Thicker Posterior Insula Is Associated With Disease Duration in Women With Irritable Bowel Syndrome (IBS) Whereas Thicker Orbitofrontal Cortex Predicts Reduced Pain Inhibition in Both IBS Patients and Controls

Patients with irritable bowel syndrome (IBS) are affected by chronic abdominal pain and show decreased pain inhibition. Moreover, they exhibit differences in brain morphology compared with healthy volunteers. The aim of this study was to examine whether decreased pain inhibition is associated with altered brain morphology in IBS patients. Structural magnetic resonance imaging scans were acquired in 14 female patients with diarrhea-predominant IBS and 14 controls. Pain and anxiety modulation were characterized using electrical stimulation of the sural nerve and heterotopic noxious counterstimulation. IBS patients reported decreased pain inhibition (P = .02) as well as increased shock anxiety, pain catastrophizing, depressive symptoms, and trait anxiety (P's ≤ .05). IBS patients also showed a thicker right posterior insula (pINS), associated with longer IBS duration (r = .67, P = .02). In addition, thicker right lateral orbitofrontal cortex was strongly associated with less pain inhibition in both IBS patients (r = .70, P = .02) and controls (r = .68, P = .01). Results are consistent with the role of the insula in interoception and pain and suggest that IBS may induce thickening of the pINS. Reduced pain inhibition may further involve a modification of the regulatory influence of the orbitofrontal cortex on pain-related processes.     

Defective Endogenous Pain Modulation in Fibromyalgia: A Meta-Analysis of Temporal Summation and Conditioned Pain Modulation Paradigms

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.

Analysis of Meaningful Conditioned Pain Modulation Effect in a Pain-Free Adult Population

Conditioned pain modulation (CPM) encompasses the effects of inhibitory and facilitatory pain modulatory systems and is inefficient in some chronic pain states. A proportion of healthy subjects also exhibit little or no CPM, perhaps suggesting that inherent factors such as gender or genetics may be influential. However, there is no consensus on how best to determine a meaningful CPM effect. This study aimed to determine the proportion of pain-free subjects exhibiting a meaningful CPM effect. Analyses of associations between 5HTTLPR (serotonin transporter-linked polymorphic region) polymorphisms on the serotonin transporter gene (SLC6A4), gender, and CPM effect were also carried out. A total of 125 healthy subjects (47 male; 78 female) underwent pressure pain threshold testing before, during, and after a cold pressor conditioning stimulus. A buccal cell sample was collected for analysis of 5HTTLPR genotype. Meaningful CPM effect was determined as an increase in pressure pain threshold values from baseline greater than the inherent error of measurement, calculated as 5.3%. During the conditioning stimulus, 116 subjects (92.8%) exhibited a CPM effect whereas 9 did not. CPM effect did not differ significantly between genders or between 5HTTLPR genotypes. This provides a clear basis on which to determine the proportion of patients with a chronic pain disorder that exhibit a meaningful CPM effect.PerspectiveThis study proposes a method for calculating meaningful CPM effect and reports the proportion and magnitude of effect elicited in a large sample. Associations between CPM, gender, and genotype were also analyzed. Clarification of normal CPM response may help to elucidate the mechanisms driving CPM inefficiency in chronic pain.     

Pain Adaptability in Individuals With Chronic Musculoskeletal Pain Is Not Associated With Conditioned Pain Modulation

Healthy humans can be divided into the pain adaptive (PA) and the pain nonadaptive (PNA) groups; PA showed a greater decrease in pain rating to a cold pressor test (CPT) than PNA. This study examined if the dichotomy of pain adaptability existed in individuals with chronic musculoskeletal pain. CPTs at 2°C and 7°C were used to assess the status of pain adaptability in participants with either chronic nonspecific low back pain or knee osteoarthritis. The participants' potency of conditioned pain modulation (CPM) and local inhibition were measured. The strengths of pain adaptability at both CPTs were highly correlated. PA and PNA did not differ in their demographic characteristics, pain thresholds from thermal and pressure stimuli, or potency of local inhibition or CPM. PA reached their maximum pain faster than PNA (t₄₁ = ?2.76, P?<?.01), and had a gradual reduction of pain unpleasantness over 7 days whereas PNA did not (F_6,246?=?3.01, P?=?.01). The dichotomy of pain adaptability exists in musculoskeletal pain patients. Consistent with the healthy human study, the strength of pain adaptability and potency of CPM are not related. Pain adaptability could be another form of endogenous pain inhibition of which clinical implication is yet to be understood.

Patients with Chronic Pain After Abdominal Surgery Show Less Preoperative Endogenous Pain Inhibition and More Postoperative Hyperalgesia: A Pilot Study

ABSTRACT

Chronic pain is common and undesirable after surgery. Progression from acute to chronic pain involves altered pain processing. The authors studied relationships between presence of chronic pain versus preoperative descending pain control (diffuse noxious inhibitory controls; DNICs) and postoperative persistence and spread of skin and deep tissue hyperalgesia (change in electric/pressure pain tolerance thresholds; ePTT/pPTT) up to 6 months postoperatively. In 20 patients undergoing elective major abdominal surgery under standardized anesthesia, we determined ePTT/pPTT (close to [abdomen] and distant from [leg] incision), eDNIC/pDNIC (change in ePTT/pPTT with cold pressor pain task; only preoperatively), and a 100 mm long pain visual analogue scale (VAS) (0 mm = no pain, 100 mm = worst pain imaginable), both at rest and on movement preoperatively, and 1 day and 1, 3, and 6 months postoperatively. Patients reporting chronic pain 6 months postoperatively had more abdominal and leg skin hyperalgesia over the postoperative period. More inhibitory preoperative eDNIC was associated with less late postoperative pain, without affecting skin hyperalgesia. More inhibitory pDNIC was linked to less postoperative leg deep tissue hyperalgesia, without affecting pain VAS. This pilot study for the first time links chronic pain after surgery, poorer preoperative inhibitory pain modulation (DNIC), and greater postoperative degree, persistence, and spread of hyperalgesia. If confirmed, these results support the potential clinical utility of perioperative pain processing testing.     

Chronic Pain and Surgery: A Review of New Insights from Sensory Testing

ABSTRACT

Chronic pain is increasingly recognized as an undesirable outcome after surgery. Predicting risk of postoperative chronic pain, as well as chronic pain prevention or treatment, requires understanding of the processes underlying its development. Quantitative sensory testing research over the last decade has made it possible to start understanding the alterations in central pain processing associated with chronic pain and its development. Chronic pain syndromes are typically characterized by a pronociceptive state of pain processing, e.g., generalized hyperalgesia as a sign of supraspinal central sensitization and poor inhibitory or even facilitatory descending modulation. In the perioperative context, development and progression of chronic pain are accompanied by signs congruent with a shift towards a pronociceptive state. Preoperatively, hyperalgesia and poor descending inhibitory modulation appear to increase the risk of subsequent chronic pain. Postoperatively, abnormal persistence and spread of hyperalgesia, compatible with rostral neuraxial spread of central sensitization, are increasingly linked to the development and progression of chronic pain. These findings, which need further confirmation, suggest that perioperative quantitative sensory testing of pain sensitivity and pain modulation has the potential to become a valuable clinical tool for assessing risk of chronic pain development and for managing its prevention and treatment.     

DRD3 Ser9Gly Polymorphism Is Related to Thermal Pain Perception and Modulation in Chronic Widespread Pain Patients and Healthy Controls

Experimental studies showed that dopamine influences pain perception in healthy volunteers. Dopamine dysfunctions have been linked to the physiopathology of fibromyalgia (FM), which is associated with hyperalgesia and deficient pain inhibition. We sought to investigate the relationships between catecholamine-related polymorphisms [dopamine-D₃ receptor (DRD3) Ser9Gly and catechol-O-methyltransferase (COMT) Val158Met] and thermal pain measures in healthy subjects and FM patients. Seventy-three subjects (37 FM patients and 36 controls) participated in this study. Thermal pain thresholds (TPTs) were measured using a Peltier thermode. Inhibitory systems were elicited using a thermal tonic pain stimulation administered before and after activation of the diffuse noxious inhibitory controls (DNIC) by means of a cold-pressor test. Genetic analyses were performed using polymerase chain reaction. Regression analyses were performed across and within groups. FM was associated with lower TPTs and deficient pain inhibition. DRD3 Ser9Gly polymorphism predicted (1) DNIC efficacy across groups and (2) thermal TPTs in FM patients. COMT Val158Met and thermal pain measures were not related. These preliminary results suggest that the DRD3 Ser9Gly polymorphism influences DNIC efficacy and TPTs and that this latter relationship is present only in FM patients. Two core psychophysical features of FM appear to be significantly influenced by limbic dopamine functioning.

Perspective

This experimental study is the first to relate DNIC and TPTs to a functional polymorphism of limbic dopamine-D3 receptors. As lowered pain thresholds and deficient pain inhibition are 2 core features of fibromyalgia, these preliminary results may help identify a subgroup of FM patients who require closer medical attention.     

Temporal stability of conditioned pain modulation in healthy women over four menstrual cycles at the follicular and luteal phases

Conditioned pain modulation (CPM) is a phenomenon that may be tested with a dynamic quantitative sensory test that assesses the inhibitory aspect of this pain modulatory network. Although CPM has been adopted as a clinical assessment tool in recent years, the stability of the measure has not been determined over long time intervals. The question of stability over time is crucial to our understanding of pain processing, and critical for the use of this tool as a clinical test. The primary objective of this study was to evaluate the stability of a CPM paradigm over time in healthy women. The secondary objective was to determine the potential influence of menstrual cycle phase on CPM. CPM was assessed 8 times in 22 healthy women during the follicular and luteal phases of 4 different cycles. The CPM effect was evidenced by a reduction in the pain rating of a test stimulus (6.3 ± 0.2) with the introduction of a conditioning stimulus (5.0 ± 0.3; P < 0.001). The intraclass correlation coefficient for the CPM effect was modest (0.39; CI = 0.23–0.59), suggesting that there is significant variation in CPM over long time intervals. CPM did not vary across phases in the menstrual cycle. Prior to the adoption of CPM as a clinical tool to predict individual risk and aid diagnosis, additional research is needed to establish the measurement properties of CPM paradigms and evaluate factors that influence CPM effects.     

Altered Resting-State Functional Connectivity in Complex Regional Pain Syndrome

This study explored the functional connectivity between brain regions implicated in the default mode network, the sensorimotor cortex (S1/M1), and the intraparietal sulcus (IPS/MIP) at rest in patients with complex regional pain syndrome. It also investigated how possible alterations are associated with neuropathic pain. Our group used functional magnetic resonance imaging to investigate functional brain connectivity in 12 complex regional pain syndrome patients in comparison with that in 12 age- and sex-matched healthy controls. Data were analyzed using a seed voxel correlation analysis and an independent component analysis. An analysis of covariance was employed to relate alterations in functional connectivity with clinical symptoms. We found significantly greater reductions in functional default mode network connectivity in patients compared to controls. The functional connectivity maps of S1/M1 and IPS/MIP in patients revealed greater and more diffuse connectivity with other brain regions, mainly with the cingulate cortex, precuneus, thalamus, and prefrontal cortex. In contrast, controls showed greater intraregional connectivity within S1/M1 and IPS/MIP. Furthermore, there was a trend for correlation between alterations in functional connectivity and intensity of neuropathic pain. In our findings, patients with complex regional pain syndrome have substantial spatial alterations in the functional connectivity between brain regions implicated in the resting-state default mode network, S1/M1, and IPS/MIP; these alterations show a trend of correlation with neuropathic pain intensity.     

Psychological Characteristics and Pain Frequency Are Associated With Experimental Pain Sensitivity in Pediatric Patients With Sickle Cell Disease

Sickle cell disease (SCD) is associated with episodes of severe vaso-occlusive pain beginning in infancy with a subset of patients with SCD transitioning to chronic pain. Response to experimental pain using quantitative sensory testing in these patients suggests altered pain processing. The objectives of this study were to characterize sensitivity to multiple modalities of experimental pain stimuli and to interrogate the relationship of psychological covariates, clinical pain burden, and pain-related outcomes to experimental pain sensitivity in children with SCD compared with healthy individuals of similar age and sex. Cross-sectional assessments of psychological characteristics were performed, and quantitative sensory testing methods were used to measure experimental pain sensitivity in children age 8 to 21 years. Anxiety, depressive symptoms, catastrophizing, and somatization were found to be associated with increased sensitivity to experimental pain stimuli. Increased frequency of painful episodes in SCD was associated with decreased sensitivity to heat pain and decreased mechanical temporal summation. These data suggest that careful consideration be given to psychological factors, age, sex, and clinical burden of pain when studying response to experimental pain in SCD.

Somatosensory perception in a remote pain-free area and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from long-term trapezius myalgia.

In patients with localized musculoskeletal pain, spread of pain and tenderness outside the primarily painful area and sometimes even generalization of pain have been reported, the latter possibly indicating a dysfunction of endogenous pain modulatory systems. The purpose of the study was to use patients with long-term trapezius myalgia as a model to investigate the possible influence of a localized muscle pain on somatosensory processing in a remote pain-free area and the effect of heterotopic noxious conditioning stimulation (HNCS) on 'diffuse noxious inhibitory controls' (DNIC) related mechanisms. Altered somatosensory processing may indicate subclinical derangement of endogenous modulatory systems. Ten patients with long-term (> or = 1 year) trapezius myalgia and 10 age- and sex-matched healthy controls participated. Pressure pain sensitivity, low threshold mechanoreceptive function and thermal sensitivity, including thermal pain, were assessed at the right thigh before, during and following HNCS. Pain was induced in the forearm by the tourniquet test. At rest allodynia to pressure was found at the thigh in conjunction with hypoaesthesia to cold (p<0.03 and p<0.01 respectively), in patients compared with controls. During HNCS, the sensitivity to pressure pain and suprathreshold heat pain decreased in patients and controls alike (p<0.02 and p<0.04 respectively) and returned to baseline following HNCS. In conclusion, in a remote non-painful area allodynia to pressure and hypoaesthesia to cold were found in conjunction with preserved function of DNIC-related mechanisms. Whether altered central somatosensory processing at rest may indicate a predisposition for further spread of pain is at present unclear.     

Enhancement of Analgesic Effect by Combination of Non‐Noxious Stimulation and Noxious Stimulation in Humans

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.     

Altered Neural Correlates of Emotion Associated Pain Processing in Persistent Somatoform Pain Disorder: An fMRI Study

Patients with persistent somatoform pain disorder (PSPD) suffer from long‐term pain and emotional conflicts. Recently, accumulating evidence indicated that emotion has a significant role in pain perception of somatoform pain disorder. To further understand the association between emotion and pain‐related brain activities, functional activities of patients with PSPD fulfilling ICD‐10 criteria and healthy controls were assessed using functional magnetic resonance imaging technology, while participants viewed a series of positive, neutral, or negative pictures with or without pinprick pain stimulation. Results showed that patients with PSPD had altered brain activities in the parietal gyrus, temporal gyrus, posterior cingulate cortex, prefrontal cortex, and parahippocampus in response to pinprick pain stimuli during different emotions compared with the healthy control group. Moreover, patients with PSPD consistently showed hyperactivities in the prefrontal, the fusiform gyrus and the insula in response to negative stimuli under pinprick pain vs. non‐pain condition. The current findings provide some insights into the underlying relationship between emotion and pain‐related brain activity in patients with PSPD, which is of both theoretical and clinical importance.     

正常人脑静息态功能磁共振的脑功能连接

目的探讨正常人脑静息状态下的不同专属脑网络间的连接强度及其意义。方法选取36名健康受试者进行静息态功能磁共振(rs-fMRI)扫描,采用独立成分分析(ICA)方法分离静息状态五大专属性功能脑网络,将五大脑网络分别作为感兴趣区,并采用多变量Granger因果分析方法(GCA)分析相关脑网络之间的功能因果连接的强度关系。采用SPM5.0软件进行分析处理。结果应用ICA方法得到5个经典的正常人静息态脑网络成分,分别为默认网络(DMN)、记忆网络(MeN)、运动网络(MoN)、听觉网络(AN)和执行控制网络(ECN)。GCA分析表明,DMN和其余4个网络之间、MeN和ECN之间、AN和MoN之间、ECN和AN之间均存在显著的因果联系。结论正常人在静息状态下存在特定的脑功能连接网络,且这些网络之间有着显著的因果联系。     

A Functional Neuroimaging Study of Expectancy Effects on Pain Response in Patients With Knee Osteoarthritis

Placebo treatments and healing rituals share much in common, such as the effects of expectancy, and have been used since the beginning of human history to treat pain. Previous mechanistic neuroimaging studies investigating the effects of expectancy on placebo analgesia have used young, healthy volunteers. Using functional magnetic resonance imaging (fMRI), we aimed to investigate the neural mechanisms by which expectancy evokes analgesia in older adults living with a chronic pain disorder and determine whether there are interactions with active treatment. In this fMRI study, we investigated the brain networks underlying expectancy in participants with chronic pain due to knee osteoarthritis (OA) after verum (genuine) and sham electroacupuncture treatment before and after experiencing calibrated experimental heat pain using a well tested expectancy manipulation model. We found that expectancy significantly and similarly modulates the pain experience in knee OA patients in both verum (n?=?21, 11 female; mean?±?SD age 57?±?7 years) and sham (n?=?22, 15 female; mean?±?SD age 59?±?7 years) acupuncture treatment groups. However, there were different patterns of changes in fMRI indices of brain activity associated with verum and sham treatment modalities specifically in the lateral prefrontal cortex. We also found that continuous electroacupuncture in knee OA patients can evoke significant regional coherence decreases in pain associated brain regions. Our results suggest that expectancy modulates the experience of pain in knee OA patients but may work through different pathways depending on the treatment modality and, we speculate, on pathophysiological states of the participants.