on patients\' physical and mental status, efforts preoperatively to confirm patients at risk of developing PAP to offer more efficient pain management to minimize this complication have a high priority. The aim of this study is to investigate the role of preoperative dynamic quantitative sensory testing (QST) in predicting the PAP after posterior cervical decompression.
METHODS: This longitudinal observational study included 122 patients with degenerative cervical myelopathy undergoing laminoplasty or laminectomy. Preoperatively, all patients underwent the assessment of pressure pain thresholds (PPTs) at local and remote pain-free areas and both temporal summation (TS) and conditioned pain modulation (CPM) at remote pain free-areas. These patients underwent further pain-related, psychosocial and clinical function assessments before and/or after operation.
RESULTS: In the present study, 21 patients (21/122, 17.2%) developed PAP, and the 6-month postoperative follow-up demonstrated that 8 of these 21 patients developed chronic PAP (CPAP). All preoperative covariates with significant differences between the PAP and non-PAP groups were subjected to multivariate logistic regression, and the presence of preoperative axial pain, surgical plan including C2 decompression, total international physical activity questionnaire score (cutoff value [CV]: 2205.5, sensitivity: 82.4%; specificity: 61.1%) and TS value (CV: 2.5, sensitivity: 42.9%; specificity: 83.2%) were independently associated with PAP (P < 0.05). Logistic regression further revealed that the presence of preoperative axial pain, TS value (CV: 2.5, sensitivity: 62.5%; specificity: 83.2%) and CPM value (CV: 0.65, sensitivity: 87.5%; specificity: 61.4%) were significant predictors of CPAP (P < 0.05).
CONCLUSIONS: The findings of this study support the hypothesis that preoperative endogenous pain modulation efficiency may be associated with axial pain after posterior cervical decompression. Clinically, preoperative estimation of both TS and CPM in remote pain-free areas may provide additional useful information for identifying patients who may be at risk of developing both PAP and CPAP, which may be beneficial in enabling stratification in the perioperative period of patients based on individual vulnerabilities to avoid/reduce this complication.

The disorder of the conditioned pain modulation (CPM) system is one of the main causes of pain perception in individuals. High-definition transcranial direct current stimulation (HD-tDCS) targeting specific brain areas was indicated to have an analgesic effect possibly by activating the endogenous pain inhibition pathway evident in CPM. However, discrepancies were found in previous limited studies of varied homogeneity and quality. Therefore, the present study applied 2 mA HD-tDCS (20 min) in the left primary motor cortex (M1) among 35 healthy adults with a blinded crossover study design, to investigate its effectiveness on optimizing the analgesic effect in healthy individuals through assessing changes of the CPM. The univariate and multivariate general linear models were used to evaluate the intervention effect between-group on the Δ-value (after-intervention minus before-intervention) during CPM (primary outcome), pressure pain threshold (PPT), and cold pressure threshold (CPT) (secondary outcome), respectively. A significant between-group difference in Δ-CPM was found for active stimulation. HD-tDCS significantly improved the analgesic efficiency of Δ-CPM, compared with the sham control, after adjusting the confounding factors including age, gender, psychological status, as well as the sequence effect. The changes of CPM were positively correlated with the total physical activity volume. In conclusion, our findings provide evidence support to the effectiveness of HD-tDCS on endogenous pain modulation among healthy adults. Further studies are required to explore the analgesic effect of tDCS among patients with chronic pain, thereby facilitating optimal chronic pain management.

Transcranial direct current stimulation (tDCS) is increasingly used in pain treatment. tDCS targeting both primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) may modulate the descending pain inhibitory system, however, it remains controversial regarding the optimal stimulation region for pain modulation. Therefore, this study aimed to explore the effects of high-definition anodic stimulation of M1 and DLPFC on conditioned pain modulation (CPM) and pain thresholds and establish a preferred stimulation setting. Twenty-six healthy adults were randomly assigned to M1-tDCS, DLPFC-tDCS, or sham-tDCS groups. During the three sessions, each participant received an active or sham stimulation of 2 mA for 20 min, with at least 3 days\' interval between sessions. Quantitative sensory tests were performed to obtain pressure pain threshold (PPT), cold pain threshold (CPT), and CPM before and after the tDCS intervention. Only M1-tDCS significantly increased CPM in healthy individuals compared with sham control (P = 0.004). No statistically significant difference was found in PPT and CPT between tDCS vs. sham control (P > 0.05). Our findings further support the important role of M1 as a target in pain regulation. Further large-scale, multicenter studies in chronic pain populations are needed to validate the alterations of distinct target brain regions related to pain and thus for an optimal target stimulation strategy in pain management.

OBJECTIVE: Previous researches have reported gray and white matter microalterations in primary trigeminal neuralgia (TN) with neurovascular compression (NVC). The central mechanism underlying TN without NVC are unknown but may include changes in specific brain regions or circuitries. This study aimed to investigate abnormalities in the gray matter (GM) and white matter (WM) of the whole brain and the possible pathogenetic mechanism underlying this disease.
METHODS: We analyzed brain morphologic images of TN patients, 23 with NVC (TN wNVC) and 22 without NVC (TN wNVC) compared with 45 healthy controls (HC). All subjects underwent 3T-magnetic resonance imaging and pain scale evaluation. Voxel-based morphometry (VBM) and surface-based morphometry (SBM) were used to investigate whole brain grey matter quantitatively; graph theory was applied to obtain network measures based on extracted DTI data based on DTI data of the whole brains. Sensory and affective pain rating indices were assessed using the visual analog scale (VAS) and short-form McGill Pain Questionnaire (SF-MPQ).
RESULTS: The VBM and SBM analyses revealed widespread decreases in GM volume and cortical thickness in TN wNVC compared to TN woNVC, and diffusion metrics measures and topology organization changes revealed DTI showed extensive WM integrity alterations. However, above structural changes differed between TN wNVC and TN woNVC, and were related to specific chronic pain modulation mechanism.
CONCLUSIONS: Abnormalities in characteristic regions of GM and WM structural network were found in TN woNVC compared with TN wNVC group, suggesting differences in pathophysiology of two types of TN.

OBJECTIVE: Chronic pain is one of the most common and challenging symptoms in fibromyalgia (FM). Currently, self-reported pain is the main criterion used by clinicians assessing patients with pain. However, it is subjective, and multiple factors can affect pain levels. In this study, we investigated the neural correlates of FM pain using conditioned pain modulation (CPM), electroencephalography (EEG), and transcranial magnetic stimulation (TMS).
METHODS: In this cross-sectional neurophysiological analysis of a randomized, double-blind controlled trial, 36 patients with fibromyalgia were included. We analyzed CPM, EEG variables and TMS measures and their correlation with pain levels as measured by a visual analog scale. Univariate and multivariate linear regression analyses were performed to identify the predictors of pain severity.
RESULTS: We found: (1) no association between pain levels and CPM; (2) an association between reduced alpha and beta power over the central region in resting-EEG and higher pain levels; (3) an association between smaller event-related desynchronization (ERD) responses in theta and delta bands over the central region and higher pain levels; (4) an association between smaller ERD responses in theta and delta bands and smaller intracortical inhibition and higher intracortical facilitation ratios; (5) an association between smaller ERD responses in delta band and reduced CPM.
CONCLUSIONS: Our results do not support CPM as a biomarker for pain intensity in FM. However, our specific EEG findings showing the relationship between pain, CPM and TMS measures suggest that FM leads to a disruption of inhibitory neural modulators and thus support CPM as a likely predictive marker of disrupted pain modulation system. These neurophysiological markers need to be further explored in potential future trials as to find novel targets for the treatment of FM.