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Calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypetide-38 (PACAP-38) have relevant roles in migraine pathophysiology. Their serum levels have been proposed as biomarkers for migraine. Our aim was to assess their diagnostic value in real clinical practice in a cohort of chronic migraine (CM), episodic migraine (EM) and healthy controls (HC). We recruited subjects with CM, EM and HC at two medical centers. Blood samples were drawn under fasting conditions in the interictal period, immediately centrifuged and stored at – 80 ºC. Serum levels were determined by ELISA. Neuropeptide levels, the effect of preventatives, correlations with clinical and demographic variables, and their diagnostic value were studied among clinical categories. 296 age- and sex-matched subjects (101 CM, 98 EM and 97 HC) were included. All three neuropeptide serum levels were higher in CM [median and IQ for CGRP = 18.023 pg/ml (14.4-24.7); VIP = 121.732 pg/ml (48.72-186.72) and PACAP = 204.931 pg/ml (101.08-597.64)] vs EM [CGRP = 14.659 pg/ml (10.29-17.45); VIP = 75.603 pg/ml (28.722-107.10); and PACAP = 94.992 pg/ml (65.77-128.48)] and vs HC [CGRP = 13.988 pg/ml (10.095-17.87); VIP = 84.685 pg/ml (35.32-99.79), and PACAP = 103.142 pg/ml (59.42-123.97)]. Using multinomial modeling, only VIP (OR 1.011, 95% CI 1.003-1.018, p = 0.005) and PACAP (OR 1.003, 95% CI 1.001-1.005, p = 0.002) increased the risk for CM, but not for EM. CGRP did not predict CM or EM. This model could correctly classify only 62/101 (61.38%) of CM, 75/98 (76.53%) of EM, and 5/97 (4.12%) of HC [globally 147/296 (49.8%)]. Individually, PACAP performed the best for classifying clinical categories [global accuracy 150/296 (50.67%)]. In CM, neuropeptide levels were higher in those OnaBT-treated than in no-treated patients. Although interictal serum CGRP and VIP were higher in CM than both EM or HC, their utility to discriminate migraine categories was low. Contrary to other studies, PACAP serum levels were also higher in CM than in EM or HC and had more discriminative capability to distinguish CM from EM and HC. Further investigation is needed for determination technique standardization.
Learn More >To estimate all-cause and overdose crude mortality rates and standardized mortality ratios among people prescribed opioids for chronic noncancer pain and risk of overdose death in this population relative to people with similar clinical profiles but not prescribed opioids.
Learn More >Previous studies examining the resting-state functional connectivity of the periaqueductal gray (PAG) in chronic visceral pain have localized PAG coordinates derived from BOLD responses to provoked acute pain. These coordinates appear to be several millimeters anterior of the anatomical location of the PAG. Therefore, we aimed to determine whether measures of PAG functional connectivity are sensitive to the localization technique, and if the localization approach has an impact on detecting disease-related differences in chronic visceral pain patients. We examined structural and resting-state functional MRI (rs-fMRI) images from 209 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. We applied three different localization techniques to define a region-of-interest (ROI) for the PAG: 1) a ROI previously-published as a Montreal Neurological Institute (MNI) coordinate surrounded by a 3 mm radius sphere (MNI-sphere), 2) a ROI that was hand-traced over the PAG in a MNI template brain (MNI-trace), and 3) a ROI that was hand-drawn over the PAG in structural images from 30 individual participants (participant-trace). We compared the correlation among the rs-fMRI signals from these PAG ROIs, as well as the functional connectivity of these ROIs with the whole brain. First, we found important non-uniformities in brainstem rs-fMRI signals, as rs-fMRI signals from the MNI-trace ROI were significantly more similar to the participant-trace ROI than to the MNI-sphere ROI. We then found that choice of ROI also impacts whole-brain functional connectivity, as measures of PAG functional connectivity throughout the brain were more similar between MNI-trace and participant-trace compared to MNI-sphere and participant-trace. Finally, we found that ROI choice impacts detection of disease-related differences, as functional connectivity differences between pelvic pain patients and healthy controls were much more apparent using the MNI-trace ROI compared to the MNI-sphere ROI. These results indicate that the ROI used to localize the PAG is critical, especially when examining brain functional connectivity changes in chronic visceral pain patients.
Learn More >This prospective study examined 1) whether antenatal pain is associated with postnatal maternal bonding disorder (MBD) through postnatal depression and 2) whether intimate partner violence (IPV) has a moderating effect on the association between antenatal pain and postnatal MBD. We analyzed 77,326 pregnancies of women who completed self-report questionnaires including the SF-8 bodily pain item, the Edinburgh Postnatal Depression Scale, the Mother-to-Infant Bonding Scale, and an assessment of IPV. We conducted a mediation analysis to assess whether postnatal depression mediated the association between antenatal pain and MBD 1 year after delivery. A moderated mediation model was used to examine the conditional effect of IPV during pregnancy on the association between antenatal pain and postnatal MBD, operating through postnatal depression. All analyses were adjusted for demographic factors, socioeconomic factors, perinatal and infant factors, medical history, and psychological status. Of the 77,326 pregnancies, 5,420 (7.0%) were characterized by persistent moderate-to-severe pain. The total effect of antenatal pain on MBD was significant (standardized path coefficient = 0.06, 95% CI, 0.05-0.06) and postnatal depression dominantly mediated the association between antenatal pain and postnatal MBD (70.8% mediation). Contrary to our hypothesis, IPV during pregnancy did not moderate the association between antenatal pain and postnatal MBD. However, IPV during pregnancy did have independent negative effects on both postnatal depression and MBD. Our findings suggest that antenatal pain and postnatal depression should be assessed and treated with consideration of the presence of IPV during pregnancy to better monitor and prevent the development of MBD.
Learn More >Previous meta-analyses investigating attentional biases towards pain have utilized reaction time measures. Eye-tracking methods have been adopted to more directly and reliably assess biases, but this literature has not been synthesized in relation to pain. This meta-analysis aimed to investigate the nature and time-course of attentional biases to pain-related stimuli in participants of all ages with and without chronic pain using eye-tracking studies; and determine the role of task parameters and theoretically relevant moderators. After screening, 24 studies were included with a total sample of 1425 participants. Between-group analyses revealed no significant overall group differences for people with and without chronic pain on biases to pain-related stimuli. Results indicated significant attentional biases towards pain related words or pictures across both groups on probability of first fixation (k = 21, g = 0.43, 95% CI 0.15: 0.71, p = 0.002), how long participants looked at each picture in the first 500ms (500ms epoch dwell: k = 5, g = 0.69, 95% CI 0.034: 1.35, p = 0.039) and how long participants looked at each picture overall (total dwell time: k = 25, g = 0.44, 95% CI 0.15: 0.72, p = 0.003). Follow-up analyses revealed significant attentional biases on probability of first fixation, latency to first fixation and dwell time for facial stimuli, and number of fixations for sensory word stimuli. Moderator analyses revealed substantial influence of task parameters and some influence of threat status and study quality. Findings support biases in both vigilance and attentional maintenance for pain-related stimuli but suggest attentional biases towards pain are ubiquitous and not related to pain status.
Learn More >In the central nervous system, hyperpolarization-activated, cyclic nucleotide-gated (HCN1-4) channels have been implicated in neuronal excitability and synaptic transmission. It has been reported that HCN channels are expressed in the spinal cord, but knowledge about their physiological roles, as well as their distribution profiles, appear to be limited. We generated a transgenic mouse in which the expression of HCN4 can be reversibly knocked down using a genetic tetracycline-dependent switch and conducted genetically validated immunohistochemistry for HCN4. We found that the somata of HCN4-immunoreactive (IR) cells were largely restricted to the ventral part of the inner lamina II and lamina III. Many of these cells were either parvalbumin- or protein kinase Cγ (PKCγ)-IR. By using two different mouse strains in which reporters are expressed only in inhibitory neurons, we determined that the vast majority of HCN4-IR cells were excitatory neurons. Mechanical and thermal noxious stimulation did not induce c-Fos expression in HCN4-IR cells. PKCγ-neurons in this area are known to play a pivotal role in the polysynaptic pathway between tactile afferents and nociceptive projection cells that contributes to tactile allodynia. Therefore, pharmacological and/or genetic manipulations of HCN4-expressing neurons may provide a novel therapeutic strategy for the pain relief of tactile allodynia.
Learn More >Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which promotes the activation of astrocytes, is known to be synthesized in microglia. However, it is unclear whether microglia-astrocyte communication via C1q is involved in orofacial neuropathic pain. Here, we analyzed microglia-astrocyte communication in a rat model with infraorbital nerve injury (IONI). The orofacial mechanical hypersensitivity induced by IONI was significantly attenuated by preemptive treatment with minocycline. Immunohistochemical analyses revealed that minocycline inhibited the increase in c-Fos immune-reactive (IR) cells and the fluorescence intensity of both Iba1 and glial fibrillary acidic protein (GFAP) in the Vc following IONI. Intracisternal administration of C1q caused orofacial mechanical hypersensitivity and an increase in the number of c-Fos-IR cells and fluorescence intensity of GFAP. C1q-induced orofacial mechanical hypersensitivity was completely abrogated by intracisternal administration of fluorocitrate. The present findings suggest that the enhancement in the excitability of Vc nociceptive neurons is produced by astrocytic activation via the signaling of C1q released from activated microglia in the Vc following IONI, resulting in persistent orofacial neuropathic pain.
Learn More >Psychological factors such as fear avoidance beliefs, depression, anxiety, catastrophic thinking and familial and social stress, have been associated with high disability levels in people with chronic low back pain (LBP). Guidelines endorse the integration of psychological interventions in the management of chronic LBP. However, uncertainty surrounds the comparative effectiveness of different psychological approaches. Network meta-analysis (NMA) allows comparison and ranking of numerous competing interventions for a given outcome of interest. Therefore, we will perform a systematic review with a NMA to determine which type of psychological intervention is most effective for adults with chronic non-specific LBP.
Learn More >A growing body of research highlights the pervasive harms of adverse childhood experiences (ACEs) on health throughout the life-course. However, findings from prior reviews and recent longitudinal studies investigating the association between types of ACEs and persistent pain have yielded inconsistent findings in the strength and direction of associations. The purpose of this review is to appraise and summarize evidence on the relationship between ACEs and persistent pain and disability outcomes in adulthood. The specific aims are (1) to determine whether there is a relationship between exposure to ACE and persistent pain and disability in adults and (2) to determine whether unique and cumulative ACEs exposures (number and type) increase the risk of developing persistent pain and disability in adulthood.
Learn More >Exercise has been shown to significantly improve pain and function in individuals with fibromyalgia. Research into the effectiveness of exercise is often based on standardised exercise programmes that are chosen by the investigating clinical research team. However, such programmes may not necessarily be appealing to the participating patients. Furthermore, in addition to being taught exercises, patients with chronic conditions like fibromyalgia also need to learn to manage their condition themselves and so be actively involved in their treatment. The primary aim of this study is to compare the effects of two, 6-month physical activity programs on quality of life in patients with fibromyalgia. One group followed a patient-led, fibromyalgia-orientated programme (experimental) whilst the control group followed a standard, general exercise programme.
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