Abnormalities of the Descending Inhibitory Nociceptive Pathway in Functional Motor Disorders.

BACKGROUND: Pain is a common disabling non-motor symptom affecting patients with functional motor disorders (FMD). OBJECTIVE: We aimed to explore ascending and descending nociceptive pathways with laser evoked potentials (LEPs) in FMD. METHODS: We studied a "bottom-up and top-down" noxious paradigm applying a conditioned pain modulation (CPM) protocol and recorded N2/P2 amplitude in 21 FMD and 20 controls following stimulation of both right arm and leg at baseline (BS) (bottom-up), during heterotopic noxious conditioning stimulation (HNCS) with ice test (top-down) and post-HNCS. RESULTS: We found a normal ascending pathway, but reduced CPM response (lower reduction of the N2/P2 amplitude) in FMD patients, by stimulating both upper and lower limbs. The N2/P2 amplitude ratio*100 (between the HNCS and BS) was significantly higher in patients with FMD than HC. CONCLUSIONS: Our results suggest that pain in FMD possibly reflects a descending pain inhibitory control impairment, therefore, providing a novel venue to explore the pathophysiology of pain in FMD. © 2024 International Parkinson and Movement Disorder Society.

Chronic sleep deficiency and its impact on pain perception in healthy females.

Acute sleep deprivation in experimental studies has been shown to induce pain hypersensitivity in females. However, the impact of natural sleep deficiency and fluctuations across the week on pain perception remains unclear. A sleep-monitoring headband and self-reports were utilized to assess objective and subjective sleep in longer (> 6 hr) and short sleepers (< 6 hr). Pain sensitivity measures including heat, cold, pressure pain thresholds, pain inhibition (conditioned pain modulation) and facilitation (tonic pain summation) were assessed on Mondays and Fridays. Forty-one healthy young (23.9 ± 0.74 years) women participated. Short sleepers slept on average 2 hr less than longer sleepers (297.9 ± 8.2 min versus 418.5 ± 10.9 min) and experienced impaired pain inhibitory response (mean = -21.14 ± 7.9°C versus mean = 15.39 ± 9.5°C; p = 0.005). However, no effect was observed in pain thresholds and pain summation (p > 0.05). Furthermore, pain modulatory responses differed between Mondays and Fridays. Chronic sleep deficiency (< 6 hr) compromises pain responses, notably on Mondays. Maintaining a consistent sleep pattern with sufficient sleep (> 6 hr) throughout the week may protect against pain sensitization and the development of chronic pain in females. Further research is needed, especially in patients with chronic pain.

Conditioned pain modulation and psychological factors in young adults with recurrent or chronic neck pain.

BACKGROUND: Controversy exists with the presence of alterations in descending pain inhibition mechanisms in patients with non-specific neck pain (NSNP). The aim of the present study was to evaluate the status of conditioned pain modulation CPM, remote pressure pain thresholds (PPT), and psychological factors in a specific subgroup of patients with NSNP such as young adult students. In addition, possible associations between CPM, psychological factors, and pain characteristics were analyzed. METHODS: Thirty students with recurrent or chronic NSNP and 30 pain-free students were included in this cross-sectional study. The following measures were assessed: CPM, remote PPT, psychological factors (depression, anxiety, pain catastrophizing, and kinesiophobia), pain characteristics (duration, intensity, severity of chronic pain, interference with daily life), and central sensitization inventory (CSI). RESULTS: No significant differences were found in the efficacy of CPM between students with chronic or recurrent NSNP and pain-free students (ß coefficient = -0.67; 95% CI = -1.54, 0.20). However, students with pain showed a significantly higher remote PPT (mean difference = -1.94; 95% CI = -2.71, -1.18). and a greater presence of anxious (mean difference = 6; 95% CI = 2, 9) and depressive symptoms (mean difference = 8.57; 95% CI = 3.97, 13.16). In addition, significant moderate or strong correlations were found between CPM and pain intensity (partial r = 0.41), pain catastrophizing and mean pain intensity (r = 0.37), grade (r = 0.50), and interference of pain (r = 0.57), kinesiophobia and disability (r = 0.38), and depression and CSI (r = 0.39). CONCLUSIONS: Young adult students with chronic or recurrent NSNP present remote hyperalgesia and symptoms of depression and anxiety but not dysfunctional CPM.

Psychophysical assessment of pain in adults with moderate and severe haemophilia: A cross-sectional study.

BACKGROUND: Joint pain is the hallmark of haemophilia; therefore it seems clinically rather a musculoskeletal than a bleeding disorder. Although joint pain in people with haemophilia (PwH) is a complex and multidimensional problem, pain assessment remains primarily focused on the structural evaluation of their joints. Whereas, only few data are available on the potential implication of psychophysical and psychological factors. OBJECTIVE: This study aimed to perform a psychophysical pain assessment including quantitative sensory testing (QST) and an evaluation of psychological factors in a large sample of PwH, to get insight into the individuals' pain system. METHODS: Ninety-nine adults (36.9 ± 13.5 years) with moderate/severe haemophilia A/B and 46 healthy controls filled in self-reported pain and psychological questionnaires and underwent a QST evaluation including static and dynamic tests. Static tests focused on the determination of thermal detection and pain thresholds and mechanical pressure pain thresholds. Dynamic tests evaluated pain facilitation and the efficacy of endogenous pain inhibition. Besides comparing PwH and healthy controls, between-subgroup differences were studied in PwH based on their pain distribution. RESULTS: The study revealed increased thermal and mechanical pain sensitivity and the presence of unhelpful psychological factors such as anxiety/depression in PwH. Among the subgroups, especially PwH with widespread pain showed altered somatosensory functioning. Enhanced pain facilitation and impaired efficacy of endogenous pain inhibition in PwH could not be observed. CONCLUSION: Altered somatosensory functioning and unhelpful psychological factors, appear to play an important role in the pathophysiology of pain in PwH, especially in PwH with widespread pain.

EEG-based sensory testing reveals altered nociceptive processing in elite endurance athletes.

Increased exercise loads, as observed in elite athletes, seem to modulate the subjective pain perception in healthy subjects. The combination of electroencephalography (EEG) and standardized noxious stimulation can contribute to an objective assessment of the somatosensory stimulus processing. We assessed the subjective pain ratings and the electroencephalogram (EEG)-based response after standardized noxious mechanical and thermal stimuli as well as during conditioned pain modulation (CPM) in 26 elite endurance athletes and compared them to 26 recreationally active controls. Elite endurance athletes had consistently stronger somatosensory responses in the EEG to both mechanical and thermal noxious stimuli than the control group. We observed no significant group differences in the subjective pain ratings, which may have been influenced by our statistics and choice of stimuli. The CPM testing revealed that our conditioning stimulus modulated the subjective pain perception only in the control group, whereas the EEG indicated a modulatory effect of the conditioning stimulus on the spectral response only in the athletes group. We conclude that a higher activation in the cortical regions that process nociceptive information may either be an indicator for central sensitization or an altered stimulus salience in the elite endurance athletes' group. Our findings from our CPM testing were limited by our methodology. Further longitudinal studies are needed to examine if exercise-induced changes in the somatosensory system might have a critical impact on the long-term health of athletes.

Harnessing the conditioned pain modulation response in migraine diagnosis, outcome prediction, and treatment-A narrative review.

OBJECTIVE: To present the potential use and relevance of the conditioned pain modulation (CPM) response to migraine diagnosis, outcome prediction, and treatment. BACKGROUND: The CPM response is a widely used laboratory test to examine inhibitory pain modulation capabilities. METHODS: This narrative review summarizes and synthesizes the findings on the CPM response in patients with migraine. RESULTS: For diagnosis, we summarized the studies comparing CPM responses between patients with migraine and individuals without migraine or with other headache syndromes, as well as between patients with subtypes of migraine. For prediction, we summarized the studies utilizing the CPM response to predict migraine outcome, such as response to interventions. For treatment, we described a device that utilizes the CPM response for acute and preventative migraine treatment. In addition, we suggest the requirements needed for the CPM response to be used for migraine diagnosis, outcome prediction, and treatment. CONCLUSIONS: Although more research is needed, the CPM response could be a useful tool for improving migraine management.

Effects of Percutaneous and Transcutaneous Electrical Nerve Stimulation on Endogenous Pain Mechanisms in Patients with Musculoskeletal Pain: A Systematic Review and Meta-Analysis.

OBJECTIVES: The main aim was to determine the effects of percutaneous electrical nerve stimulation (PENS) and transcutaneous electrical nerve stimulation (TENS) on endogenous pain mechanisms in patients with musculoskeletal pain. DESIGN: A systematic review and meta-analysis. METHODS: The search was conducted on March 1, 2022, in the EMBASE, CINAHL, PubMed, PEDro, Cochrane Library, Web of Science, Medline, and SCOPUS databases. Randomized controlled trials comparing the use of transcutaneous or percutaneous electrostimulation with a placebo, control group, or standard treatment in patients with musculoskeletal pain were included. Outcome measurements were quantitative sensory testing somatosensory variables like pressure pain threshold (PPT), conditioned pain modulation, and temporal summation of pain. The pooled data were evaluated in Review Manager 5.4. RESULTS: Twenty-four randomized controlled trials (n = 24) were included in the qualitative analysis and 23 in the meta-analysis. The immediate effects of PENS and TENS on local PPTs were significant, with a moderate effect size (standardized mean difference [SMD] 0.53; 95% confidence interval [CI]: 0.34 to 0.72; P < 0.00001). When only studies with a lower risk of bias were analyzed, the heterogeneity decreased from I2 = 58% (P < 0.00001) to I2 = 15% (P = 0.01), and a decrease in the overall effect was observed (SMD 0.33; 95% CI: 0.7 to 0.58). The short-term effects on local PPTs were not significant when compared with the control group (P = 0.13). The mid-term effects on local PPTs were significant, showing a large effect size (SMD 0.55; 95% CI: 0.9 to 1.00; P = 0.02). The immediate effects on conditioned pain modulation were significant, with a large effect size (SMD 0.94; 95% CI: 0.48 to 1.41; P < 0.0001). CONCLUSION: PENS and TENS have a mild-moderate immediate effect on local mechanical hyperalgesia in patients with musculoskeletal pain. It appears that these effects are not sustained over time. Analyses suggest an effect on central pain mechanisms producing a moderate increase in remote PPT, an increase in conditioned pain modulation, but further studies are needed to draw clearer conclusions.

Pain inhibition-the unintended benefit of electrically elicited muscle strengthening contractions.

BACKGROUND: Neuromuscular electrical stimulation (NMES) is effective in muscle strengthening after orthopedic injury particularly when muscle activation failure is present, but the associated pain can be a barrier. Pain itself can produce a pain inhibitory response called Conditioned Pain Modulation (CPM). CPM is often used in research studies to assess the state of the pain processing system. However, the inhibitory response of CPM could make NMES more tolerable to patients and could improve functional outcomes in people with pain. This study compares the pain-inhibitory effect of NMES compared to volitional contractions and noxious electrical stimulation (NxES). METHODS: Healthy participants, 18-30 years of age experienced 3 conditions: 10 NMES contractions, 10 bursts of NxES on the patella, and 10 volitional contractions on the right knee. Pressure pain thresholds (PPT) were measured before and after each condition in both knees and the middle finger. Pain was reported on an 11-point VAS. Repeated measures ANOVAs with 2 factors: site and time were performed for each condition followed by post-hoc paired t-tests, with Bonferroni correction. RESULTS: Pain ratings were higher in the NxES condition compared to NMES (p = .000). No differences in PPTs prior to each condition were observed but PPTs were significantly higher in the right and left knees after the NMES contractions (p = .000, p = .013, respectively) and after the NxES (p = .006, P-.006, respectively). Pain during NMES and NxES did not correlate with pain inhibition (p > .05). Self-reported pain sensitivity correlated with pain during NxES. CONCLUSION: NxES and NMES produced higher PPTs in both knees but not in the finger, suggesting that the mechanisms responsible for the reduction in pain are located in the spinal cord and local tissues. Pain reduction was elicited during the NxES and NMES conditions regardless of the self-reported pain ratings. When NMES is used for muscle strengthening significant pain reduction can also occur, which is an unintended benefit of the intervention that could improve functional outcomes in patients.

Allodynia, Hyperalgesia, (Quantitative) Sensory Testing and Conditioned Pain Modulation in Patients With Complex Regional Pain Syndrome Before and After Spinal Cord Stimulation Therapy.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a chronic debilitating disease characterized by sensory abnormalities. Spinal cord stimulation (SCS) is an effective therapy for CRPS, but few studies have investigated the effects of SCS therapy on sensory characteristics. Therefore, this study investigated the effect of SCS on allodynia, hyperalgesia, electrical quantitative sensory testing (QST) parameters, and conditioned pain modulation (CPM) effect. MATERIALS AND METHODS: This study is part of a multicenter randomized controlled trial (ISRCTN 36655259). Patients with CRPS in one extremity and eligible for SCS were included. The outcome parameters allodynia (symptom and sign), hyperalgesia (symptom), sensory thresholds with QST, CPM effect, and pain scores were tested before and after three months of SCS (40-Hz tonic SCS). Both the CRPS-affected extremity and the contralateral, clinically unaffected extremity were used to test three sensory thresholds with electrical QST: current perception threshold (CPT), pain perception threshold (PPT), and pain tolerance threshold (PTT). The PTT also was used as a test stimulus for the CPM paradigm both before and after the conditioning ice-water test. Nonparametric testing was used for all statistical analyses. RESULTS: In total, 31 patients were included for analysis. Pain, allodynia (sign and symptom), and hyperalgesia (symptom) were all significantly reduced after SCS therapy. On the unaffected side, none of the QST thresholds (CPT, PPT, and PTT) was significantly altered after SCS therapy. However, the CPT on the CRPS-affected side was significantly increased after SCS therapy. A CPM effect was present both before and after SCS. CONCLUSIONS: Standard 40-Hz tonic SCS significantly reduces pain, hyperalgesia, and allodynia in patients with CRPS. These findings suggest that SCS therapy should not be withheld from patients who suffer from allodynia and hyperalgesia, which contradicts previous findings derived from retrospective analysis and animal research. ISRCTN Registry: The ISRCTN registration number for the study is ISRCTN 36655259.

The Effect of Praying on Endogenous Pain Modulation and Pain Intensity in Healthy Religious Individuals in Lebanon: A Randomized Controlled Trial.

Prayer is considered to be the most common therapy used in alternative medicine. This study aimed to explore the effect of prayers on endogenous pain modulation, pain intensity, and sensitivity in healthy religious participants. A total of 208 healthy religious participants were enrolled in this study and randomly distributed into two groups, a prayer group (n = 156) and a poem reading or control group (n = 52). Participants from the prayer group were then selectively allocated using the prayer function scale to either an active prayer group (n = 94) receiving an active type of praying or to a passive prayer group (n = 62) receiving a passive type of praying. Pain assessments were performed before and following the interventions and included pressure pain threshold assessment (PPT), conditioned pain modulation (CPM), and a numerical pain rating scale. A significant group-by-time interaction for PPT (p = 0.014) indicated post-intervention increases in PPT in the prayer group but not in the poem reading control group. Participants experienced a decrease in CPM efficacy (p = 0.030) and a reduction in their NPRS (p < 0.001) following the interventions, independent of their group allocation. The results showed that prayer, irrespective of the type, can positively affect pain sensitivity and intensity, but does not influence endogenous pain inhibition during hot water immersion. Future research should focus on understanding the mechanism behind "prayer-induced analgesia."

Descending pain modulatory efficiency in healthy subjects is related to structure and resting connectivity of brain regions.

The descending pain modulatory system in humans is commonly investigated using conditioned pain modulation (CPM). Whilst variability in CPM efficiency, i.e., inhibition and facilitation, is normal in healthy subjects, exploring the inter-relationship between brain structure, resting-state functional connectivity (rsFC) and CPM readouts will provide greater insight into the underlying CPM efficiency seen in healthy individuals. Thus, this study combined CPM testing, voxel-based morphometry (VBM) and rsFC to identify the neural correlates of CPM in a cohort of healthy subjects (n =40), displaying pain inhibition (n = 29), facilitation (n = 10) and no CPM effect (n = 1). Clusters identified in the VBM analysis were implemented in the rsFC analysis alongside key constituents of the endogenous pain modulatory system. Greater pain inhibition was related to higher volume of left frontal cortices and stronger rsFC between the motor cortex and periaqueductal grey. Conversely, weaker pain inhibition was related to higher volume of the right frontal cortex - coupled with stronger rsFC to the primary somatosensory cortex, and rsFC between the amygdala and posterior insula. Overall, healthy subjects showed higher volume and stronger rsFC of brain regions involved with descending modulation, while the lateral and medial pain systems were related to greater pain inhibition and facilitation during CPM, respectively. These findings reveal structural alignments and functional interactions between supraspinal areas involved in CPM efficiency. Ultimately understanding these underlying variations and how they may become affected in chronic pain conditions, will advance a more targeted subgrouping in pain patients for future cross-sectional studies investigating endogenous pain modulation.

Somatosensory dysfunction in patients with posttraumatic headache: A systematic review.

OBJECTIVES: Aim of the review is to summarize the knowledge about the sensory function and pain modulatory systems in posttraumatic headache and discuss its possible role in patients with posttraumatic headache. BACKGROUND: Posttraumatic headache is the most common complication after traumatic brain injury, and significantly impacts patients' quality of life. Even though it has a high prevalence, its origin and pathophysiology are poorly understood. Thereby, the existing treatment options are insufficient. Identifying its mechanisms can be an important step forward to develop target-based personalized treatment. METHODS: We searched the PubMed database for studies examining pain modulation and/or quantitative sensory testing in individuals with headache after brain injury. RESULTS: The studies showed heterogenous alterations in sensory profiles (especially in heat and pressure pain perception) compared to healthy controls and headache-free traumatic brain injury-patients. Furthermore, pain inhibition capacity was found to be diminished in subjects with posttraumatic headache. CONCLUSIONS: Due to the small number of heterogenous studies a distinct sensory pattern for patients with posttraumatic headache could not be identified. Further research is needed to clarify the underlying mechanisms and biomarkers for prediction of development and persistence of posttraumatic headache.

Place and Pain: Association Between Neighborhood SES and Quantitative Sensory Testing Responses in Youth With Functional Abdominal Pain.

OBJECTIVE: Neighborhood socioeconomic status (SES) is linked to self-reported pain severity and disability but its association with evoked pain responsiveness in individuals with chronic pain remains unclear. The present study examined relations between neighborhood SES, assessed through the area deprivation index (ADI), and static and dynamic pain response indices. It was hypothesized that youth with functional abdominal pain (FAP) living in lower SES neighborhoods would exhibit lower pain threshold, lower pain tolerance, and reduced conditioned pain modulation (CPM) compared to youth living in higher SES neighborhoods. METHODS: Participants were 183 youth with FAP and their parents. Youth completed a quantitative sensory testing protocol. Family addresses were used to compute ADI scores. Thermal stimuli for pain threshold and tolerance were delivered to participants' forearms using thermodes. CPM, an index of descending pain inhibition, was determined using a thermode as test stimulus and a hot water bath as conditioning stimulus. RESULTS: As hypothesized, youth with FAP living in lower SES neighborhoods exhibited weaker CPM. Contrary to hypotheses, lower neighborhood SES was associated with neither pain thresholds nor with pain tolerance. CONCLUSIONS: These findings demonstrated the independent contribution of place of residence-an often neglected component of the biopsychosocial model-to efficiency of descending pain inhibition. Understanding the mechanisms that account for such associations between place and pain could guide the development of public health and policy initiatives designed to mitigate chronic pain risk in underserved and economically marginalized communities.

Electroencephalography Signatures for Conditioned Pain Modulation and Pain Perception in Nonspecific Chronic Low Back Pain-An Exploratory Study.

Conditioned pain modulation (CPM) can discriminate between healthy and chronic pain patients. However, its relationship with neurophysiological pain mechanisms is poorly understood. Brain oscillations measured by electroencephalography (EEG) might help gain insight into this complex relationship. OBJECTIVE: To investigate the relationship between CPM response and self-reported pain intensity in non-specific chronic low back pain (NSCLBP) and explore respective EEG signatures associated to these mechanisms. DESIGN: Cross-sectional analysis. PARTICIPANTS: Thirty NSCLBP patients participated. METHODS: Self-reported low back pain, questionnaires, mood scales, CPM (static and dynamic quantitative sensory tests), and resting surface EEG data were collected and analyzed. Linear regression models were used for statistical analysis. RESULTS: CPM was not significantly correlated with self-reported pain intensity scores. Relative power of EEG in the beta and high beta bands as recorded from the frontal, central, and parietal cortical areas were significantly associated with CPM. EEG relative power at delta and theta bands as recorded from the central area were significantly correlated with self-reported pain intensity scores while controlling for self-reported depression. CONCLUSIONS: Faster EEG frequencies recorded from pain perception areas may provide a signature of a potential cortical compensation caused by chronic pain states. Slower EEG frequencies may have a critical role in abnormal pain processing.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Preoperative dynamic quantitative sensory testing in remote pain-free areas is associated with axial pain after posterior cervical spinal surgeries.

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.

A Randomized, Sham-Controlled Trial of Repetitive Transcranial Magnetic Stimulation Targeting M1 and S2 in Central Poststroke Pain: A Pilot Trial.

OBJECTIVES: Central poststroke pain (CPSP), a neuropathic pain condition, is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) targeted to the primary motor cortex (M1) can alleviate the condition, but not all patients respond. We aimed to assess a promising alternative rTMS target, the secondary somatosensory cortex (S2), for CPSP treatment. MATERIALS AND METHODS: This prospective, randomized, double-blind, sham-controlled three-arm crossover trial assessed navigated rTMS (nrTMS) targeted to M1 and S2 (10 sessions, 5050 pulses per session at 10 Hz). Participants were evaluated for pain, depression, anxiety, health-related quality of life, upper limb function, and three plasticity-related gene polymorphisms including Dopamine D2 Receptor (DRD2). We monitored pain intensity and interference before and during stimulations and at one month. A conditioned pain modulation test was performed using the cold pressor test. This assessed the efficacy of the descending inhibitory system, which may transmit TMS effects in pain control. RESULTS: We prescreened 73 patients, screened 29, and included 21, of whom 17 completed the trial. NrTMS targeted to S2 resulted in long-term (from baseline to one-month follow-up) pain intensity reduction of ≥30% in 18% (3/17) of participants. All stimulations showed a short-term effect on pain (17-20% pain relief), with no difference between M1, S2, or sham stimulations, indicating a strong placebo effect. Only nrTMS targeted to S2 resulted in a significant long-term pain intensity reduction (15% pain relief). The cold pressor test reduced CPSP pain intensity significantly (p = 0.001), indicating functioning descending inhibitory controls. The homozygous DRD2 T/T genotype is associated with the M1 stimulation response. CONCLUSIONS: S2 is a promising nrTMS target in the treatment of CPSP. The DRD2 T/T genotype might be a biomarker for M1 nrTMS response, but this needs confirmation from a larger study.

Evidence for alterations to dynamic quantitative sensory tests in patients with chronic temporomandibular myalgia: A systematic review of observational studies with meta-analysis.

BACKGROUND: Conflicting results exist between somatosensory profiles of patients with temporomandibular myalgia (TMDm). The objective of this review was to examine whether adults with TMDm show altered responses to dynamic quantitative sensory tests compared with healthy controls. METHODS: We searched five electronic databases for studies, excluding those without suitable controls or where TMDm was associated with confounding non-musculoskeletal disorders. Risk of bias was assessed with the SIGN case-control study checklist. Findings were structured around dynamic quantitative sensory tests and their localization. Where possible, we performed meta-analysis with a random inverse variance model to compare patients with TMDm and healthy controls. Statistical heterogeneity was estimated with Chi² test and inconsistency index, I². RESULTS: We extracted data from 23 studies comprising 1284 adults with chronic TMDm and 2791 healthy controls. Risk of bias was assessed as high for 20 studies. Mechanical temporal summation, the most studied phenomenon (14 studies), is increased in the upper limb of patients with TMDm (SMD = 0.43; 95% CI: .11 to .75; p = .009) but not in the jaw area (p = .09) or in the cervical area (p = .29). Very little evidence for altered thermal temporal summation (five studies), conditioned pain modulation (seven studies), exercise-induced hypoalgesia (two studies), placebo analgesia (two studies), stress-induced hypoalgesia (one study) and offset analgesia (one study) was found. DISCUSSION: A major limitation of this review was the risk of bias of included studies. Future studies would benefit from following methodological guidelines and consideration of confounding factors.

Genetic variation in catechol-O-methyltransferase is associated with individual differences in conditioned pain modulation in healthy subjects.

BACKGROUND: Genetic variation in the catechol-O-methyltransferase (COMT) gene is associated with sensitivity to both acute experimental pain and chronic pain conditions. Four single nucleotide polymorphisms (SNPs) have traditionally been used to infer three common haplotypes designated as low, average and high pain sensitivity and are reported to affect both COMT enzymatic activity and pain sensitivity. One mechanism that may partly explain individual differences in sensitivity to pain is conditioned pain modulation (CPM). We hypothesized that variation in CPM may have a genetic basis. METHODS: We evaluated CPM in 77 healthy pain-free Caucasian subjects by applying repeated mechanical stimuli to the dominant forearm using 26-g von Frey filament as the test stimulus with immersion of the non-dominant hand in hot water as the conditioning stimulus. We assayed COMT SNP genotypes by the TaqMan method using DNA extracted from saliva. RESULTS: SNP rs4680 (val158 met) was not associated with individual differences in CPM. However, CPM was associated with COMT low pain sensitivity haplotypes under an additive model (p = 0.004) and the effect was independent of gender. CONCLUSIONS: We show that, although four SNPs are used to infer COMT haplotypes, the low pain sensitivity haplotype is determined by SNP rs6269 (located in the 5' regulatory region of COMT), suggesting that inherited variation in gene expression may underlie individual differences in pain modulation. Analysis of 13 global populations revealed that the COMT low pain sensitivity haplotype varies in frequency from 13% to 44% and showed that two SNPs are sufficient to distinguish all COMT haplotypes in most populations.

CGRP monoclonal antibody prevents the loss of diffuse noxious inhibitory controls (DNIC) in a mouse model of post-traumatic headache.

AIM: Determine the role of calcitonin-gene related peptide in promoting post-traumatic headache and dysregulation of central pain modulation induced by mild traumatic brain injury in mice. METHODS: Mild traumatic brain injury was induced in lightly anesthetized male C57BL/6J mice by a weight drop onto a closed and unfixed skull, which allowed free head rotation after the impact. We first determined possible alterations in the diffuse noxious inhibitory controls, a measure of net descending pain inhibition called conditioned pain modulation in humans at day 2 following mild traumatic brain injury. Diffuse noxious inhibitory control was assessed as the latency to a thermally induced tail-flick that served as the test stimulus in the presence of right forepaw capsaicin injection that provided the conditioning stimulus. Post-traumatic headache-like behaviors were assessed by the development of cutaneous allodynia in the periorbital and hindpaw regions after mild traumatic brain injury. We then determined if intraperitoneal fremanezumab, an anti-calcitonin-gene related peptide monoclonal antibody or vehicle administered 2 h after sham or mild traumatic brain injury induction could alter cutaneous allodynia or diffuse noxious inhibitory control responses on day 2 post mild traumatic brain injury. RESULTS: In naïve and sham mice, capsaicin injection into the forepaw elevated the latency to tail-flick, reflecting the antinociceptive diffuse noxious inhibitory control response. Periorbital and hindpaw cutaneous allodynia, as well as a loss of diffuse noxious inhibitory control, was observed in mice 2 days after mild traumatic brain injury. Systemic treatment with fremanezumab blocked mild traumatic brain injury-induced cutaneous allodynia and prevented the loss of diffuse noxious inhibitory controls in mice subjected to a mild traumatic brain injury. INTERPRETATION: Sequestration of calcitonin-gene related peptide in the initial stages following mild traumatic brain injury blocked the acute allodynia that may reflect mild traumatic brain injury-related post-traumatic headache and, additionally, prevented the loss of net descending inhibition within central pain modulation pathways. As loss of conditioned pain modulation has been linked to multiple persistent pain conditions, dysregulation of descending modulatory pathways may contribute to the persistence of post-traumatic headache. Additionally, evaluation of the conditioned pain modulation/diffuse noxious inhibitory controls response may serve as a biomarker of vulnerability for chronic/persistent pain. These findings suggest that early anti-calcitonin-gene related peptide intervention has the potential to be effective both for the treatment of mild traumatic brain injury-induced post-traumatic headache, as well as inhibiting mechanisms that may promote post-traumatic headache persistence.