Search

Traumatic brain injury (TBI) can cause acute and chronic pain along with motor, cognitive, and emotional problems. Although the mechanisms are poorly understood, previous studies suggest disruptions in endogenous pain modulation may be involved. Voluntary exercise after a TBI has been shown to reduce some consequences of injury including cognitive impairment. We hypothesized, therefore, that voluntary exercise could augment endogenous pain control systems in a rodent model of TBI. For these studies, we used a closed-head impact procedure in male mice modeling mild TBI. We investigated the effect of voluntary exercise on TBI-induced hindpaw nociceptive sensitization, diffuse noxious inhibitory control failure, and periorbital sensitization after bright light stress, a model of post-traumatic headache. Furthermore, we investigated the effects of exercise on memory, circulating markers of brain injury, neuroinflammation, and spinal cord gene expression. We observed that exercise significantly reduced TBI-induced hindpaw allodynia and periorbital allodynia in the first week following TBI. We also showed that exercise improved the deficits associated with diffuse noxious inhibitory control and reduced bright light stress-induced allodynia up to 2 months after TBI. In addition, exercise preserved memory and reduced TBI-induced increases in spinal BDNF, CXCL1, CXCL2, and prodynorphin expression, all genes previously linked to TBI-induced nociceptive sensitization. Taken together, our observations suggest that voluntary exercise may reduce pain after TBI by reducing TBI-induced changes in nociceptive signaling and preserving endogenous pain control systems. PERSPECTIVE: This article evaluates the effects of exercise on pain-related behaviors in a preclinical model of traumatic brain injury (TBI). The findings show that exercise reduces nociceptive sensitization, loss of diffuse noxious inhibitory control, memory deficits, and spinal nociception-related gene expression after TBI. Exercise may reduce or prevent pain after TBI., (Copyright © 2023 United States Association for the Study of Pain, Inc. All rights reserved.)

Background: People with neuropathic-like symptoms had more unfavourable pain features than people with nociceptive. Moreover, deficient conditioned pain modulation is common in people with neuropathic-like symptoms. PainDETECT questionnaire have been used to assess the central sensitisation sign and symptoms. However, whether the painDETECT questionnaire can identify the conditioned pain modulation's impairment is still unknown. Therefore, the current study aimed to evaluate the diagnostic accuracy of the painDETECT questionnaire in detecting the impairment of conditioned pain modulation in people with musculoskeletal pain., Methods: We conducted a diagnostic accuracy comparing the painDETECT questionnaire (index method) with the cold pressor test, the psychophysical test used to assess the conditioned pain modulation (reference standard). We determined diagnostic accuracy by calculating sensitivity, specificity, predictive values, and likely hood ratios., Results: We retrospectively enrolled 308 people with musculoskeletal pain in outpatient departments. Most participants were female (n 20 = 220, 71.4%) and had a mean age of 52.2 (± 15.0) years. One hundred seventy-three (56.1%) participants were classified as nociceptive pain, 69 (22.4%) as unclear, and 66 (21.4%) as neuropathic-like symptoms. According to the cold pressor test, 60 (19.4%) participants presented impairment of conditioned pain modulation. The cutoff point of 12 of the painDETECT questionnaire showed values of diagnostic accuracy below 70% compared to the cold pressor test, except for a negative predictive value [76.9 95% Confidence Interval (CI) 71.7 to 81.5]. The cutoff point 19 showed high specificity (78.6%, 95% CI 73.0 to 83.5), high negative predictive value (80.5%, 95% CI 78.1 to 82.7), and accuracy of 67.5% compared to the cold pressor test., Conclusion: The painDETECT questionnaire seems valuable for ruling out people with musculoskeletal pain and impairment of conditioned pain modulation., (© 2023. Italian Society of Physiotherapy.)

To examine the effects of photobiomodulation (PBM) in healthy volunteers using photonic stimulation of acupuncture points on conditioned pain modulation (CPM), temporal summation of pain (TSP), and offset analgesia (OA), which reflect some aspects of endogenous pain modulation. We included 15 men and 15 women (age, 31.5 [27.3-37.0], body mass index, 25.7 [24.4-27.1], Fitzpatrick skin typing, II: 20, III: 8, IV: 2). CPM, TSP, and OA were evaluated after a sham procedure (control session) and after acupuncture point stimulation (LI4 and LI10 on the non-dominant forearm) using linear polarized near-infrared light irradiation (LPNILI; wavelengths peaked at approximately 1000 nm, output: 1.4 W/cm 2 , spot diameter: 10 mm, spot size: 1.02 cm 2 , maximum temperature: 40.5 °C, pulse width: 1 s, frequency: 0.2 Hz) (PBM session). Differences in CPM, TSP, and OA between the two sessions were evaluated by the paired t-test and Fisher's exact test (statistical significance: p < 0.05). Values indicate median [interquartile range]. LPNILI significantly increased CPM in all participants (control session: 12.1 [-4.5-37.4], PBM session: 23.9 [8.3-44.8], p < 0.05) and women (control session: 16.7 [-3.4-36.6], PBM session: 38.7 [24.6-52.1], p < 0.05). The CPM effect increment was significantly higher in women than in men (p = 0.0253). LPNILI decreased TSP in participants with higher TSP ratios (p = 0.0219) and increased OA in participants with lower OA scores (p = 0.0021). LPNILI enhanced endogenous pain modulation in healthy volunteers, particularly in women, as evaluated using CPM. CPM, TSP, and OA evaluations are potentially useful for discriminating PBM responders from non-responders., (© 2022. The Author(s).)

Background: Deficient endogenous pain modulation has been implicated in the development and exacerbation of chronic orofacial pain. To date, relatively little is known regarding the function of the endogenous pain modulation in patients with burning mouth syndrome (BMS). This case-control study investigated endogenous pain modulation in women with BMS., Methods: Conditioned pain modulation (CPM) was assessed upon temporal summation (TSP) of thermal pain. Forty female subjects, 20 BMS patients and 20 age-matched control subjects, were included in a 2 session-protocol. Mechanical and thermal pain thresholds were measured on the forearm and hand. TSP was obtained using repetitive laser-evoked thermal stimuli applied on the non-dominant hand, at an intensity yielding to moderate pain. During TSP, CPM was produced by immersing the contralateral foot in a water bath at painful cold (8 °C) temperature. In control conditions, the foot was immersed in a water bath at not painful (30 °C) temperature., Results: BMS was not associated with any impairment in thermal as well as mechanical extracephalic pain thresholds. TSP and CPM efficacy were similar in BMS patients and control subjects. However, BMS patients exhibited enhanced extracephalic heat hyperalgesia., Conclusion: This study reveals that there is no impairment of endogenous pain inhibition mechanisms in BMS patients, but rather an increase in pain facilitation., (© 2022. The Author(s).)

Objectives: Treating chronic pain patients with multimodal pain therapy (MMPT) alters perception, awareness, and processing of pain at multiple therapeutic levels. Several clinical observations suggest that the effects of therapy may go beyond the possible sum of each level of therapy and may be due to a central descending inhibitory effect measurable by conditioned pain modulation (CPM). Thus, we investigated whether CPM is able to identify a group of patients that benefit particularly from MMPT., Methods: This was an observational prospective cohort study. Patients were hospitalized on a special pain medicine ward with specially trained staff for 10 days. The patients were questioned and had investigations before and shortly after MMPT and were followed-up on 3 months post discharge. Before and after treatment, subjects were investigated via CPM and quantitative sensory testing (QST) as well as completing questionnaires. The study was registered in the German Clinical Trials Register (DRKS00006850)., Results: During the study period of 24 months, 224 chronic pain patients were recruited. 51 percent of patients completed the study period. There was an improvement in overall groups regarding all domains assessed, lasting beyond the end of the intervention. Patients with a sufficient CPM effect, defined as a reduction in pain during the conditioning stimulus, at baseline did show a more pronounced reduction in mean pain ratings than those without. This was not the case 3 months after therapy. Furthermore, sufficient CPM was identified as a predictor for pain reduction using a linear regression model., Conclusion: In conclusion, this study shows that while a heterogeneous group of patients with chronic pain disorders does sustainably benefit from MMPT in general, patients with a sufficient CPM effect do show a more pronounced decrease in pain ratings directly after therapy in comparison to those without.

Background: Musculoskeletal pain patients present similar pain characteristics regardless of the clinical diagnosis. PainDETECT questionnaire is useful for screening neuropathic-like symptoms in many musculoskeletal conditions. However, no previous studies compared pain phenotypes of patients with musculoskeletal pain using the painDETECT. Therefore, the current study aimed to compare the pain characteristics of patients with musculoskeletal pain classified according to the painDETECT as nociceptive pain, unclear, and neuropathic-like symptoms., Methods: A cross-sectional study was conducted in 308 participants with musculoskeletal pain. Demographic and clinical characteristics of the participants were examined. Neuropathic-like symptoms, pain intensity, pain area, Central Sensitization-related sign and symptoms, functional limitation, and conditioned pain modulation were assessed in patients with musculoskeletal pain. Independent one-way analysis of variance (ANOVA) was used to test for between-group differences for the outcome measures with continuous variables and Pearson chi-square test verified between-group differences on the efficiency of the conditioned pain modulation., Results: Participants had a mean age of 52.21 (±15.01) years old and 220 (71.42%) were females. One hundred seventy-three (56.16%) participants present nociceptive pain, 69 (22.40%) unclear, and 66 (21.42%) neuropathic-like symptoms. A one-way ANOVA showed differences for the pain intensity [F (2,305) = 20.097; p < .001], pain area [F (2,305) = 28.525; p < .001], Central Sensitization-related sign and symptoms [F (2,305) = 54.186; p < .001], and functional limitation [F (2,256) = 8.061; p < .001]. However, conditioned pain modulation was similarly impaired among the three groups (X 2  = 0.333, p = 0.847)., Conclusion: Patients with neuropathic-like symptoms revealed unfavorable pain characteristics compared to their counterparts, including pain intensity, generalized pain, Central Sensitization-related sign and symptoms, and functional limitation., (© 2022. The Author(s).)

Conditioned pain modulation (CPM) is a centrally processed measure of the net effect of the descending pain pathway. This comprises both the facilitatory as well as the inhibitory effect. In the past, CPM or similar effects have been previously described using different terminologies such as diffuse noxious inhibitory control (DNIC), heterotopic noxious conditioning stimulation (HNCS) or endogenous analgesia (EA). A variety of patient-related factors such as age, gender, hormones, race, genetic and psychological factors have been thought to influence the CPM paradigms. CPM paradigms have also been associated with a wide range of methodological variables including the mode of application of the 'test' as well as the 'conditioning' stimuli. Despite all these variabilities, CPM seems to reliably lend itself to the pain modulation profile concept and could in future become one of the phenotypic biomarkers for pain and also a guide for mechanism-based treatment in chronic pain. Future research should focus on establishing consistent methodologies for measuring CPM and thereby enhancing the robustness of this emerging biomarker for pain., (Crown Copyright © 2020. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: The literature on conditioned pain modulation (CPM) is inconclusive in relation to low-back pain and it is unclear how CPM affects temporal summation as a proxy of central pain integration. The aim of this study was to examine whether the CPM effect would be different on pain induced by temporal summation than single stimuli in a group of low back pain patients., Methods: A total of 149 low-back pain patients were included. CPM was examined using single, repeated and temporal summation (repeated-single difference) of mechanical pressure pain as test stimuli at an individualized, fixed supra-pain-threshold force, before and after 2 min of cold pressor test (0-2 degrees Celsius). Participants were categorized as CPM responders or non-responders according to three different criteria: simple (any pain inhibition), strict (pain inhibition of more than 10VAS) and reversed (pain inhibition or facilitation of less than 10VAS). Clinical data on back pain was collected for correlation and descriptive purposes., Results: Significant modulation was observed for all three test stimuli. Effects sizes were comparable in relative terms, but repeated pressure pain modulation was greater in absolute terms. No correlations to clinical data were observed, for any measure., Conclusions: The current data suggests that repeated pressure pain may be better suited as the CPM test stimuli, than single pressure pain and temporal summation of pressure pain, as the CPM effect in absolute terms was greater. Employing temporal summation as the test stimulus in a CPM paradigm may be more sensitive than a single test stimulus., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Our primary objective was to report the presence of a conditioned pain modulation (CPM) effect in people with localised mid-portion Achilles tendinopathy and whether changes occur over a 12-week period. Our secondary objectives were to quantify the proportion of participants who present for tendinopathy research with previous interventions or co-morbidities, which may impact the CPM-effect and investigate modulating factors., Design: Prospective, observational cohort pilot study., Method: 215 participants presented for this Achilles tendinopathy research and were screened for inclusion with nine being included. Included participants had the CPM-effect (cold-pressor test) assessed using pressure pain thresholds at the Achilles tendon and quantified as absolute, relative and meaningful change at baseline and 12-week follow-up., Results: The most common reasons for exclusion were failure to meet a load-related diagnosis for Achilles tendinopathy (15.5%), presence of confounding other injury (14.1%) and previous injection therapy (13.6%). All participants had a meaningful CPM-effect at baseline and 12-week follow-up. The mean (SD, n) baseline relative CPM effect (reduction in PPTs) was -40.5 (32.7, 9) percent. Moderators of the CPM-effect as well as follow-up changes were not statistically analysed due to a small sample size., Conclusion: Based on these data, we would suggest that a homogenous population of patients with chronic, unilateral mid-portion Achilles tendinopathy and no other co-morbidities are likely to exhibit a meaningful CPM-effect. Impairments to endogenous analgesic mechanisms seen in people presenting with mid-portion Achilles tendinopathy may be due to other confounding variables., (Copyright © 2020 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Objective: The current study aimed to evaluate the concurrent validity and the diagnostic accuracy of the Central Sensitization Inventory (CSI) in detecting the impairment of the pain modulation in patients with chronic musculoskeletal pain., Methods: A cross-sectional study was conducted in 267 patients with chronic musculoskeletal pain enrolled consecutively in an outpatient department. The CSI (index method) were compared with the cold pressor test, which was the psychophysical test used to assess the conditioned pain modulation (CPM), (reference standard). Spearman's correlations assessed the concurrent validity, and measurements of the diagnostic accuracy were performed., Results: Ninety-three (34.8%) patients had CSI scores≥40. No significant correlation was found between CSI findings and the results of the CPT (dorsal forearm site or tibialis anterior site) was found. The cutoff point of 40 of the CSI showed values of sensitivity (35.1%, 95% CI: 22.6, 49.3) and specificity (65.2%, 95% CI: 58.4, 71.6) below 70%, and an accuracy of 59.1 (95% CI: 53.0, 65.1) when compared to the CPT to detect deficit. The ROC curve analysis yielded an area under the curve of 0.54 (95% CI: 0.45, 0.63, P>0.05)., Conclusions: The CSI is a useless instrument to detect the deficit in the CPM in patients with chronic musculoskeletal pain due to the absence of correlation with the psychophysical test result and the insufficient measurements of diagnostic accuracy., (Copyright © 2020 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Background: The 'pain-inhibits-pain' effect stems from neurophysiological mechanisms involving endogenous modulatory systems termed diffuse noxious inhibitory controls (DNIC) or conditioned pain modulation (CPM). Laser-evoked potentials (LEPs) components, the N2/P2 complex, and the N1 wave, reflect the medial and lateral pain pathway, respectively: anatomically, the lateral thalamic nuclei (LT) project mainly to the somatosensory cortex (N1 generator), while the medial thalamic nuclei (MT) are bound to the limbic cortices (N2/P2 generators)., Methods: We applied a CPM protocol in which the test stimulus was laser stimulation and the conditioning stimulus was a cold pressor test. LEPs recordings were obtained from 15 healthy subjects in three different conditions: baseline, during heterotopic noxious conditioning stimulation (HNCS) and post-HNCS., Results: We observed a significant reduction in N2/P2 amplitude during HNCS and a return to pre-test amplitude post-HNCS, whereas the N1 wave remained unchanged during and post-HNCS., Conclusions: Our results indicate that CPM affects only the medial pain system. The spinothalamic tract (STT) transmits to both the LT and the MT, while the spinoreticulothalamic (SRT) projects only to the MT. The reduction in the amplitude of the N2/P2 complex and the absence of change in the N1 wave suggest that DNIC inhibition on the dorsal horn neurons affects only pain transmission via the SRT, while the neurons that give rise to the STT are not involved. The N1 wave can be a reliable neurophysiological parameter for assessment of STT function in clinical practice, as it does not seem to be influenced by CPM., Significance: No reports have described the effect of DNIC on lateral and medial pain pathways. We studied the N1 wave and the N2/P2 complex to detect changes during a CPM protocol. We found a reduction in the amplitude of the N2/P2 complex and no change in the N1 wave. This suggests that the DNIC inhibitory effect on dorsal horns neurons affects only pain transmission via the SRT, whereas the neurons that give rise to the STT are not involved., (© 2020 European Pain Federation - EFIC®.)

Background: The identification of central sensitization (CS) is an important aspect in the management of patients with chronic musculoskeletal pain. Several methods have been developed, including clinical indicators and psychophysical measures. However, whether clinical indicators coincide with the psychophysical test of CS-related sign and symptoms is still unknown. Therefore, the present study aimed to analyze the diagnostic accuracy of the clinical indicators in identifying CS-related sign and symptoms in patients with musculoskeletal pain., Methods: One-hundred consecutive patients with musculoskeletal pain were included. Clinical indicators (index method) based on a combination of patient self-report pain characteristics and physical examination were used to identify the phenotype of patients with musculoskeletal pain and the predominance of the CS-related sign and symptoms. Conditioned pain modulation (CPM) was assessed by the Cold Pressor Test (reference standard), which is a psychophysical test used to detect impairment of CPM. Measurements of the diagnostic accuracy were performed., Results: Twenty-seven patients presented predominance of CS-related sign and symptoms in the assessment of the clinical indicators, and 20 had impairment of CPM. Clinical indicators showed high accuracy (75.0%; 95% confidence interval = 65.3 to 83.1), high specificity (80.0%; 95% confidence interval = 69.6 to 88.1), high negative predictive value (87.7%; 95% confidence interval = 81.2 to 92.1), and a relevant positive likelihood ratio (2.8, 95% confidence interval = 1.5 to 5.0) when compared to the Cold Pressor Test., Conclusion: Clinical indicators demonstrated a valuable tool for detecting the impaired CPM, which is a remarkable feature of the CS-related sign and symptoms. Clinicians are encouraged to use the clinical indicators in the management of patients with musculoskeletal pain.

Background and aims Pain is a disabling symptom in knee osteoarthritis (KOA) and its underlying mechanism remains poorly understood. Dysfunction of descending pain modulatory pathways and reduced pain inhibition enhance pain facilitation in many chronic pain syndromes but do not fully explain pain levels in chronic musculoskeletal conditions. The objective of this study is to explore the association of clinical variables with pain intensity perception in KOA individuals with varying levels of Conditioned Pain Modulation (CPM) response. Methods This is a cross-sectional, exploratory analysis using baseline data of a randomized clinical trial investigating the effects of a non-invasive brain stimulation treatment on the perception of pain and functional limitations due to KOA. Sixty-three subjects with KOA were included in this study. Data on pain perception, mood perception, self-reported depression, physical function, quality of life, and quantitative sensory testing was collected. Multiple linear regression analysis was performed to explore the association between the clinical variables with pain perception for individuals with different levels of CPM response. Results For KOA patients with limited CPM response, perception of limitations at work/other activities due to emotional problems and stress scores were statistically significantly associated with pain scores, F(2, 37) = 7.02, p < 0.01. R-squared = 0.275. For KOA patients with normal CPM response, general health perception scores were statistically significantly associated with pain scores, F(1, 21) = 5.60, p < 0.05. R-squared = 0.2104. Limitations of this study include methodology details, small sample size and study design characteristics. Conclusions Pain intensity perception is associated differently with clinical variables according to the individual CPM response. Mechanistic models to explain pain perception in these two subgroups of KOA subjects are discussed.

Background: Diffuse noxious inhibitory controls (DNIC) as measured in rat and conditioned pain modulation (CPM), the supposed psychophysical paradigm of DNIC measured in humans, are unique manifestations of an endogenous descending modulatory pathway that is activated by the application of a noxious conditioning stimulus. The predictive value of the human CPM processing is crucial when deliberating the translational worth of the two phenomena., Methods: For CPM or DNIC measurement, test and conditioning stimuli were delivered using a computer-controlled cuff algometry system or manual inflation of neonate blood pressure cuffs, respectively. In humans (n = 20), cuff pain intensity (for pain detection and pain tolerance thresholds) was measured using an electronic visual analogue scale. In isoflurane-anaesthetized naïve rats, nociception was measured by recording deep dorsal horn wide dynamic range (WDR) neuronal firing rates (n = 7) using in vivo electrophysiology., Results: A painful cuff-pressure conditioning stimulus on the leg increased pain detection and pain tolerance thresholds recorded by cuff stimulation on the contralateral leg in humans by 32% ± 3% and 24% ± 2% (mean ± SEM) of baseline responses, respectively (p < .001). This finding was back-translated by revealing that a comparable cuff-pressure conditioning stimulus (40 kPa) on the hind paw inhibited the responses of WDR neurons to noxious contralateral cuff test stimulation to 42% ± 9% of the baseline neuronal response (p = .003)., Conclusions: These data substantiate that the noxious cuff pressure paradigm activates the descending pain modulatory system in rodent (DNIC) and man (CPM), respectively. Future back and forward translational studies using cuff pressure algometry may reveal novel mechanisms in varied chronic pain states., Significance: This study provides novel evidence that a comparable noxious cuff pressure paradigm activates a unique form of endogenous inhibitory control in healthy rat and man. This has important implications for the forward translation of bench and experimental pain research findings to the clinical domain. If translatable mechanisms underlying dysfunctional endogenous inhibitory descending pathway expression (previously evidenced in painful states in rat and man) were revealed using cuff pressure algometry, the identification of new analgesic targets could be expedited., (© 2020 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation EFIC ®.)

Background and aims Elite athletes reportedly have superior pain tolerances, but it is unclear if results extend to conditioned pain modulation (CPM). The aim of our study was to synthesize existing literature in order to determine whether CPM is increased in elite athletes compared to healthy controls. Methods A systematic review and random-effects meta-analysis was conducted. Cochrane Central Register of Controlled Trials, SPORTDiscus, PsycINFO, CINAHL, Web of Science, and PubMed were searched for English-language studies that examined CPM in adult elite athlete populations. Results Seven studies were identified; all were of poor to fair methodological quality. There was no overall difference in CPM between elite athletes and controls (Hedges g = 0.37, CI95 -0.03-0.76; p = 0.07). There was heterogeneity between studies, including one that reported significantly less CPM in elite athletes compared to controls. An exploratory meta-regression indicated that a greater number of hours trained per week was associated with higher CPM. Conclusions The overall number and quality of studies was low. Despite nominally favoring higher CPM in elite athletes, aggregate results indicate no significant difference compared to healthy controls. A possible factor explaining the high degree of variability between studies is the number of hours elite athletes spent training. Implications Based on available evidence, athletes do not have remarkable endogenous pain modulation compared to controls. High quality experimental studies are needed to address the effect of hours trained per week on CPM in athletes.

Objectives The present study attempts to understand the role of supraspinal nociceptive pain modulation in typical trigeminal neuralgia (TN) patients by using a conditioned pain modulation paradigm and estimation of plasma levels of two important neuromodulators; Calcitonin Gene-Related Peptide and β-endorphin. Methods Twenty TN patients and 20 healthy, age and gender-matched subjects participated in the study. The participants' hot pain thresholds (HPT) were measured over their affected side on the face. Testing sites were matched for healthy controls. For the conditioned pain modulation their contralateral foot was immersed in noxious cold (5 °C) water bath (conditioning stimuli) for 30 s and HPT (testing stimuli) was determined before, during and till 5 min after the immersion. Plasma Calcitonin Gene-Related Peptide and β-endorphin levels were estimated to understand their role in disease pathogenesis and pain modulation. Results Change in HPT during foot immersion was significantly higher in healthy controls compared to TN patients (p<0.0001). The changes recorded in HPT in patients, were significant only in 2nd and 3rd minute post immersion. While in healthy controls, the effect lasted till the 4th minute. The concentration of beta-endorphin was significantly lower in TN patients (p=0.003) when compared to healthy controls. Conclusions The results suggest that there is an impairment in supraspinal pain modulation also known as Diffuse Noxious Inhibitory Controls in typical TN and that the reduced levels of β-endorphin may contribute to the chronic pain state experienced by patients.

Diffuse noxious inhibitory control (DNIC) is a phenomenon to reflect descending pain modulation in animals. Conditioned pain modulation (CPM) is the human counterpart of DNIC and is reduced in patients with several chronic pain conditions. Duloxetine is a serotonin and noradrenaline reuptake inhibitor that ameliorates CPM impairment in patients with diabetic neuropathy. Although some studies have reported the effects of different pharmacological agents on CPM, few studies have compared the effects of some analgesics in both humans and rodents. Therefore, we established a stable evaluation method for DNIC in rats and determined whether duloxetine and other specific analgesics affect DNIC impairment in rat models of peripheral neuropathic pain and osteoarthritis pain, two types of chronic pain. As a conditioning stimulus, capsaicin was injected into the forepaw of rats. The paw withdrawal threshold (PWT) in response to mechanical pressure was measured for the hindpaw. Peripheral neuropathic pain and osteoarthritis pain models were developed by partial sciatic nerve ligation (PSNL) and the intra-articular injection of 2 mg monoiodoacetate (MIA), respectively. Capsaicin (30-100 μg/site) increased the PWT, in a dose-dependent manner, in naive rats. The threshold significantly increased at 30 μg and reached its maximal level at 100 μg. The change in PWT following capsaicin injection was significantly reduced in PSNL-treated rats, but the threshold was increased by the subcutaneous administration of duloxetine (10 mg/kg). The oral administrations of pregabalin (10 mg/kg) and celecoxib (3 mg/kg) did not affect the PWT in PSNL-treated rats. Similarly, MIA-injected rats also showed a reduced change in PWT following capsaicin injection. Duloxetine, but not pregabalin and celecoxib, significantly increased the PWT in MIA-injected rats. These results suggested that duloxetine can directly ameliorate DNIC impairment in rat models of chronic pain. Duloxetine may be useful for modulating chronic pain by restoring function to the endogenous, descending, inhibitory pathway., Competing Interests: Declaration of Competing Interest All authors are employees of Shionogi & Co., Ltd., which is the manufacturer of duloxetine., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Endogenous pain inhibition is less efficient in chronic pain patients. Diffuse noxious inhibitory control (DNIC), a form of endogenous pain inhibition, is compromised in women and older people, making them more vulnerable to chronic pain. However, the underlying mechanisms remain unclear. Here, we used a capsaicin-induced DNIC test and resting-state functional MRI to investigate the impact of aging and sex on endogenous pain inhibition and associated brain circuitries in healthy rats. We found that DNIC was less efficient in young females compared with young males. Diffuse noxious inhibitory control response was lost in old rats of both sexes, but the brain networks engaged during DNIC differed in a sex-dependent manner. Young males had the most efficient analgesia with the strongest connectivity between anterior cingulate cortex (ACC) and periaqueductal gray (PAG). The reduced efficiency of DNIC in young females seemed to be driven by widespread brain connectivity. Old males showed increased connectivity between PAG, raphe nuclei, pontine reticular nucleus, and hippocampus, which may not be dependent on connections to ACC, whereas old females showed increased connectivity between ACC, PAG, and more limbic regions. These findings suggest that distinct brain circuitries including the limbic system may contribute to higher susceptibility to pain modulatory deficits in the elderly population, and sex may be a risk factor for developing age-related chronic pain.

The noradrenergic system is paramount for controlling pain and emotions. We aimed at understanding the descending noradrenergic modulatory mechanisms in joint inflammatory pain and its correlation with the diffuse noxious inhibitory controls (DNICs) and with the onset of anxiodepressive behaviours. In the complete Freund's adjuvant rat model of Monoarthritis, nociceptive behaviors, DNICs, and anxiodepressive-like behaviors were evaluated. Spinal alpha2-adrenergic receptors (a2-AR), dopamine beta-hydroxylase (DBH), and noradrenaline were quantified concomitantly with a2-AR pharmacologic studies. The phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) were quantified in the Locus coeruleus (LC), amygdala, and anterior cingulate cortex (ACC). DNIC was attenuated at 42 days of monoarthritis while present on days 7 and 28. On day 42, in contrast to day 28, noradrenaline was reduced and DBH labelling was increased. Moreover, spinal a2-AR were potentiated and no changes in a2-AR levels were observed. Additionally, at 42 days, the activation of ERKs1/2 was increased in the LC, ACC, and basolateral amygdala. This was accompanied by anxiety- and depressive-like behaviors, while at 28 days, only anxiety-like behaviors were observed. The data suggest DNIC is attenuated in prolonged chronic joint inflammatory pain, and this is accompanied by impairment of the descending noradrenergic modulation and anxiodepressive-like behaviors.

Objective: To assess the effect of different dosages of pain neuroscience education (PNE) programs on central nociceptive processing in patients with fibromyalgia. Second, to compare the effects of different dosages of PNE programs on numerical pain rating scale (NPRS), disability, and psychological variables., Design: Single-blind randomized controlled trial., Setting: Three fibromyalgia centers in Spain (Valencia, Alcorcón, Alcalá de Henares)., Subjects: Seventy-seven patients with fibromyalgia., Methods: Participants were randomized to four groups of PNE: 1) high-dose PNE (N = 20), 2) low-concentrated dose PNE (N = 20), 3) diluted low-dose PNE (N = 20), and (4) control treatment (N = 17), conducted in two 30-50-minute sessions in groups of four to six participants. Conditioned pain modulation (CPM), temporal summation (TS), and pressure pain thresholds (PPTs) were assessed at baseline and at three-month follow-up. Secondary outcome measures were the Fibromyalgia Impact Questionnaire, Pain Catastrophizing Scale, and Pain Anxiety Symptoms Scale., Results: There were significant between-group differences for NPRS in favor of the groups receiving high-dose PNE, with a large effect size at three-month follow-up (P < 0.01, η2p = 0.170), but there were no significant differences between groups for the remaining variables (P > 0.05). All groups improved for central nociceptive processing, psychological variables, disability, and pain intensity (NPRS)., Conclusions: In patients with fibromyalgia, higher dosages of PNE produced a larger improvement in pain severity at three-month follow-up than other dosages of PNE and biomedical education. However, PNE was not superior to biomedical education in the central nociceptive processing, disability, or psychological variables in patients with fibromyalgia., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Diffuse noxious inhibitory controls (DNIC) are a mechanism of endogenous descending pain modulation and are deficient in a large proportion of chronic pain patients. However, the pathways involved remain only partially determined with several cortical and brainstem structures implicated. This study examined the role of the dorsal reticular nucleus (DRt) and infralimbic (ILC) region of the medial prefrontal cortex in DNIC. In vivo electrophysiology was performed to record from dorsal horn lamina V/VI wide dynamic range neurones with left hind paw receptive fields in anaesthetised sham-operated and L5/L6 spinal nerve-ligated (SNL) rats. Evoked neuronal responses were quantified in the presence and absence of a conditioning stimulus (left ear clamp). In sham rats, DNIC were reproducibly recruited by a heterotopically applied conditioning stimulus, an effect that was absent in neuropathic rats. Intra-DRt naloxone had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. In addition, intra-DRt naloxone blocked DNIC in sham rats, but had no effect in SNL rats. Intra-ILC lidocaine had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. However, differential effects were observed in relation to the expression of DNIC; intra-ILC lidocaine blocked activation of DNIC in sham rats but restored DNIC in SNL rats. These data suggest that the ILC is not directly involved in mediating DNIC but can modulate its activation and that DRt involvement in DNIC requires opioidergic signalling., (© 2019 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The 10 Hz repetitive transcranial magnetic stimulation (10 Hz-rTMS) to the left dorsolateral prefrontal cortex produces analgesia, probably by activating the pain modulation system. A newer rTMS paradigm, called theta burst stimulation (TBS), has been developed. Unlike 10 Hz-rTMS, prolonged continuous TBS (pcTBS) mimics endogenous theta rhythms, which can improve induction of synaptic long-term potentiation. Therefore, this study investigated whether pcTBS to the left dorsolateral prefrontal cortex reduced pain sensitivity more efficiently compared with 10 Hz-rTMS, the analgesic effects lasted beyond the stimulation period, and the reduced pain sensitivity was associated with increased efficacy of conditioned pain modulation (CPM) and/or intracortical excitability. Sixteen subjects participated in a randomized cross-over study with pcTBS and 10 Hz-rTMS. Pain thresholds to heat (HPT), cold, pressure (PPT), intracortical excitability assessment, and CPM with mechanical and heat supra-pain threshold test stimuli and the cold pressor test as conditioning were collected before (Baseline), 3 (Day3) and 4 days (Day4) after 3-day session of rTMS. HPTs and PPTs increased with 10 Hz-rTMS and pcTBS at Day3 and Day4 compared with Baseline (P = .007). Based on pooled data from pcTBS and 10 Hz-rTMS, the increased PPTs correlated with increased efficacy of CPM at Day3 (P = .008), while no correlations were found at Day4 or with the intracortical excitability. PERSPECTIVE: Preliminary results of this comparative study did not show stronger pain sensitivity reduction by pcTBS compared with 10 Hz-rTMS to the L-DPFC. Both protocols maintained increased pain thresholds up to 24-hours after the last session, which were partially associated with modulation of CPM efficacy but not with the intracortical excitability changes., (Copyright © 2019 the American Pain Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Several observations would suggest that dystonic pain is not simply muscular in origin. While ascending nociceptive pathways are normal in cervical dystonia, it is unknown whether descending inhibitory pain pathways are also normal., Methods: We applied a conditioned pain modulation protocol and concomitantly recorded laser evoked potentials in patients with cervical dystonia (n = 15), blepharospasm (n = 15) and healthy volunteers (n = 15)., Results: During the application of a heterotopic noxious conditioning stimulation, patients with cervical dystonia, but not with blepharospasm, lacked the physiological reduction of the perceived intensity of a painful test stimulus as well as of the related evoked potential. This was observed in cervical dystonia patients regardless of the presence of clinical pain., Conclusions: Our results suggest that pain in CD is not simply muscular in origin but it also possibly reflects a dysfunction of the descending pain inhibitory control, thus providing a novel venue to explore the pathophysiology of pain in CD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Conditioned pain modulation (CPM) is impaired in people with chronic pain such as knee osteoarthritis (KOA). The purpose of this randomized, controlled clinical trial was to investigate whether strong electroacupuncture (EA) was more effective on chronic pain by strengthening the CPM function than weak EA or sham EA in patients with KOA., Methods: In this multicenter, three-arm parallel, single-blind randomized controlled trial, 301 patients with KOA were randomly assigned. Patients were randomized into three groups based on EA current intensity: strong EA (> 2 mA), weak EA (< 0.5 mA), and sham EA (non-acupoint). Treatments consisted of five sessions per week, for 2 weeks. Primary outcome measures were visual analog scale (VAS), CPM function, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)., Results: Three hundred one patients with KOA were randomly assigned, among which 271 (90.0%) completed the study (mean age 63.93 years old). One week of EA had a clinically important improvement in VAS and WOMAC but not in CPM function. After 2 weeks treatment, EA improved VAS, CPM, and WOMAC compared with baseline. Compared with sham EA, weak EA (3.8; 95% CI 3.45, 4.15; P < .01) and strong EA (13.54; 95% CI 13.23, 13.85; P < .01) were better in improving CPM function. Compared with weak EA, strong EA was better in enhancing CPM function (9.73; 95% CI 9.44, 10.02; P < .01), as well as in reducing VAS and total WOMAC score., Conclusion: EA should be administered for at least 2 weeks to exert a clinically important effect on improving CPM function of KOA patients. Strong EA is better than weak or sham EA in alleviating pain intensity and inhibiting chronic pain., Trial Registration: This study was registered with the Chinese Clinical Trial Registry ( ChiCTR-ICR-14005411 ), registered on 31 October 2014.

Background Context: Although 40% of adolescent idiopathic scoliosis (AIS) patients present with chronic back pain, the pathophysiology and underlying pain mechanisms remain poorly understood. We hypothesized that development of chronic pain syndrome in AIS is associated with alterations in pain modulatory mechanisms., Purpose: To identify the presence of sensitization in nociceptive pathways and to assess the efficacy of the diffuse noxious inhibitory control in patients with AIS presenting with chronic back pain., Study Design: Cross-sectional study., Patient Sample: Ninety-four patients diagnosed with AIS and chronic back pain., Outcome Measures: Quantitative sensory testing (QST) assessed pain modulation and self-reported questionnaires were used to assess pain burden and health-related quality of life., Methods: Patients underwent a detailed pain assessment using a standard and validated quantitative sensory testing (QST) protocol. The measurements included mechanical detection thresholds (MDT), pain pressure threshold (PPT), heat pain threshold (HPT), heat tolerance threshold (HTT), and a conditioned pain modulation (CPM) paradigm. Altogether, these tests measured changes in regulation of the neurophysiology underlying the nociceptive processes based on the patient's pain perception. Funding was provided by The Louise and Alan Edwards Foundation and The Shriners Hospitals for Children., Results: Efficient pain inhibitory response was observed in 51.1% of patients, while 21.3% and 27.7% had sub-optimal and inefficient CPM, respectively. Temporal summation of pain was observed in 11.7% of patients. Significant correlations were observed between deformity severity and pain pressure thresholds (p=.023) and CPM (p=.017), neuropathic pain scores and pain pressure thresholds (p=.015) and temporal summation of pain (p=.047), and heat temperature threshold and pain intensity (p=.048)., Conclusions: Chronic back pain has an impact in the quality of life of adolescents with idiopathic scoliosis. We demonstrated a high prevalence of impaired pain modulation in this group. The association between deformity severity and somatosensory dysfunction may suggest that spinal deformity can be a trigger for abnormal neuroplastic changes in this population contributing to chronic pain syndrome., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To determine if the perceived pain intensity during the application of shock waves (SWs) is a determinant mechanism in producing hypoalgesic changes in pressure pain thresholds (PPTs) in asymptomatic individuals., Design: A randomised, single-blind controlled trial [NCT03455933]., Setting: University., Participants: Sixty-three asymptomatic individuals., Interventions: Participants were randomised into three groups: 1-SWs causing mild pain (SW-DP); 2-SWs generating moderate pain (SW-MP); and 3-cold pressor test (CPT)., Main Outcome Measurements: Before and after the intervention, the PPT was evaluated bilaterally at the following points: lateral epicondyle, median nerve in the flexure of the elbow, and tibia., Results: The results showed differences between various groups over time for all PPTs assessments, due to the existence of statistically significant differences in the interaction group x times (dominant arm lateral epicondyle [P < 0.001; η 2 p = 0.255]; dominant arm median nerve [P = 0.001; η 2 p = 0.212]; nondominant arm lateral epicondyle [P < 0.001; η 2 p = 0.275]; nondominant arm median nerve [P < 0.001; η 2 p = 0.268]; tibia [P = 0.012, η 2 p = 0.138]). The SW-MP group obtained a significant increase in all the PPT evaluations compared with the SW-DP group (d > 0.80). The CPT group only showed significantly higher results, and of high magnitude (d > 0.80), regarding the SW-DP group for the PPT evaluation in the dominant member. The SW-MP group showed differences compared with the CPT only for the PPT obtained in the nondominant arm., Conclusions: The findings show that SW treatment generates a hypoalgesic effect on the application point, with moderate pain. Further studies are necessary in order to link these hypoalgesic changes to the activation of the descending inhibitory systems., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Heterotopic conditioned pain modulation (CPM) has provided potentially useful clinical information such as response to medication in neuropathic pain or the prediction of pain after surgical procedures. Despite these advances, several methodological aspects of CPM remain to be determined, such as the impact of the conditioning stimulus (CS) type upon CPM, if its evoked-pain intensity is controlled for [measured on a visual analogue scale (VAS: 0-100mm)]., Objectives: To explore potential differential effects of CPM using three distinct CS (having similar evoked-pain intensity) in the same individuals., Methods: We conducted a cross-over randomized study in healthy volunteers (HV) and looked-for differences in the CPM effect evoked by three differing CS [cuff-pressure pain stimulation (CuPS), cold pressor test (CoPT), and thermode-based cold painful stimulation (TCPS)] on the same test stimulus [(TS)-supra-threshold heat pain stimulation with a contact-heat thermode). CPM was calculated as a ratio: [conditioned TS VAS - unconditioned TS VAS]/[unconditioned TS VAS]. Importantly, the range of pain evoked by the unconditioned-TS and by the CS was controlled for. Also, the unpleasantness evoked by the CS [visual analogue scale (VAS: 0-100mm)] was measured before the initiation of the conditioned-TS., Results: Pain intensity VAS of the three unconditioned-TSs were similar between the three sessions. CPM was significantly different between the three types of CS (CoPT=-0.43±0.29; CuPS=-0.25±0.24; and TCPS=-0.23±0.35; P=.005): CoPT induced significantly more robust CPM compared to CuPS (P=.004) and TCPS (P=.005)., Conclusions: Significantly different intensities of CPM can be evoked on the same individual according to the nature of the CS, even when controlling for the intensity of the unconditioned-TS, and the pain evoked by the CS. This may have implications for the design of future recommendations and may impact the translation of CPM from the laboratory to clinical practice., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Diffuse noxious inhibitory control (DNIC), which involves endogenous pain modulation, has been investigated as a potential mechanism for the differences in pain modulation observed between men and women, though the literature shows contradictory findings. We used a capsaicin-induced DNIC behavioral assay and resting state functional magnetic resonance imaging (rsfMRI) to assess the effect of testosterone on pain modulation and related brain circuitry in rats. We hypothesized that testosterone is required for DNIC that leads to efficient pain inhibition by increasing descending pain modulation. Male, female, and orchidectomized (GDX) male rats had a capsaicin injection into the forepaw to induce DNIC and mechanical thresholds were observed on the hindpaw. rsfMRI scans were acquired before and after capsaicin injection to analyze the effects of DNIC on periaqueductal gray (PAG), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) connectivity to the whole brain. The strength of DNIC was higher in males compared to females and GDX males. PAG connectivity with prelimbic cortex (PrL), ACC and insula was stronger in males compared to females and GDX males, whereas females and GDX males had increased connectivity between the right ACC, hippocampus and thalamus. GDX males also showed a stronger connectivity between right ACC and NAc, and right NAc with PrL, ACC, insula and thalamus. Our findings suggest that testosterone plays a key role in reinforcing the endogenous pain inhibitory system, while circuitries related to reward and emotion are more strongly recruited in the absence of testosterone., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

To study the characteristics of temporal summation (TS) and conditioned pain modulation (CPM) in fibromyalgia (FM) patients, we systematically searched Pubmed and EMBASE for studies using TS or CPM comparing FM patients with healthy controls. We computed Hedges' g, risk of bias, sensitivity analysis, and meta-regression tests with 10,000 Monte-Carlo permutations. Twenty-three studies (625 female and 23 male FM patients and 591 female and 81 male healthy controls) were included. The meta-analyses showed an effect size of .53 for TS (P < .001; 95% confidence interval = .23-.83), which is a 68% relative difference between patients and controls, and of .57 for CPM (P < .001; 95% confidence interval = -.88 to -.26), representing a 65% relative difference between the groups. The qualitative analyses revealed large heterogeneity between study protocols. Although studies were of low risk of bias, lack of blinding was substantial. Sensitivity analysis and meta-regression identified type and site of stimulation, age, lab, sample size, and medication control as important sources of between-study variability. We showed a significant alteration of pain modulation mechanisms in FM patients., Perspective: This novel meta-analysis provides evidence for defective endogenous pain modulation in FM patients. We explored the effect of covariates on between-study variability in these paradigms. These biomarkers may aid in diagnosis, and treatment of patients. However, validation requires further investigation under strict methodological settings, and into individual patient covariates., (Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.)

Accumulating evidence reveal important applications of endogenous pain modulation assessment in healthy controls and in patients in clinical settings, as dysregulations in the balance of pain modulatory circuits may facilitate pain and promote chronification of pain. This article reviews data on pain modulation, focusing on the mechanisms and translational aspects of pain modulation from conditioned pain modulation (CPM) to placebo and nocebo effects in experimental and clinical pain. The specific roles of expectations, learning, neural and neurophysiological mechanisms of the central nervous system are briefly reviewed herein. The interaction between CPM and placebo systems in pain inhibitory pathways is highly relevant in the clinic and in randomized controlled trials yet remains to be clarified. Examples of clinical implications of CPM and its relationship to placebo and nocebo effects are provided. A greater understanding of the role of pain modulation in various pain states can help characterize the manifestation and development of chronic pain and assist in predicting the response to pain-relieving treatments. Placebo and nocebo effects, intrinsic to every treatment, can be used to develop personalized therapeutic approaches that improve clinical outcomes while limiting unwanted effects., (© 2018 Elsevier Inc. All rights reserved.)

Conditioned pain modulation (CPM) is a powerful endogenous analgesic mechanism which can completely inhibit incoming nociceptor signals at the primary synapse. The circuitry responsible for CPM lies within the brainstem and involves the subnucleus reticularis dorsalis (SRD). While the brainstem is critical for CPM, the cortex can significantly modulate its expression, likely via the brainstem circuitry critical for CPM. Since higher cortical regions such as the anterior, mid-cingulate, and dorsolateral prefrontal cortices are activated by noxious stimuli and show reduced activations during other analgesic responses, we hypothesized that these regions would display reduced responses during CPM analgesia. Furthermore, we hypothesized that functional connectivity strength between these cortical regions and the SRD would be stronger in those that express CPM analgesia compared with those that do not. We used functional magnetic resonance imaging to determine sites recruited during CPM expression and their influence on the SRD. A lack of CPM analgesia was associated with greater signal intensity increases during each test stimulus in the presence of the conditioning stimulus compared to test stimuli alone in the mid-cingulate and dorsolateral prefrontal cortices and increased functional connectivity with the SRD. In contrast, those subjects exhibiting CPM analgesia showed no change in the magnitude of signal intensity increases in these cortical regions or strength of functional connectivity with the SRD. These data suggest that during multiple or widespread painful stimuli, engagement of the prefrontal and cingulate cortices prevents the generation of CPM analgesia, raising the possibility altered responsiveness in these cortical regions underlie the reduced CPM observed in individuals with chronic pain. Hum Brain Mapp 37:2630-2644, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Conditioned pain modulation (CPM) is believed to play an important role in the development and exacerbation of chronic pain, because dysfunction of CPM is associated with a shift in balance between pain facilitation and pain inhibition. In many patients with central sensitization, CPM is less efficacious. Besides that, efficacy of CPM is highly variable in healthy people. Consequently, it seems that several individual variables may influence CPM. A systematic review examining personal factors influencing CPM was conducted., Methods: This systematic review follows the PRISMA guidelines. "Pubmed" and "Web of Science" were searched using different synonyms of CPM. Full-text clinical reports addressing the influence of personal factors on CPM in healthy adults were included. Checklists for RCTs and case-control studies provided by the Dutch Institute for Healthcare Improvement (CBO) and the Dutch Cochrane Centre were utilized to assess methodological quality. Levels of evidence and strength of conclusion were assigned using the CBO guidelines., Results: Forty-six articles were identified that reported the influence of personal factors on CPM. Quality assessment revealed 10 studies with a methodological quality less than 50% wherefore they were excluded (21.8%), resulting in a general total methodological quality score of 72.5%. Overall younger adult age, male gender, ovulatory phase, positive expectations, attention to the conditioning stimulus, and carrier of the 5-HTTLPR long allele result in better CPM., Conclusion: It is advised for future studies to take these factors into account. Further research regarding the influence of oral contraceptives, catastrophizing, information about conditioning stimulation, distraction, physical activity, and genetics on CPM magnitude is required., (© 2015 World Institute of Pain.)

Study Design: An experimental laboratory study with a repeated-measures crossover design., Background: Treatment effects of joint mobilization may occur in part by decreasing excitability of central nociceptive pathways. Impaired conditioned pain modulation (CPM) has been found experimentally in persons with knee and hip osteoarthritis, indicating impaired inhibition of central nociceptive pathways. We hypothesized increased effectiveness of CPM following application of joint mobilization, determined via measures of deep tissue hyperalgesia., Objective: To examine the effect of joint mobilization on impaired CPM., Methods: An examination of 40 individuals with moderate/severe knee osteoarthritis identified 29 (73%) with impaired CPM. The subjects were randomized to receive 6 minutes of knee joint mobilization (intervention) or manual cutaneous input only, 1 week apart. Deep tissue hyperalgesia was examined via pressure pain thresholds bilaterally at the knee medial joint line and the hand at baseline, postintervention, and post-CPM testing. Further, vibration perception threshold was measured at the medial knee epicondyle at baseline and post-CPM testing., Results: Joint mobilization, but not cutaneous input intervention, resulted in a global increase in pressure pain threshold, indicated by diminished hyperalgesic responses to pressure stimulus. Further, CPM was significantly enhanced following joint mobilization. Diminished baseline vibration perception threshold acuity was enhanced following joint mobilization at the knee that received intervention, but not at the contralateral knee. Resting pain was also significantly lower following the joint intervention., Conclusion: Conditioned pain modulation was enhanced following joint mobilization, demonstrated by a global decrease in deep tissue pressure sensitivity. Joint mobilization may act via enhancement of descending pain mechanisms in patients with painful knee osteoarthritis.

The aim of the this study was to investigate the combined effects of heterosegmental non-noxious and noxious stimulation on electrically induced tooth pain. The late component of somatosensory-evoked potentials (SEP), induced by electrical tooth stimulation and pain intensity, were examined under electrical stimulation to forearms. Noxious, non-noxious, and combined non-noxious and noxious electrical stimulation were applied to median nerves on the forearms. Four experimental sessions (ie, control session, combined non-noxious and noxious stimulation session, non-noxious stimulation session, and noxious stimulation session were performed for each subject at each 10-minute interval for 30 minutes. The amplitudes of the SEP and VAS scores in the combined stimulation session decreased significantly compared with those in the control session and the reduction rates were 51.1% (13.4 μV) and 41.0% (23.5 mm), respectively. These results show that the combined stimulation has a more potent analgesic effect than that of either the non-noxious or the noxious stimulation. It is suggested that a potent analgesia was produced by an activated central mechanism, including endogenous opioid and descending pain inhibitory systems due to combined non-noxious and noxious stimulation., (© 2014 World Institute of Pain.)

Conditioned pain modulation is a powerful analgesic mechanism, occurring when a painful stimulus is inhibited by a second painful stimulus delivered at a different body location. Reduced conditioned pain modulation capacity is associated with the development of some chronic pain conditions and the effectiveness of some analgesic medications. Human lesion studies show that the circuitry responsible for conditioned pain modulation lies within the caudal brainstem, although the precise nuclei in humans remain unknown. We employed brain imaging to determine brainstem sites responsible for conditioned pain modulation in 54 healthy individuals. In all subjects, 8 noxious heat stimuli (test stimuli) were applied to the right side of the mouth and brain activity measured using functional magnetic resonance imaging. This paradigm was then repeated. However, following the fourth noxious stimulus, a separate noxious stimulus, consisting of an intramuscular injection of hypertonic saline into the leg, was delivered (conditioning stimulus). During this test and conditioning stimulus period, 23 subjects displayed conditioned pain modulation analgesia whereas 31 subjects did not. An individual's analgesic ability was not influenced by gender, pain intensity levels of the test or conditioning stimuli or by psychological variables such as pain catastrophizing or fear of pain. Brain images were processed using SPM8 and the brainstem isolated using the SUIT toolbox. Significant increases in signal intensity were determined during each test stimulus and compared between subjects that did and did not display CPM analgesia (p<0.05, small volume correction). The expression of analgesia was associated with reduction in signal intensity increases during each test stimulus in the presence of the conditioning stimulus in three brainstem regions: the caudalis subdivision of the spinal trigeminal nucleus, i.e., the primary synapse, the region of the subnucleus reticularis dorsalis and in the dorsolateral pons in the region of the parabrachial nucleus. Furthermore, the magnitudes of these signal reductions in all three brainstem regions were significantly correlated to analgesia magnitude. Defining conditioned pain modulation circuitry provides a framework for the future investigations into the neural mechanisms responsible for the maintenance of persistent pain conditions thought to involve altered analgesic circuitry., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Unlabelled: The purpose of this investigation was to identify modifiable risk factors for the development of first-onset chronic neck pain among an inception cohort of healthy individuals working in a high-risk occupation. Candidate risk factors identified from previous studies were categorized into psychosocial, physical, and neurophysiological domains, which were assessed concurrently in a baseline evaluation of 171 office workers within the first 3 months of hire. Participants completed monthly online surveys over the subsequent year to identify the presence of chronic interfering neck pain, defined as a Neck Disability Index score ≥5 points for 3 or more months. Data were analyzed using backward logistic regression to identify significant predictors within each domain, which were then entered into a multivariate regression model adjusted for age, sex, and body mass index. Development of chronic interfering neck pain was predicted by depressed mood (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 1.10-10.31, P = .03), cervical extensor endurance (OR = .92, 95% CI, .87-.97, P = .001), and diffuse noxious inhibitory control (OR = .90, 95% CI, .83-.98, P = .02) at baseline. These findings provide the first evidence that individuals with preexisting impairments in mood and descending pain modulation may be at greater risk for developing chronic neck pain when exposed to peripheral nociceptive stimuli such as that produced during muscle fatigue., Perspective: Depressed mood, poor muscle endurance, and impaired endogenous pain inhibition are predisposing factors for the development of new-onset chronic neck pain of nonspecific origin in office workers. These findings may assist with primary prevention by allowing clinicians to screen for individuals at risk of developing chronic neck pain., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objective: Pain facilitation as well as pain inhibition might be present in chronic pain patients. A decreased efficacy of pain inhibition can be measured by conditioned pain modulation (CPM). The use of the CPM paradigm in scientific research has boosted over the last few years and is recognized for its high clinical relevance in chronic pain patients. It is, however, unclear whether the presence of pain and possible modulations of pain influences the efficacy of endogenous pain inhibition, measured by CPM. This systematic literature study aimed to provide an overview of the effects of clinical pain and experimental pain induction or pain reduction on CPM in adults., Methods: A systematic literature search was conducted in the databases "Pubmed" and "Web of Science". Only full texts of original studies regarding the effect of clinical pain and experimentally induced pain and pain reduction on CPM in adults were included. The included articles were scored on methodological quality and through a CPM paradigm., Results: Twelve articles of good to moderate quality were included in this review. Some pain inhibitory medication and oral contraceptives inhibit the CPM mechanism. Removing chronic pain by surgery results in an improved CPM response. This effect is not observed when removing acute pain., Conclusion: Analgesic medication and oral contraceptives might inhibit the CPM response, whereas there is limited evidence that pain-relieving surgery improves CPM in chronic pain patients. However, the results merely suggest that decreased CPM values (as in chronic pain patients) can improve after elimination of pain., (© 2014 World Institute of Pain.)

Human studies have shown that heterotopic nociceptive conditioning stimulation (HNCS) applied to a given body location reduces the percept and brain responses elicited by noxious test stimuli delivered at a remote body location. It remains unclear to what extent this effect of HNCS relies on the spinal-bulbar-spinal loop mediating the effect of diffuse noxious inhibitory controls (DNICs) described in animals, and/or on top-down cortical mechanisms modulating nociception. Importantly, some studies have examined the effects of HNCS on the brain responses to nociceptive input conveyed by Aδ-fibres. In contrast, no studies have explored the effects of HNCS on the responses to selective nociceptive C-fibre input and non-nociceptive Aβ-fibre input. In this study, we measured the intensity of perception and event-related potentials (ERPs) to stimuli activating Aδ-, C- and Aβ-fibres, before, during and after HNCS, obtained by immersing one foot in painful cold water. We observed that (i) the perceived intensity of nociceptive Aδ- and C-stimuli was reduced during HNCS, and (ii) the ERPs elicited by Aδ- and Aβ- and C-stimuli were also reduced during HNCS. Importantly, because Aβ-ERPs are related to primary afferents that ascend directly through the dorsal columns without being relayed at spinal level, the modulation of these responses may not be explained by an influence of descending projections modulating the transmission of nociceptive input at spinal level. Therefore, our results indicate that, in humans, HNCS should be used with caution as a direct measure of DNIC-related mechanisms., (© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Race and ethnicity shape the experience of pain in adults. African Americans typically exhibit greater pain intensity and evoked pain responsiveness than non-Hispanic whites. However, it remains unclear whether there are racial differences in conditioned pain modulation (CPM) and if these are present in youth. CPM refers to a reduction in perceived pain intensity for a test stimulus during application of a conditioning stimulus and may be especially relevant in determining risk for chronic pain. The present study assessed CPM to evoked thermal pain in 78 healthy youth (ages 10-17 years), 51% of whom were African American and 49% of whom were non-Hispanic white. African American youth reported lower mean conditioning pain ratings than non-Hispanic white youth, controlling for mean preconditioning pain ratings, which is consistent with stronger CPM. Multilevel models demonstrated stronger CPM effects in African American than non-Hispanic white youth, as evident in more rapid within-person decreases in pain ratings during the conditioning phase. These findings suggest that diminished CPM likely does not account for the enhanced responsiveness to evoked thermal pain observed in African American youth. These results may have implications for understanding racial differences in chronic pain experienced in adulthood. Perspective: This study evaluated conditioned pain modulation to evoked thermal pain in African American and non-Hispanic white youth. Findings could have implications for the development of personalized chronic pain treatment strategies that are informed by race and ethnicity., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess the effects of nonpharmacologic approaches to pain relief during labor, according to their endogenous mechanism of action, on obstetric interventions, maternal, and neonatal outcomes., Data Source: Cochrane library, Medline, Embase, CINAHL and the MRCT databases were used to screen studies from January 1990 to December 2012., Study Selection: According to Cochrane criteria, we selected randomized controlled trials that compared nonpharmacologic approaches for pain relief during labor to usual care, using intention-to-treat method., Results: Nonpharmacologic approaches, based on Gate Control (water immersion, massage, ambulation, positions) and Diffuse Noxious Inhibitory Control (acupressure, acupuncture, electrical stimulation, water injections), are associated with a reduction in epidural analgesia and a higher maternal satisfaction with childbirth. When compared with nonpharmacologic approaches based on Central Nervous System Control (education, attention deviation, support), usual care is associated with increased odds of epidural OR 1.13 (95% CI 1.05-1.23), cesarean delivery OR 1.60 (95% CI 1.18-2.18), instrumental delivery OR 1.21 (95% CI 1.03-1.44), use of oxytocin OR 1.20 (95% CI 1.01-1.43), labor duration (29.7 min, 95% CI 4.5-54.8), and a lesser satisfaction with childbirth. Tailored nonpharmacologic approaches, based on continuous support, were the most effective for reducing obstetric interventions., Conclusion: Nonpharmacologic approaches to relieve pain during labor, when used as a part of hospital pain relief strategies, provide significant benefits to women and their infants without causing additional harm., (© 2014 Wiley Periodicals, Inc.)

Diffuse noxious inhibitory controls (DNIC) are very powerful long-lasting descending inhibitory controls which are pivotal in modulating the activity of spinal and trigeminal nociceptive neurons. DNIC are subserved by a loop involving supraspinal structures such as the lateral parabrachial nucleus and the subnucleus reticularis dorsalis. Surprisingly, though, whether the nucleus raphe magnus (NRM), another supraspinal area which is long known to be important in pain modulation, is involved in DNIC is still a matter of discussion. Here, we reassessed the role of the NRM neurons in DNIC by electrophysiologically recording from wide dynamic range (WDR) neurons in the trigeminal subnucleus oralis and pharmacologically manipulating the NRM OFF- and ON-cells. In control conditions, C-fiber-evoked responses in trigeminal WDR neurons are inhibited by a conditioning noxious heat stimulation applied to the hindpaw. We show that inactivating the NRM by microinjecting the GABAA receptor agonist, muscimol, both facilitates C-fiber-evoked responses of trigeminal WDR neurons and strongly attenuates their inhibition by heat applied to the hindpaw. Interestingly, selective blockade of ON-cells by microinjecting the broad-spectrum excitatory amino acid antagonist, kynurenate, into the NRM neither affects C-fiber-evoked responses nor attenuates DNIC of trigeminal WDR neurons. These results indicate that the NRM tonically inhibits trigeminal nociceptive inputs and is involved in the neuronal network underlying DNIC. Moreover, within NRM, OFF-cells might be more specifically involved in both the tonic and phasic descending inhibitory controls of trigeminal nociception., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Multiple studies have demonstrated that in healthy subjects, painful stimuli applied to one part of the body inhibit pain sensation in other parts of the body, a phenomenon referred to as conditioned pain modulation. Conditioned pain modulation is related to the presence of endogenous pain control systems. Studies have demonstrated deficits in conditioned pain modulation associated inhibition in many but not all chronic pain disorders. In this study we determine whether conditioned pain modulation is altered in subjects with interstitial cystitis/bladder pain syndrome., Materials and Methods: Female subjects with and without the diagnosis of interstitial cystitis/bladder pain syndrome were studied psychophysically using quantitative cutaneous thermal, forearm ischemia and ice water immersion tests. Conditioned pain modulation was assessed by quantifying the effects of immersion of the hand in ice water (conditioning stimulus) on threshold and tolerance of cutaneous heat pain (test stimulus) applied to the contralateral lower extremity., Results: The conditioned pain modulation responses of the subjects with interstitial cystitis/bladder pain syndrome were statistically different from those of healthy control subjects for cutaneous thermal threshold and tolerance measures. Healthy control subjects demonstrated statistically significant increases in thermal pain tolerance whereas subjects with the diagnosis of interstitial cystitis/bladder pain syndrome demonstrated statistically significant reductions in thermal pain tolerance., Conclusions: An endogenous pain inhibitory system normally observed with conditioned pain modulation was altered in subjects with interstitial cystitis/bladder pain syndrome. This finding identifies interstitial cystitis/bladder pain syndrome as similar to several other chronic pain disorders such as fibromyalgia and irritable bowel syndrome, and suggests that a deficit in endogenous pain inhibitory systems may contribute to such chronic pain disorders., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Conditioned pain modulation (CPM) is a phenomenon of 'pain inhibiting pain' that is important for understanding idiopathic pain syndromes. Because the pathophysiology of posttraumatic cold intolerance is still unknown but it could involve similar mechanisms as idiopathic pain syndromes, we evaluated the functioning of the CPM system in patients with posttraumatic cold intolerance compared to healthy controls., Methods: Fourteen healthy controls and 24 patients diagnosed with cold intolerance using the Cold Intolerance Symptom Severity questionnaire were included in the study. Of the 24 patients with cold intolerance, 11 had a nerve lesion and 13 an amputation of one or more digits. To quantify the CPM, pain threshold for mechanical pressure was measured at the affected region as a baseline measure. Then, the contralateral hand received a cold stimulus of ice water to evoke the noxious conditioning. After the cold stimulus, the pain threshold for mechanical pressure was determined again., Results: The absolute and relative changes in algometer pressure (CPM effect) between pre- and post-conditioning were significantly smaller in the cold intolerance group compared to the control group (absolute p = 0.019, relative p = 0.004). The CPM effect was significantly different between the control group and the subgroups of nerve lesion (p = 0.003) and amputation patients (p = 0.011)., Conclusions: In this study, we found a CPM effect after a cold stimulus in both controls and patients. A significant weaker CPM effect compared to the controls was found, as in other chronic pain conditions. The CPM system within patients with cold intolerance is altered., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

The pathogenesis of medication overuse headache is unclear. Clinical and preclinical studies have consistently demonstrated increased excitability of neurons in the cerebral cortex and trigeminal system after medication overuse. Cortical hyperexcitability may facilitate the development of cortical spreading depression, while increased excitability of trigeminal neurons may facilitate the process of peripheral and central sensitization. These changes may be secondary to the derangement of central, probably serotonin (5-HT)-, and perhaps endocannabinoid-dependent or other, modulating systems. Increased expression of excitatory cortical 5-HT2A receptors may increase the susceptibility to developing cortical spreading depression, an analog of migraine aura. A reduction of diffuse noxious inhibitory controls may facilitate the process of central sensitization, activate the nociceptive facilitating system, or promote similar molecular mechanisms to those involved in kindling. Low 5-HT levels also increase the expression and release of calcitonin gene-related peptide from the trigeminal ganglion and sensitize trigeminal nociceptors. Thus, derangement of central modulation of the trigeminal system as a result of chronic medication use may increase sensitivity to pain perception and foster or reinforce medication overuse headache., (© 2013 American Headache Society.)

This paper reports on the neurophysiology of the esophagus, including on the uneven distribution of innervation in the esophagus, reflected by the increased sensitivity and perception of gastroesophageal reflux disease (GERD) events in the proximal rather than distal esophagus; the role of the enteric nervous system (ENS) in swallowing; the role of the physiological stress-responsive systems, including the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis in mediating esophageal pain; the advances in understanding pain mechanisms and brain structure provided by technological imaging advances; investigations into the efficacy of the descending-pain control system, including diffuse noxious inhibitory control (DNIC); the role of abnormal nervous signaling in afferent pathways in the pathogenesis of Barrett's esophagus (BE); and the contribution of the esophageal mucosa to reflux symptoms., (© 2013 New York Academy of Sciences.)

Objective: To assess the decay of the conditioned pain modulation (CPM) response along repeated applications as a possible expression of subtle pronociception in migraine., Background: One of the most explored mechanisms underlying the pain modulation system is "diffuse noxious inhibitory controls," which is measured psychophysically in the lab by the CPM paradigm. There are contradicting reports on CPM response in migraine, questioning whether migraineurs express pronociceptive pain modulation., Methods: Migraineurs (n = 26) and healthy controls (n = 35), all females, underwent 3 stimulation series, consisting of repeated (1) "test-stimulus" (Ts) alone that was given first followed by (2) parallel CPM application (CPM-parallel), and (3) sequential CPM application (CPM-sequential), in which the Ts is delivered during or following the conditioning-stimulus, respectively. In all series, the Ts repeated 4 times (0-3). In the CPM series, repetition "0" consisted of the Ts-alone that was followed by 3 repetitions of the Ts with a conditioning-stimulus application., Results: Although there was no difference between migraineurs and controls for the first CPM response in each series, we found waning of CPM-parallel efficiency along the series for migraineurs (P = .005 for third vs first CPM), but not for controls. Further, greater CPM waning in the CPM-sequential series was correlated with less reported extent of pain reduction by episodic medication (r = 0.493, P = .028)., Conclusions: Migraineurs have subtle deficits in endogenous pain modulation which requires a more challenging test protocol than the commonly used single CPM. Waning of CPM response seems to reveal this pronociceptive state. The clinical relevance of the CPM waning effect is highlighted by its association with clinical parameters of migraine., (© 2013 American Headache Society.)

Background: Descending inhibition of pain, part of the endogenous pain modulation system, is important for normal pain processing. Dysfunction is associated with various chronic pain states. Here, the effect of ketamine and morphine on descending inhibition is examined using the conditioned pain modulation (CPM) paradigm in chronic neuropathic pain patients., Methods: CPM responses were obtained in 10 adult neuropathic pain subjects (two men/eight women). All subjects had peripheral neuropathy as defined by abnormal quantitative sensory testing. The effects of S(+)-ketamine (0.57 mg kg(-1) h(-1) for 1 h) and morphine (0.065 mg kg(-1) h(-1) for 1 h) were tested in a randomized, placebo-controlled double-blind study. CPM was measured at baseline and 100 min after the start of treatment and was induced by immersion of the leg into a cold-water bath. The test stimulus was a 30 s static thermal stimulus to the skin of the forearm., Results: Without treatment, no CPM was detectable. Treatment with ketamine, morphine, and placebo produced CPM responses of 40.2 (10.9)%, 28.5 (7.0)%, and 22.1 (12.0)%, respectively (for all treatments, CPM effect P<0.05), with no statistical difference in the magnitude of CPM among treatments. The magnitude of CPM correlated positively with the magnitude and duration of spontaneous pain relief., Conclusions: The observed treatment effects in chronic pain patients suggest a role for CPM engagement in analgesic efficacy of ketamine, morphine, and placebo treatment.