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Poor sleep quality has been associated with greater pain and fatigue in people living with osteoarthritis (OA). The objective of this micro-longitudinal study was to determine whether sleep impacts the diurnal pattern of next-day OA-related pain and fatigue. Community-dwelling older adults (≥65 years) with hip and/or knee OA provided data over 5 days using daily diaries and wrist-worn actigraphs. Pain and fatigue intensity were measured on awakening, at 11 am, 3 pm, 7 pm, and bedtime. Subjective previous night sleep quality was measured on awakening. Multilevel linear regression models examined interactions between sleep variables and time of next-day symptom reports. One hundred sixty participants provided 785 days of data (median age = 71 years; 62% female). Analysis of time interaction effects identified an association between poor sleep quality and more morning pain and fatigue. Although the effect on awakening was more pronounced for fatigue, differences in both symptoms attributable to sleep quality attenuated as the day progressed. Investigation of actigraphy-based sleep parameters revealed no significant interactions with time of symptom measurement. These findings observed in a sample of older adults with mild-to-moderate OA symptoms warrant further investigation in a sample with more severe symptoms and more pronounced sleep dysfunction and/or sleep disorders. PERSPECTIVE: This article investigates the impact of sleep on next-day pain and fatigue of older adults with OA. On awakening from a night of poor quality sleep, pain and fatigue intensity were heightened. However, the effect was not sustained throughout the day, suggesting the morning may be an optimal time for symptom interventions.
Learn More >Mind-body therapies (MBTs) are emerging as potential tools for addressing the opioid crisis. Knowing whether mind-body therapies may benefit patients treated with opioids for acute, procedural, and chronic pain conditions may be useful for prescribers, payers, policy makers, and patients.
Learn More >Sodium channel Na1.7 controls firing of nociceptors, and its role in human pain has been validated by genetic and functional studies. However, little is known about Na1.7 trafficking or membrane distribution along sensory axons, which can be a meter or more in length. We show here with single-molecule resolution the first live visualization of Na1.7 channels in dorsal root ganglia neurons, including long-distance microtubule-dependent vesicular transport in Rab6A-containing vesicles. We demonstrate nanoclusters that contain a median of 12.5 channels at the plasma membrane on axon termini. We also demonstrate that inflammatory mediators trigger an increase in the number of Na1.7-carrying vesicles per axon, a threefold increase in the median number of Na1.7 channels per vesicle and a ~50% increase in forward velocity. This remarkable enhancement of Na1.7 vesicular trafficking and surface delivery under conditions that mimic a disease state provides new insights into the contribution of Na1.7 to inflammatory pain.
Learn More >Chemotherapy-induced neuropathic pain is a dose-limiting side effect of many cancer therapies due to their propensity to accumulate in peripheral nerves, which is facilitated by the permeability of the blood-nerve barrier. Preclinically, the chemotherapy agent vincristine (VCR) activates endothelial cells in the murine peripheral nervous system and in doing so allows the infiltration of monocytes into nerve tissue where they orchestrate the development of VCR-induced nociceptive hypersensitivity. In this study we demonstrate that VCR also activates endothelial cells in the murine central nervous system, increases paracellular permeability and decreases trans endothelial resistance. In in vivo imaging studies in mice, VCR administration results in trafficking of inflammatory monocytes through the endothelium. Indeed, VCR treatment affects the integrity of the blood-spinal cord-barrier as indicated by Evans Blue extravasation, disrupts tight junction coupling and is accompanied by the presence of monocytes in the spinal cord. Such inflammatory monocytes (Iba-1 CCR2 Ly6C TMEM119 cells) that infiltrate the spinal cord also express the pro-nociceptive cysteine protease Cathepsin S. Systemic treatment with a CNS-penetrant, but not a peripherally-restricted, inhibitor of Cathepsin S prevents the development of VCR-induced hypersensitivity, suggesting that infiltrating monocytes play a functional role in sensitising spinal cord nociceptive neurons. Our findings guide us towards a better understanding of central mechanisms of pain associated with VCR treatment and thus pave the way for the development of innovative antinociceptive strategies.
Learn More >Canine studies of spontaneous osteoarthritis (OA) pain add valuable data supporting drug treatment mechanisms that may translate to humans. A multicenter, randomized, double-blind, placebo- and active-controlled study was conducted in client-owned dogs with moderate OA pain to evaluate efficacy of LYA, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES1), an EP4 antagonist (LYB), and carprofen, versus placebo. Of 255 dogs screened, 163 were randomized (placebo/LYA/LYB/carprofen: = 43/39/42/39) and 158 completed treatment. Efficacy versus placebo was assessed using Bayesian mixed-effect model for repeated measure analyses of the Canine Brief Pain Inventory (CBPI) pain interference score (PIS; primary endpoint), pain severity score, and overall impression, as well as the Liverpool Osteoarthritis in Dogs (LOAD) mobility score. The posterior probability that the difference to placebo was <0 at week 2 was 80% for LYA and 54% for LYB for CBPI PIS (both <95% predefined threshold). For secondary endpoints, the posterior probability that the difference to placebo was <0 at week 2 ranged from 89 to 96% for LYA and from 56 to 89% for LYB. The posterior probabilities comparing carprofen to placebo groups were ≥90% for all efficacy endpoints. The proportion of dogs with one or more adverse event was not significantly different from placebo (32.6%) for LYA (35.9%) or carprofen (25.6%), but the rate for LYB (59.5%) was higher versus placebo ( = 0.017). LYA treatment demonstrated consistent improvement in all efficacy measures, suggesting that inhibition of mPGES1 may be an effective treatment for chronic pain associated with OA.
Learn More >The Transient Receptor Potential Ankyrin TRPA channels are Ca-permeable non-selective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the N-terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This include a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel, and many other chemically-unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat and mechanical stimuli, and its function is modulated by multiple factors, including Ca, trace metals, pH, and reactive oxygen, nitrogen and carbonyl species. TRPA1 is involved in acute and chronic pain, inflammation, plays a role in the pathophysiology of nearly all organ systems and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties and complex regulation to its roles in multiple pathophysiological conditions.
Learn More >Migraine is one of the most prevalent and disabling diseases worldwide, but until recently, few migraine-specific therapies had been developed. Extensive basic and clinical scientific investigation has provided strong evidence that the neuropeptide calcitonin gene-related peptide (CGRP) has a key role in migraine. This evidence led to the development of small molecule CGRP receptor antagonists and monoclonal antibodies targeting either CGRP or its receptor. Clinical trials investigating these therapies have consistently shown statistically significant efficacy for either the acute or preventive treatment of migraine. No serious safety or tolerability issues have been identified in the trials of the monoclonal antibody therapies. Although the appropriate place of these new migraine-specific therapies relative to other available acute and preventive treatments remains to be determined, a growing body of evidence shows that therapeutic approaches targeting CGRP have the potential to transform the clinical management of migraine.
Learn More >Altered pro-nociceptive and anti-nociceptive mechanisms are often implicated in painful conditions and have been increasingly studied over the past decade. For some painful conditions alterations are well-established, but in low back pain (LBP) populations there remains considerable debate whether these mechanisms are altered. The present systematic review aimed to address this issue by identifying studies assessing Conditioned Pain Modulation (CPM) and/or Temporal Summation of Pain (TSP) in LBP patients, comparing to either a healthy control group or using a method with reference data available. Qualitative synthesis and quantitative meta-analysis of group differences were performed. For CPM and TSP, 20 and 29 original articles were eligible, with data for meta-analysis obtainable from 18 (1500 patients, 505 controls) and 27 (1507 patients, 1127 controls) studies, respectively. Most studies were of poor-to-fair quality with significant heterogeneity in study size, population, assessment methodology and outcome. Nonetheless, CPM was impaired in LBP patients compared to controls (standardized mean difference = -0.44 [-0.64, -0.23], P<0.001), and the magnitude of this impairment was related to pain chronicity (acute/recurrent versus chronic, P=0.003), duration (R=-0.62, P=0.006) and severity (R=-0.54, P=0.02). TSP was facilitated in LBP patients compared to controls (standardized mean difference = 0.50 [0.29, 0.72], P<0.001), and the magnitude of this facilitation was weakly related to pain severity (R=0.41, P=0.04) and appeared to be influenced by test modality (P<0.001). Impaired CPM and facilitated TSP was present in LBP patients compared to controls, though the magnitude of differences was small which may direct future research on the clinical utility.
Learn More >Most studies of diabetic polyneuropathy (DPN) and painful DPN are conducted in persons with longstanding diabetes. This cross-sectional study aimed to estimate the prevalence of DPN and painful DPN, important risk factors, and the association with mental health in recently diagnosed type 2 diabetes. A total of 5,514 (82%) patients (median diabetes duration 4.6 years) enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes cohort responded to a detailed questionnaire on neuropathy and pain. A score ≥ 4 on the MNSI questionnaire determined possible DPN whereas pain presence in both feet together with a score ≥ 3 on the DN4 questionnaire determined possible painful DPN. The prevalence of possible DPN and possible painful DPN was 18% and 10%, respectively. Female sex, age, diabetes duration, BMI, and smoking were associated with possible DPN, whereas only smoking showed a clear association with possible painful DPN (OR 1.52 [95% CI: 1.20; 1.93]). Possible DPN and painful DPN were independently and additively associated with lower quality-of-life, poorer sleep, and symptoms of depression and anxiety. Possible DPN itself had greater impact on mental health than neuropathic pain. This large study emphasizes the importance of careful screening for DPN and pain early in the course of type 2 diabetes.
Learn More >The complex mechanisms underlying migraine are not entirely understood. It has been suggested that descending endogenous pain modulation is an important contributing factor, although research is controversial. A frequently used method to quantify the inhibitory pain modulation system is offset analgesia (OA), defined as a disproportionally large decrease in pain perception in response to a small decrease of painful stimulation. The aim of this study is to evaluate the OA response in patients with migraine and healthy controls, measured at the forehead (trigeminal, V1) and forearm (extra-trigeminal). Patients with episodic migraine during the headache free interval (n=26) and age and sex matched headache-free controls (n=26) were included in this cross-sectional study. All participants underwent an individualized OA paradigm consisting of three-stimulus offset trials and three constant temperature trials examined at both, a trigeminal and an extra-trigeminal test site. Items from the quantitative sensory testing protocol were additionally included. In contrast to the extra-trigeminal area, a reduced offset analgesia response was shown in the trigeminal area in patients with migraine compared to healthy controls (p<0.01, MD: 13.7, 95%CI: 3.8; 23.6). Statistically significant differences between the trigeminal area and the extra-trigeminal area were neither observed in healthy controls nor in patients with migraine (p>0.05). Mechanical detection, mechanical pain threshold, warm detection and heat pain threshold showed no significant differences between groups or test sites (p>0.05). In summary, patients with episodic migraine in the headache free interval exhibited somatotopically specific differences in endogenous pain modulation.
Learn More >Chronic neuropathic pain (NP) is debilitating and impacts sleep health and quality of life. Treatment with gabapentinoids (GB) has been shown to reduce pain, but its effects on sleep health have not been systematically evaluated. The objective of this systematic review and meta-analysis was to assess the relationship between GB therapy dose and duration on sleep quality, daytime somnolence, and intensity of pain in patients with neuropathic pain. Subgroup comparisons were planned for high vs. low dose GB, where 300mg per day or more of pregabalin was used to classify high-dose therapy. Trial data was segregated by duration less than 6 weeks and 6 weeks or greater. Twenty randomized controlled trials were included. Primary outcome measures included pain-related sleep interference and incidence of daytime somnolence. Secondary outcomes included daily pain scores (NRS 0-10) and patient global impression of change (PGIC). Significant improvement in sleep quality was observed after 6 weeks of GB treatment when compared to placebo (SMD 0.39, 95% CI 0.32 to 0.46 p<.001). Increased daytime somnolence was observed among all GB-treated groups when compared to placebo. Treated patients were also more likely to report improvement of PGIC scores. Pain scores decreased significantly in patients both after 6 weeks of treatment (p<.001) and in trials less than 6 weeks (p=0.017) when compared to placebo. Our data demonstrates that GBs have a positive impact on sleep health, quality of life, and pain in patients with NP syndromes. However, these benefits come at the expense of daytime somnolence.
Learn More >Central neuropathic pain (CNP) after spinal cord injury (SCI) is debilitating and immensely impacts the individual. CNP is relatively resistant to treatment administered after it develops, perhaps owing to irreversible pathological processes. Although preemptive treatment may overcome this shortcoming, its administration necessitates screening patients with clinically relevant biomarkers that could predict CNP early post-SCI. The aim was to search for such biomarkers by measuring pro-nociceptive and for the first time, anti-nociceptive indices early post-SCI.Participantswere 47 patients with acute SCI and 20 healthy controls (HC). Pain adaptation, conditioned pain modulation (CPM), pain temporal summation (TSP), windup pain, and allodynia were measured above, at, and below the injury level, at 1.5 months post-SCI. HC were tested at corresponding regions. SCI patients were monitored for CNP emergence and characteristics at 3-4, 6-7, and 24 months post-SCI.CNP prevalence was 57.4%. CNP severity, quality and aggravating factors but not location somewhat changed over 24 months. SCI patients who eventually developed CNP exhibited early, reduced at-level pain adaptation and CPM magnitudes than those who did not. The best predictor for CNP emergence at 3-4 and 7-8 months was at-level pain adaptation with odds ratios of 3.17 and 2.83, respectively (∼77% probability) and a cut-off value with 90% sensitivity. Allodynia and at-level CPM predicted CNP severity at 3-4 and 24 months, respectively.Reduced pain inhibition capacity precedes, and may lead to CNP. At-level pain adaptation is an early CNP biomarker with which individuals at risk can be identify to initiate preemptive treatment.
Learn More >To test the hypothesis that statistically defined subgroups of migraine (based on constellations of comorbidities and concomitant conditions; henceforth comorbidities), previously identified using Chronic Migraine Epidemiology and Outcomes (CaMEO) Study data, differ in prognosis, as measured by rates of progression from episodic migraine (EM) to chronic migraine (CM).
Learn More >Pain-related fear is typically associated with avoidance behavior and pain-related disability in youth with chronic pain. Youth with elevated pain-related fear have attenuated treatment responses, thus targeted treatment is highly warranted. Evidence supporting graded in-vivo exposure treatment (GET) for adults with chronic pain is considerable, but just emerging for youth. The current investigation represents the first sequential replicated and randomized single-case experimental phase design with multiple measures evaluating GET for youth with chronic pain, entitled GET Living. A cohort 27 youth (81% female) with mixed chronic pain completed GET Living. For each participant, a no-treatment randomized baseline period was compared with GET Living and 3- and 6-month follow-ups. Daily changes in primary outcomes fear and avoidance and secondary outcomes pain catastrophizing, pain intensity, and pain acceptance were assessed using electronic diaries and subjected to descriptive and model-based inference analyses (MLM). Based on individual effect size calculations, a third of participants significantly improved by the end of treatment on fear, avoidance, and pain acceptance. By follow-up over 80% of participants had improved across all primary and secondary outcomes. MLM results to examine the series of replicated cases were generally consistent. Improvements during GET Living was superior to the no-treatment randomized baseline period for avoidance, pain acceptance, and pain intensity, whereas fear and pain catastrophizing did not improve. All five outcomes emerged as significantly improved at 3- and 6-month follow-up. The results of this replicated SCED support the effectiveness of graded exposure for youth with chronic pain and elevated pain-related fear avoidance.
Learn More >Persons with chronic musculoskeletal pain may be hypervigilant for pain-related cues which, paradoxically, may be maintaining their pain. Several randomized controlled trials have assessed whether a modified dot-probe protocol (i.e., attention bias modification; ABM) reduces chronic pain- and pain-related symptoms in persons with several diagnoses, including fibromyalgia. Scalability and economic efficiency potentiates the appeal of ABM protocols; however, research results have been mixed, with only some studies evidencing significant symptom gains from ABM and some evidencing gains for the control group. The current randomized controlled trial sought to replicate and extend previous ABM research using idiosyncratic word stimuli and a 1-month follow-up. Participants included treatment-seeking adult women (n=117) with fibromyalgia who were randomly assigned to a standard (i.e., control) or active (i.e., ABM) condition. The protocol was delivered online and involved twice-weekly 15-min sessions, for 4 weeks, with questionnaires completed at baseline, post-treatment, and 1-month follow-up. Symptom reports were analysed with mixed hierarchical modelling. There was no evidence of differences between the control and ABM groups. Both groups had small significant (ps<.05) improvements in pain experiences at post-treatment, but not at follow-up (ps>.05). There were no significant changes for either group on measures of anxiety sensitivity, illness/injury sensitivity, pain-related fear, pain-related anxiety, or attentional biases (ps>.05). The current findings add to the emerging and mixed literature regarding ABM for pain by demonstrating that ABM produces no substantive improvements in pain or pain-related constructs in a large sample of patients with fibromyalgia.
Learn More >Complex regional pain syndrome (CRPS) develops after limb injury, with persistent pain and deficits in movement frequently co-occurring. The striatum is critical for mediating multiple mechanisms that are often aberrant in CRPS, which includes sensory and pain processing, motor function and goal-directed behaviors associated with movement. Yet much remains unknown with regards to the morphological and functional properties of the striatum and its sub-regions in this disease. Thus, we investigated 20, patients (15 female, age 58 ± 9 years, right-handed) diagnosed with chronic (6+ months of pain duration) CRPS in the right hand and 20 matched, healthy controls with anatomical and resting-state, functional magnetic resonance imaging (fMRI). In addition, a comprehensive clinical and behavioral evaluation was performed, where each participant's pain, motor function and medical history were assessed. CRPS patients harbored significant abnormalities in hand coordination, dexterity and strength. These clinical pain and movement-related findings in CRPS patients were concomitant with bilateral decreases in gray matter density in the putamen as well as functional connectivity increases and decreases amongst the putamen and pre-/postcentral gyri and cerebellum, respectively. Importantly, higher levels of clinical pain and motor impairment were associated with increased putamen-pre-/postcentral gyri functional connectivity strengths. Collectively, these findings suggest that putaminal alterations, specifically the functional interactions with sensorimotor structures, may underpin clinical pain and motor impairment in chronic CRPS patients.
Learn More >Pain-related fear and avoidance are increasingly demonstrated to play an important role in adult and childhood chronic pain. The Fear of Pain Questionnaire for Children (FOPQC) is a 24-item measure of pain-related fear-avoidance in youth that has demonstrated good indices of reliability and validity, treatment responsiveness, and associations with brain circuitry alterations. This study describes the development and psychometric examination of the FOPQC-SF, a short form of the original measure. We selected 10 items for the short form that best represented the content and two-factor (Fear and Avoidance) structure of the original measure from a cohort of 613 youth (Mage = 14.7 years) with chronic pain. Next, confirmatory factor analyses from a second sample of 526 youth (Mage = 14.7 years) with chronic pain who completed the FOPQC-SF supported the original two-factor model but indicated that one item should be moved to the avoidance subscale. The FOPQC-SF demonstrates strong internal consistency and moderate-to-strong construct and criterion validity. Three-month test-retest reliability estimates (N=94) were strong and there was preliminary evidence of responsivity to change. To aid integration into intervention trials and clinical practice, we provide clinical reference points and a criterion to assess reliable change. The short form could be used for rapid identification of pain-related fear and avoidance in youth during clinic evaluations, and is optimized for clinical registries.
Learn More >Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cationic channel activated by painful stimuli such as capsaicin and noxious heat, and enriched in sensory neurons of the pain pathway. During inflammation, chemical mediators activate protein kinases (such as PKC) that phosphorylate TRPV1 and thereby enhance its function, with consequent increases in nociceptor sensitization. However, the causal relationships between TRPV1 phosphorylation and pathological pain remain unexplored. To directly investigate the roles of one specific TRPV1 phosphorylation event , we genetically altered a major PKC phosphorylation site, mouse TRPV1 S801, to alanine. The TRPV1 expression pattern in sensory neurons of S801A knock-in (KI) mice was comparable to that in wildtype (WT) controls. However, sensitization of capsaicin-mediated currents following the activation of PKC was substantially impaired in sensory neurons from KI mice. Thermal hyperalgesia induced by PMA or burn injury in KI was identical to WT. Inflammatory thermal hyperalgesia was only marginally attenuated in KI mice. In contrast, PMA-evoked nocifensive responses and sensitization of capsaicin responses were significantly attenuated in the hindpaws of KI mice. Ongoing pain from inflamed masseter muscle was also reduced in KI mice, and was further inhibited by the TRPV1 antagonist AMG9810. These results suggest that PKC-mediated phosphorylation of TRPV1 S801 contributes to inflammation-mediated sensitization of TRPV1 to ligand, but not heat, Further, this suggests that interference with TRPV1 S801 phosphorylation might represent one potential way to attenuate inflammatory pain, yet spare basal sensitivity and produce fewer side effects than more general TRPV1 inhibition.TRPV1 has been considered a potential target for pain intervention. Global inhibitors of TRPV1 function, however, produce side effects which could compromise their clinical utility. By precisely removing a unique PKC phosphorylation site (TRPV1 S801) in mice through CRISPR/Cas9 editing, we provide evidence for a highly specific inhibition that leaves basal TRPV1 function intact, yet alleviates some forms of hyperalgesia. These findings support inhibition of TRPV1 S801 phosphorylation as a potential intervention for pain management.
Learn More >Exosomes are 30-150 nm extracellular vesicles mediating intercellular communication. Disease states can alter exosome composition affecting the message carried and thereby, its functional impact. The objective of this study was to identify proteins present in these vesicles in a mouse model of neuropathic pain induced by spared nerve injury (SNI). Small extracellular vesicles (sEVs) were purified from serum four weeks after SNI surgery and the protein composition was determined using tandem mass spectrometry and cytokine array. Proteomic analysis detected 274 gene products within sEVs. Of these, 24 were unique to SNI model, 100 to sham surgery control and five to naïve control samples. In addition to commonly expressed sEVs proteins, multiple members of serpin and complement family were detected in sEVs. Cytokine profiling using a membrane-based antibody array showed significant upregulation of complement component 5a (C5a) and Intercellular Adhesion Molecule 1 (ICAM-1) in sEVs from SNI model compared to sham control. We observed a differential distribution of C5a and ICAM-1 within sEVs and serum between sham and SNI, indicating changes from local or paracrine to long distance signaling under neuropathic pain. Our studies suggest critical roles for cargo sorting of vesicular proteins in mediating signaling mechanisms underlying neuropathic pain. SIGNIFICANCE: Approximately 100 million U.S. adults are burdened by chronic pain. Neuropathic pain resulting from injury or dysfunction of the nervous system is challenging to treat. Unlike acute pain that resolves over time, chronic pain persists resulting in changes in the peripheral and central nervous system. The transport of biomolecular cargo comprised of proteins and RNAs by small extracellular vesicles (sEVs) including exosomes has been proposed to be a fundamental mode of intercellular communication. To obtain insights on the role of exosome-mediated information transfer in the context of neuropathic pain, we investigated alterations in protein composition of sEVs in a mouse model of neuropathic pain induced by spared nerve injury (SNI). Our studies using mass spectrometry and cytokine array show that sEVs from SNI model harbor unique proteins. We observed an upregulation of C5a and ICAM-1 in exosomes from SNI model compared to control. There was a differential distribution of C5a and ICAM-1 within exosomes and serum, between control and SNI suggesting a switch from local to long distance signaling. Our studies suggest critical roles for cargo sorting of vesicular proteins in mediating signaling under neuropathic pain.
Learn More >The peptidergic system is the most abundant network of ligand-receptor-mediated signaling in humans. However, the physiological roles remain elusive for numerous peptides and more than 100 G protein-coupled receptors (GPCRs). Here we report the pairing of cognate peptides and receptors. Integrating comparative genomics across 313 species and bioinformatics on all protein sequences and structures of human class A GPCRs, we identify universal characteristics that uncover additional potential peptidergic signaling systems. Using three orthogonal biochemical assays, we pair 17 proposed endogenous ligands with five orphan GPCRs that are associated with diseases, including genetic, neoplastic, nervous and reproductive system disorders. We also identify additional peptides for nine receptors with recognized ligands and pathophysiological roles. This integrated computational and multifaceted experimental approach expands the peptide-GPCR network and opens the way for studies to elucidate the roles of these signaling systems in human physiology and disease. VIDEO ABSTRACT.
Learn More >Epidemiological studies have to a little extent addressed the potential fluctuations of chronic pain over time, and there is a lack of information about the long-term course of pain using repeated measurements. We wanted to identify different trajectories of pain during eight waves of follow-up over four years among individuals in the general population reporting pain lasting at least six months at baseline. Secondarily, we wanted to investigate whether biopsychosocial factors at baseline were associated with the different pain trajectories. Longitudinal Latent Class Analysis (LLCA) was performed to classify 1905 random participants from a larger population-based study (HUNT3) into groups based on their longitudinal pain severity reporting. A five-class solution gave the best fit. The terms chosen to describe the pain trajectories were: "fluctuating" (n = 586 [31 %]), "persistent mild" (n = 449 [24 %]), "persistent moderate" (n = 414 [22 %]), "persistent severe" (n = 251 [13 %]), and "gradual improvement" (n = 205 [11 %]). In a multinomial logistic regression model using "gradual improvement" as the reference category, the "persistent moderate", "persistent severe", and "fluctuating" pain groups were associated with chronic widespread pain (CWP), elevated levels of catastrophizing, and poorer mental health. The "persistent mild" group was associated with sleep difficulties only. This study finds that although most individuals have a stable pain course, individuals in the largest distinct trajectory reports pain that fluctuate between mild and moderate levels, thus fluctuating under and above the chronic pain definition using moderate pain or more as a criterion. Perspective: When examining the long-term course of chronic pain in the general population, five trajectories emerge. Although most individuals have stable pain, the largest distinct trajectory fluctuated under and above the chronic pain cut-off, using moderate pain or more as a criterion. A dichotomous categorization of chronic pain may be overly simplistic.
Learn More >To identify possible structural connectivity alterations in patients with episodic and chronic migraine using magnetic resonance imaging data.
Learn More >In this study, we investigated whether illusionary body ownership over artificial hands and non-corporeal objects modulates pain perception. Previous research has yielded to mixed results, but has separated painful stimulation used to test pain perception from the stimulation that was used to induce the illusion. Here, we used a variant of the rubber hand illusion (RHI) paradigm and induced the illusion directly via a combination of visual and painful stimuli. We presented heat pain stimuli at the real hand and visual stimuli beneath a rubber hand (part1), or a glass ball (part2). Illusion ratings were higher and pain ratings were lower in the synchronous compared to the asynchronous condition in both parts of the experiment. This study demonstrated the successful induction of a body illusion using a new visual-thermal method with painful stimuli. We showed that the RHI and interestingly also the glass ball has an analgesic effect on the perception of the heat pain stimuli. Our data suggests that induced ownership over artificial limbs but also over non-corporeal objects can reduce the perceived pain perception. This might be mediated via a partial referral of the perceived location of pain or respectively a distribution of pain over two locations. Perspective: This article presents a new visual-thermal method with painful stimuli for the induction of the Rubber Hand Illusion. An illusionary body ownership over artificial hands and non-corporeal has an analgesic effects on the perception of pain. Similar approaches might be useful to alleviate chronic pain, but needs further testing.
Learn More >Efficacy of galcanezumab, a monoclonal antibody for migraine prevention, has been demonstrated in two pivotal trials in patients with episodic migraine.
Learn More >Parental behavior can influence how well adolescents cope with chronic pain. Previous research has largely focused on how parents negatively impact adolescent functioning. Yet more recent work suggests that parents – and particularly parental psychological flexibility – can foster better adolescent pain-related functioning. In this study we examined if parental protective responses and instructions to engage in activities in the presence of pain mediate the impact of parental psychological flexibility and acceptance of adolescent pain on adolescents' daily pain-related behavior.
Learn More >This study examined whether a modified version of biofeedback (ie, Conditioned Biofeedback) that incorporated placebo analgesia-like manipulations could promote anti-nociception in healthy, pain-free participants. During Conditioned Biofeedback (n=28), sympathetic arousal level was displayed visually and participants were asked to reduce it while they received painful electric stimulations that were surreptitiously controlled by their arousal level. Thus, electric pain decreased as arousal decreased to associate successful arousal-reduction/relaxation with pain relief, and to promote expectations for future pain relief. A Biofeedback Only group (n=24) controlled for the general effects of biofeedback/relaxation. A Biofeedback+Shock group (n=21) controlled for the effects of practicing biofeedback during painful shocks. Nociceptive flexion reflex (NFR) threshold and temporal summation of pain (TS-pain) were used to assess changes in spinal nociception and pain facilitation, respectively. Results indicated all groups showed pre- to post-biofeedback increases in NFR threshold, but only the Conditioned Biofeedback group showed pre- to post-biofeedback reductions in TS-pain. Moreover, Conditioned Biofeedback resulted in a persistent (pre-biofeedback) increase in NFR threshold across sessions, whereas Biofeedback Only resulted in a persistent (pre-biofeedback) decrease in TS-pain. In sum, Conditioned Biofeedback may promote anti-nociception in healthy participants thus reducing risk for chronic pain. The study was registered prospectively on ClinicalTrials.gov (TU1560). PERSPECTIVE: A modified version of biofeedback that employs placebo analgesia manipulations was successful in increasing descending inhibition and reducing pain facilitation in healthy volunteers. As a result, it may be an effective means of reducing risk of future chronic pain onset by promoting an anti-nociceptive pain profile.
Learn More >Patients with chronic pain demonstrate interpretational bias to pain and models of pain suggest interpretational bias affects subsequent pain experience. This study developed an interpretation bias modification for pain (IBM-P) and examined its efficacy. A total of 48 patients with chronic pain were recruited and randomly assigned to either the training group (n = 24) or the control group (n = 24). Interpretational bias, negative emotions, and attentional bias to pain-related stimuli were assessed before and after conducting IBM-P. The main results indicated that the training group showed less interpretational bias and negative emotions after IBM-P than the control group. The training group also gazed at neutral words longer than at "new" affective pain words after IBM-P than they did prior to the intervention. Furthermore, significant mediating effects of post-interpretational bias were found in the relationship between the group type and post-negative emotions and post-dwell time bias. These results suggest that IBM-P can modify interpretational bias which leads to changes in negative emotions and attentional bias. Future research is needed to confirm the effect of modifying interpretational bias and its clinical utility in the field of pain management. Perspective: This article investigated the efficacy of IBM-P and suggested that modifying interpretational bias is followed by changes in negative emotions and attentional bias. These findings may help health professionals understand the role of interpretational bias in chronic pain and encourage the potential use of IBM in pain management.
Learn More >While much of the literature provides positive support for psychological interventions for chronic pain, two recent meta-analyses indicate small to moderate benefits only. This inconsistency in findings suggests that there are other treatment-related variables to consider. One possible consideration pertains to treatment format, as psychological models form the basis for both unidisciplinary psychology and integrated interdisciplinary treatments for chronic pain. Therefore, a comparative meta-analysis of unidisciplinary and interdisciplinary treatments was performed to determine whether there were differences in treatment effect size (ES) at post-treatment and follow-ups of up to one year. One specific treatment model, Acceptance and Commitment Therapy (ACT), was investigated as it was felt that this literature was extensive enough to perform the planned analysis, while also being circumscribed enough in size to make it feasible. In total, 29 articles met inclusion criteria, 13 reported outcomes for unidisciplinary ACT and 15 for interdisciplinary ACT. At both post-treatment and follow-up, interdisciplinary ACT had a greater ES for physical disability, psychosocial impact and depression compared to unidisciplinary ACT. No differences in ES were observed for pain intensity, pain-related anxiety, or pain acceptance. Findings remained the same when study heterogeneity was considered. There was a significant difference observed between treatment format and treatment duration – on average, unidisciplinary interventions were of shorter duration than interdisciplinary interventions. Moderation analyses examining the relation between total treatment duration and ES generally indicated a moderate positive relation between treatment length and ES. This relation was strong for psychosocial impact. Perspective: A comparative meta-analysis examined the relative ES of unidisciplinary (i.e., clinical psychology only) and interdisciplinary ACT for chronic pain in 29 studies. The ES for interdisciplinary ACT was larger than unidisciplinary ACT for physical disability, psychosocial impact, and depression. No differences were present for pain intensity, anxiety, and acceptance.
Learn More >Migraine has been associated with a dysfunctional activation of the trigeminovascular system. Calcitonin gene-related peptide, a neuropeptide released from the trigeminal nerve fibres, has an important role in the pathophysiology of migraine and is a current therapeutic target for migraine treatment.
Learn More >Dyadic coping is a process of coping within couples that is intended not only to support the patient with chronic pain but also to maintain equilibrium in the relationship. This study aims to investigate the effect of patient-perceived and spouse-reported dyadic coping on both the patient and their partner's relationship quality and anxiety, stress, and depression over time.
Learn More >Pain is a major symptom of bone metastases from advanced cancer and represents a clinical challenge to treat effectively. Basic neurobiology in preclinical animal models implicates enhanced sensory processing in the central nervous system, acting through -methyl-D-aspartate (NMDA) glutamate receptors, as an important mechanism underpinning persistent pain. The non-receptor tyrosine kinase Src is thought to act as a hub for regulating NMDA receptor activity and the orally available Src inhibitor saracatinib has shown promise as a potential analgesic in recent animal studies. Here we tested the efficacy of saracatinib as a novel analgesic in an exploratory phase II randomized controlled trial on cancer patients with painful bone metastases. Twelve patients completed the study, with 6 receiving saracatinib 125 mg/day for 28 days and 6 receiving placebo. Pharmacokinetic measurements confirmed appropriate plasma levels of drug in the saracatinib-treated group and Src inhibition was achieved clinically by a significant reduction in the bone resorption biomarker serum cross-linked C-terminal telopeptide of type I collagen. Differences between the saracatinib and placebo groups self-reported pain scores, measured using the short form of the Brief Pain Inventory, were not clinically significant after 4 weeks of treatment. There was also no change in consumption of maintenance analgesia in the saracatinib-treated group and no improvement in Quality-of-Life scores. The data were insufficient to demonstrate saracatinib has efficacy as analgesic, although it may have a role as an anti-bone resorptive agent.
Learn More >Various studies reported changes in grey matter volumes and modifications in functional connectivity of cortical and subcortical structures in patients suffering from trigeminal neuralgia (TN) and trigeminal neuropathic pain (TNP). This study meta-analyzed the concordant structural and functional changes in foci and provide further understanding of the anatomy and biology of TN/TNP.
Learn More >Levcromakalim opens ATP-sensitive potassium channels (K channel) and induces head pain in healthy volunteers and migraine headache in migraine patients, but no pain in other parts of the body. K channels are expressed in C- and Aδ-fibers, and these channels might directly activate nociceptors and thereby evoke pain in humans.
Learn More >ATP-sensitive potassium (K) channels are found in the nervous system and are downstream targets of opioid receptors. K channel activity can effect morphine efficacy and may beneficial for relieving chronic pain in the peripheral and central nervous system. Unfortunately, the K channels exists as a heterooctomers, and the exact subtypes responsible for the contribution to chronic pain and opioid signaling in either dorsal root ganglia (DRG) or the spinal cord are yet unknown. Chronic opioid exposure (15 mg/kg morphine, s.c., twice daily) over 5 days produces significant downregulation of Kir6.2 and SUR1 in the spinal cord and DRG of mice. studies also conclude potassium flux after K channel agonist stimulation is decreased in neuroblastoma cells treated with morphine for several days. Mice lacking the K channel SUR1 subunit have reduced opioid efficacy in mechanical paw withdrawal behavioral responses compared to wild-type and heterozygous littermates (5 and 15 mg/kg, s.c., morphine). Using either short hairpin RNA (shRNA) or SUR1 cre-lox strategies, downregulation of SUR1 subtype K channels in the spinal cord and DRG of mice potentiated the development of morphine tolerance and withdrawal. Opioid tolerance was attenuated with intraplantar injection of SUR1 agonists, such as diazoxide and NN-414 (100 μM, 10 μL) compared to vehicle treated animals. These studies are an important first step in determining the role of K channel subunits in antinociception, opioid signaling, and the development of opioid tolerance, and shed light on the potential translational ability of K channel targeting pharmaceuticals and their possible future clinical utilization. These data suggest that increasing neuronal K channel activity in the peripheral nervous system may be a viable option to alleviate opioid tolerance and withdrawal.
Learn More >Itch, also known as pruritus, is an unpleasant sensation that results in an urge to scratch. We can feel itch at any location where itch occurs from the top of the head to the toes. However, there are topographical differences in itch intensity. Itch is mainly conducted by C nerve fibers from the skin where itch emanates to the central nervous system. However, the abundancy of C fibers does not necessarily lead to higher itch intensity.Interestingly reduction and/or structural changes of C fibers seem to play a role in itch sensation. In addition, C tactile fibers (CT afferents), which are activated by gentle "affective" touch and seem to be associated with scratching pleasurability and the reward system in the brain, can be involved in itch sensation and topographical differences of itch.
Learn More >With governments' increasing efforts to curb opioid prescription use and limit dose below the Centers for Disease Control and Prevention (CDC)-recommended threshold of 90 morphine milligram equivalents per day, little is known about prescription opioid patterns preceding opioid use disorder (OUD) or overdose. This study aimed to determine prescribed opioid fills and dose trajectories in the year before an incident OUD or overdose diagnosis using a 2005-2016 commercial healthcare database.
Learn More >Central post-stroke pain (CPSP) can occur after stroke in the somatosensory pathway that includes the posterolateral region of the thalamus. Tactile allodynia, in which innocuous tactile stimuli are perceived as painful, is common in patients with CPSP. Previous brain imaging studies have reported plastic changes in brain activity in patients with tactile allodynia after stroke, but a causal relationship between such changes and the symptoms has not been established. We recently developed a non-human primate (macaque) model of CPSP based on thalamic lesions, in which the animals show behavioral changes consistent with the occurrence of tactile allodynia. Here we performed functional magnetic resonance imaging under propofol anesthesia to investigate the changes in brain activation associated with the allodynia in this CPSP model. Before the lesion, innocuous tactile stimuli significantly activated the contralateral sensorimotor cortex. When behavioral changes were observed after the thalamic lesion, equivalent stimuli significantly activated pain-related brain areas, including the posterior insular cortex (PIC), secondary somatosensory cortex (SII), anterior cingulate cortex (ACC), and amygdala. Moreover, when either PIC/SII or ACC was pharmacologically inactivated, the signs of tactile allodynia were dampened. Our results show that increased cortical activity plays a role in CPSP-induced allodynia.
Learn More >We have previously reported that the microtubule-associated collapsin response mediator protein 2 (CRMP2) is necessary for the expression of chronic pain. CRMP2 achieves this control of nociceptive signaling by virtue of its ability to regulate voltage-gated calcium and sodium channels. To date, however, no drugs exist that target CRMP2. Recently, the small molecule edonerpic maleate (1 -{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate), a candidate therapeutic for Alzheimer's disease was reported to be a novel CRMP2 binding compound with the potential to decrease its phosphorylation level in cortical tissues in vivo. Here we sought to determine the mechanism of action of edonerpic maleate and test its possible effect in a rodent model of chronic pain. We observed: (i) no binding between human CRMP2 and edonerpic maleate; (ii) edonerpic maleate had no effect on CRMP2 expression and phosphorylation in dorsal root ganglion (DRG) neurons; (iii) edonerpic maleate-decreased calcium but increased sodium current density in DRG neurons; and (iv) edonerpic maleate was ineffective in reversing post-surgical allodynia in male and female mice. Thus, while CRMP2 inhibiting compounds remain a viable strategy for developing new mechanism-based pain inhibitors, edonerpic maleate is an unlikely candidate.
Learn More >Migraine pathophysiology is complex and probably involves cortical and subcortical alterations. Structural and functional brain imaging studies indicate alterations in the higher order visual cortex in patients with migraine. Arterial spin labeling magnetic resonance imaging (ASL-MRI) is a non-invasive imaging method for assessing changes in cerebral blood flow (CBF) in vivo.
Learn More >Migraine is a complex brain disorder that involves abnormal activation of the trigeminocervical complex (TCC). Since an increase of oxytocin concentration has been found in cerebrospinal fluid in migrainous patients and intranasal oxytocin seems to relieve migrainous pain, some studies suggest that the hypothalamic neuropeptide oxytocin may play a role in migraine pathophysiology. However, it remains unknown whether oxytocin can interact with the trigeminovascular system at TCC level. The present study was designed to test the above hypothesis in a well-established electrophysiological model of migraine. Using anesthetized rats, we evaluated the effect of oxytocin on TCC neuronal activity in response to dural nociceptive trigeminovascular activation. We found that spinal oxytocin significantly reduced TCC neuronal firing evoked by meningeal electrical stimulation. Furthermore, pretreatment with L-368,899 (a selective oxytocin receptor antagonist, OTR) abolished the oxytocin-induced inhibition of trigeminovascular neuronal responses. This study provides the first direct evidence that oxytocin, probably by OTR activation at TCC level inhibited dural nociceptive-evoked action potential in this complex. Thus, targeting OTR at TCC could represent a new avenue to treat migraine.
Learn More >Migraine is a chronic neurological disorder characterized by attacks of moderate or severe headache accompanying functionally and structurally maladaptive changes in brain. As the headache days/month is often measured by patient self-report and tends to be overestimated than actually experienced, the possibility of using neuroimaging data to predict migraine attack frequency is of great interest. To identify neuroimaging features that could objectively evaluate patients' headache days, a total of 179 migraineurs were recruited from two data center with one dataset used as the training/test cohort and the other used as the validating cohort. The guidelines for controlled trials of prophylactic treatment of chronic migraine in adults were used to identify the frequency of attacks and migraineurs were divided into low (MOl) and high (MOh) subgroups. Whole-brain functional connectivity was used to build multivariate logistic regression models with model iteration optimization to identify MOl and MOh. The best model accurately discriminated MOh from MOl with AUC of 0.91 (95%CI [0.86, 0.95]) in the training/test cohort and 0.79 in the validating cohort. The discriminative features were mainly located within the limbic lobe, frontal lobe, and temporal lobe. Permutation tests analysis demonstrated that the classification performance of these features was significantly better than chance. Furthermore, the indicator of functional connectivity had a higher odds ratio than behavioral variables with implementing a holistic regression analysis. The current findings suggested that the migraine attack frequency could be distinguished by using machine-learning algorithms, and highlighted the role of brain functional connectivity in revealing underlying migraine-related neurobiology.
Learn More >It has been known that algogens and cooling could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Importantly, we show that noxious or cooling agents inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which evokes a mix of itch and pain sensations, enhances both excitatory and inhibitory spontaneous synaptic transmission onto GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby pain inhibits itch by suppressing the function of GRPR neurons.
Learn More >Voltage-gated sodium channels (Nas) are a key determinant of neuronal signalling. Neurotoxins from diverse taxa that selectively activate or inhibit Na channels have helped unravel the role of Na channels in diseases, including chronic pain. Spider venoms contain the most diverse array of inhibitor cystine knot (ICK) toxins (knottins). This review provides an overview on how spider knottins modulate Na channels and describes the structural features and molecular determinants that influence their affinity and subtype selectivity. Genetic and functional evidence support a major involvement of Na subtypes in various chronic pain conditions. The exquisite inhibitory properties of spider knottins over key Na subtypes make them the best lead molecules for the development of novel analgesics to treat chronic pain.
Learn More >Fibromyalgia syndrome (FMS) is a chronic pain syndrome characterized by widespread pain and a variety of non-pain symptoms. Central sensitivity phenomena are found consistently in FMS. Additionally, several researchers proclaimed that a subgroup of FMS patients may present with unrecognized peripheral small fiber neuropathy (SFN). Laser-evoked brain potentials (LEP) are considered as a reliable method for the functional assessment of the thermo-nociceptive system, including the evaluation of SFN.
Learn More >Itch is a somatosensory sensation that informs the organism about the presence of potentially harmful substances or parasites, and initiates scratching to remove the threat. Itch-inducing (pruritogenic) substances activate primary afferent neurons in the skin through interactions with specific receptors that converts the stimulus into an electrical signal. These signals are conveyed to the dorsal horn of the spinal cord through the release of neurotransmitters such as natriuretic polypeptide b and somatostatin, leading to an integrated response within a complex spinal interneuronal network. A large sub-population of somatostatin-expressing spinal interneurons also carry the Neuropeptide Y (NPY) Y1 receptor, indicating that NPY and somatostatin partly regulate the same neuronal pathway. This review focuses on recent findings regarding the role of the NPY/Y1 and somatostatin/SST receptor in itch, and also presents data integrating the two neurotransmitter systems.
Learn More >We previously reported that early life stress (ELS) dysregulated glucocorticoid receptor (GR) and corticotrophin-releasing hormone (CRH) expression in the central nucleus of the amygdala (CeA). Epigenetic modifications serve as memories of adverse events that occurred during early life. Therefore, we hypothesized that epigenetic mechanisms alter GR and CRH expression in the CeA and underlie chronic visceral pain after ELS.
Learn More >Neuropathic pain (NeP) is commonly encountered in patients with diseases associated with spinal cord damage (e.g., spinal cord injury (SCI) and compressive myelopathy). Recent studies described persistent glial activation and neuronal hyperactivity in SCI, but the pathomechanisms of NeP in chronic compression of the spinal cord remains elusive. The purpose of the present study was to determine the roles of microglia and infiltrating macrophages in NeP. The study was conducted in chimeric spinal hyperostotic mice (ttw/ttw), characterized by chronic progressive compression of the spinal cord as a suitable model of human compressive myelopathy. The severity of spinal cord compression correlated with proportion of activated microglia and hematogenous macrophages. Spinal cord compression was associated with overexpression of mitogen-activated protein kinases (MAPKs) in infiltrating macrophages and reversible blood-spinal cord barrier (BSCB) disruption in the dorsal horns. Our results suggested that chronic neuropathic pain in long-term spinal cord compression correlates with infiltrating macrophages, activated microglial cells and the associated damage of BSCB, together with overexpression of p-38 MAPK and p-ERK1/2 in these cells. Our findings are potentially useful for the design of new therapies to alleviate chronic neuropathic pain associated with compressive myelopathy.
Learn More >Fibromyalgia (FM) is a disabling syndrome characterized by chronic pain associated with fatigue. Its pathogenesis is unknown, but alterations in central sensitization, involving an imbalance of brain-derived neurotrophic factor (BDNF) and inflammatory biomarkers, appear to be implicated. The aim of this study was to evaluate the impact of attachment-based compassion therapy (ABCT) on levels of BDNF, the inflammatory markers TNF-α, IL-6, IL-10, and the C-reactive protein (CRP), analysing whether biomarkers play a mediating/moderating role in improvements in FM functional status. Thirty-four female patients with FM participated in a RCT and were assigned to ABCT or relaxation therapy. Blood extractions were conducted at baseline and post-intervention, with self-report assessments of functional status (FIQ) at baseline, post-intervention and 3-month follow-up. A pro-inflammatory composite was obtained by summing up IL-6, TNF-α and CRP normalized values. Non-parametric tests, analysis of variance and regression models were used to evaluate treatment and mediation/moderation. Compared to relaxation therapy, ABCT showed significant improvements in FIQ and decreases in BDNF, CRP, and pro-inflammatory composite. Changes in BDNF had a mediating role in FIQ. ABCT seems to reduce BDNF and appears to have anti-inflammatory effects in FM patients. Reductions in BDNF could be a mechanism of FM functional status improvement.Clinical Trial Registration: http://ClinicalTrials.gov , identifier NCT02454244. Date: May 27th, 2015.
Learn More >Opioids, which carry a high risk for addiction and overdose, are commonly prescribed after corneal surgery. Data are lacking describing opioid prescribing practices and opioid needs by patients after ophthalmic surgery.
Learn More >Patients with chronic pain and especially with craniomandibular disorder (CMD) show specific psychopathology in trait anxiety. In a previous longitudinal functional imaging study on CMD we found that the anterior insula was modulated by successful therapy intervention and pain relief. We here intended to investigate possible associations between anterior insula fMRI-activation during occlusal movements and trait anxiety over a splint therapy approach in patients with CMD. Three fMRI-investigations of a craniomandibular occlusion task were performed together with pain score evaluations and scoring of trait anxiety (State -Trait Anxiety Inventory; STAI) before, after two weeks and after three months of a DIR-mandibular splint therapy in a small group (n = 9) of CMD patients. Patients showed increased anxiety levels before therapy assessed with the STAI and the depression and anxiety scale (DASS). Besides of relevant reduction in pain the STAI decreased over time. Reduction in STAI was associated with anterior insular fMRI-activation reduction on both hemispheres. We conclude that the anxiety driven anticipation of pain related to occlusal trigger is processed in the anterior insula and might therefore be a main driver of therapeutic intervention by the splint therapy in CMD.
Learn More >To assess the onset of efficacy for fremanezumab in chronic migraine by evaluating pain-related clinical measures at different time points.
Learn More >Neuropathic pain is a common, debilitating clinical issue. Here, the weighted gene co-expression network analysis (WGCNA) was used to identify the specific modules and hub genes that are related to neuropathic pain. The microarray data set of a neuropathic rat model induced by tibial nerve transection (TNT), including dorsal root ganglion (DRG) tissues from TNT model (n = 7) and sham (n = 8) rats, was downloaded from the ArrayExpress database (E-MTAB-2260). The co-expression network modules were identified by the WGCNA package. The protein-protein interaction (PPI) network was constructed, and the node with highest level of connectivity in the network were identified as the hub gene. A total of 1,739 genes and seven modules were identified. The most significant module was the brown module, which contained 215 genes that were primarily associated with the biological process of the defense response and molecular function of calcium ion binding. Furthermore, Ccl2, Fos and Timp1 which were identified as the hub genes in the PPI network and two subnetworks separately. The in vivo studies validated that mRNA and protein levels of Ccl2, Fos and Timp1 were upregulated in DRG and spinal cord tissues after TNT. This study offers novel insights into the molecular mechanisms of neuropathic pain in the context of peripheral nerve injury.
Learn More >Examine the effectiveness of specific modes of exercise training in non-specific chronic low back pain (NSCLBP).
Learn More >Mechanisms of postherpetic neuralgia (PHN) are still not clear. Transcripts such as microRNA (miRNA) and circular RNA (circRNA) in the affected skin may take part in the initiation and development of this neuropathic pain; however, their expression profiles in skins of PHN patients have not been reported. The PHN affected skin and the mirror skin were collected and subjected to miRNA and circRNA microarray, and expression profiles were comparatively analyzed. There were 317 differently expressed miRNAs in PHN affected skin compared with mirror skin (fold change ≥2.0), and 13 of them showed fold change >10 in the PHN skin. Only one circRNA, hsa_circRNA_405463 showed fold change >2 in PHN skin, however, 31 circRNAs with fold change ≥1.5. To evaluate functions of differential miRNAs, their target mRNAs were predicted and bioinformatics analyses including gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway were conducted. Target mRNAs significantly (P<0.05) enriched in 85 pathways, such as FoxO, AMPK, MAPK and pathway. These data reported for the first time that miRNA and circRNA differentially expressed in the PHN skin and these transcripts with abnormal expression could be potential targets to treat PHN.
Learn More >Transient receptor potential vanilloid 1 (TRPV1) not only is activated by multiple stimuli but also is involved with histamine-induced itch. The effects of TRPV1 on morphine-induced itch are unknown. We examined the effects of intrathecal administration of TRPV1 antagonist on morphine-induced itch, body temperature, and antinociception for mice.
Learn More >Neurofibromatosis type 1 (NF1) is a neurogenetic disorder affecting 1 in 3000 people worldwide, where individuals are prone to develop benign and malignant tumors. In addition, many people with NF1 complain of pain that limits their daily functioning. Due to the complexity of the disorder, there are few options for treating pain symptoms besides surgery and medications. Moreover, the spectrum of pain symptomatology and treatment, as well as the mechanisms underlying NF1-associated pain, has been understudied.
Learn More >Effects of emotion suppression on physical health might be contingent on culture. Existing research on emotion regulation has mainly included western participants. Herewith the question arises, whether this gained expertise is transferable to an Asian culture.
Learn More >Non-synaptic transmission is pervasive throughout the nervous system. It appears especially prevalent in peripheral ganglia, where non-synaptic interactions between neighboring cell bodies have been described in both physiological and pathological conditions, a phenomenon referred to as cross-depolarization (CD) and thought to play a role in sensory processing and chronic pain. CD has been proposed to be mediated by a chemical agent, but its identity has remained elusive. Here, we report that in the rat dorsal root ganglion (DRG), the P2Y1 purinergic receptor (P2RY1) plays an important role in regulating CD. The effect of P2RY1 is cell-type specific: pharmacological blockade of P2RY1 inhibited CD in A-type neurons while enhancing it in C-type neurons. In the nodose ganglion of the vagus, CD requires extracellular calcium in a large percentage of cells. In contrast, we show that in the DRG extracellular calcium appears to play no major role, pointing to a mechanistic difference between the two peripheral ganglia. Furthermore, we show that DRG glial cells also play a cell-type specific role in CD regulation. Fluorocitrate-induced glial inactivation had no effect on A-cells but enhanced CD in C-cells. These findings shed light on the mechanism of CD in the DRG and pave the way for further analysis of non-synaptic neuronal communication in sensory ganglia.
Learn More >: Chronic neuropathic pain (NP) is an incapacitating illness caused by alesion of the somatosensory nervous system and is associated with several disease or syndromes. Since current treatment options lack adequate efficacy in the majority of patients, ketamine is often administered to treat refractory NP.: This review gives an overview of new ketamine pharmacokinetic data including data on intranasal and inhaled ketamine. The outcome of seven systematic reviews and meta-analyses, published since 2012, on ketamine efficacy in NP is discussed. The reader will additionally get an understanding of ketamine's complex metabolism with emphasis on the metabolite hydroxynorketamine.: Proof of sustained, large effects of ketamine in the treatment of NP from randomized controlled clinical trials is lacking, although we cannot exclude selective ketamine efficacy in patients with central sensitization, opioid-induced hyperalgesia or opioid tolerance. Interestingly, data from observational trials and case series do suggest efficacy of ketamine in producing effective pain relief in NP with positive patient-related outcome measures. Additional randomized trials in often ill-defined groups of chronic pain patients are not useful and we suggest to conduct future studies in NP patients with central sensitization and/or with opioid refractory severe NP.
Learn More >Given the readily increasing membership of the pain physician community, efforts toward correcting notable gender disparities are instrumental. The under-representation of women is particularly prevalent within leadership roles in academic medicine, thought to be driven largely by diminished research efforts. Consequently, we aimed to characterize gender differences among the highest impact pain literature.
Learn More >The pathogenesis of cancer induced bone pain (CIBP) is extremely complex, and glutamate receptor dysfunction plays an important role in the formation of CIBP. Synapse-associated protein 102 (SAP102) anchors glutamate receptors in the postsynaptic membrane. However, its effect on hyperalgesia formation in CIBP has not been clarified. This study investigated the role of SAP102 in the formation of hyperalgesia in rats with CIBP SAP102 is present in spinal dorsal horn neurons, but not in astrocytes or microglia. NMDAR-NR2B is localized with neurons. In addition, SAP102 and NMDAR-NR2B expression levels in spinal dorsal horn tissues were detected by Western blot and co-immunoprecipitation. Intrathecal injection of lentiviral vector of RNAi to knockdown SAP102 expression in the spinal dorsal horn significantly attenuated abnormal mechanic pain when compared to non-coding lentiviral vector. These findings indicate that SAP102 can anchor NMDA receptors to affect hyperalgesia formation in bone cancer pain.
Learn More >Pain is a major primary health care problem. Emerging studies show that inhibition of spinal microglial activation reduces pain. However, the precise mechanisms by which microglial activation contributes to nociceptive synaptic transmission remain unclear. In this study, we measured spontaneous synaptic activity of miniature excitatory postsynaptic currents (mEPSCs) in rat spinal cord superficial dorsal horn (SDH, laminae I and II) neurons. Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) increased the frequency, but not amplitude, of mEPSCs in SDH neurons. Microglial inhibitors minocycline and paeonol, as well as an astrocyte inhibitor, a P2Y1 receptor (P2Y1R) antagonist, and a metabotropic glutamate receptor 5 (mGluR5) antagonist, all prevented LPS-induced enhancement of mEPSC frequency. In mouse behavioral testing, minocycline and paeonol effectively reduced acetic acid-induced writhing and LPS-induced hyperalgesia. These results indicate that LPS-activated microglia release ATP, which stimulates astrocyte P2Y1Rs to release glutamate, triggering presynaptic mGluR5 receptors and increasing presynaptic glutamate release, leading to an increase in mEPSC frequency and enhancement of nociceptive transmission in SDH neurons. We propose that these effects can serve as a new electrophysiological model for evaluating pain. Moreover, we predict that pharmacologic agents capable of inhibiting the LPS-induced enhancement of mEPSC frequency in SDH neurons will have analgesic effects.
Learn More >Orofacial pain syndromes encompass several clinically defined and classified entities. The focus here is on the role of clinical neurophysiologic and psychophysical tests in the diagnosis, differential diagnosis, and pathophysiological mechanisms of definite trigeminal neuropathic pain and other chronic orofacial pain conditions (excluding headache and temporomandibular disorders). The International Classification of Headache Disorders 2018 classifies these facial pain disorders under the heading Painful cranial neuropathies and other facial pains. In addition to unambiguous painful posttraumatic or postherpetic trigeminal neuropathies, burning mouth syndrome, persistent idiopathic facial and dental pain, and trigeminal neuralgia have also been identified with neurophysiologic and quantitative sensory testing to involve the nervous system. Despite normal clinical examination, these all include clusters of patients with evidence for either peripheral or central nervous system pathology compatible with the subclinical end of a continuum of trigeminal neuropathic pain conditions. Useful tests in the diagnostic process include electroneuromyography with specific needle, neurography techniques for the inferior alveolar and infraorbital nerves, brain stem reflex recordings (blink reflex with stimulation of the supraorbital, infraorbital, mental, and lingual nerves; jaw jerk; masseter silent period), evoked potential recordings, and quantitative sensory testing. Habituation of the blink reflex and evoked potential responses to repeated stimuli evaluate top-down inhibition, and navigated transcranial magnetic stimulation allows the mapping of reorganization within the motor cortex in chronic neuropathic pain. With systematic use of neurophysiologic and quantitative sensory testing, many of the current ambiguities in the diagnosis, classification, and understanding of chronic orofacial syndromes can be clarified for clinical practice and future research.
Learn More >Previous studies reported that long-term nociceptive stimulation could result in neurovascular coupling (NVC) dysfunction in brain, but these studies were based mainly on unimodal imaging biomarkers, thus could not comprehensively reflect NVC dysfunction. We investigated the potential NVC dysfunction in chronic migraine by exploring the relationship between neuronal activity and cerebral perfusion maps. The Pearson correlation coefficients between these 2 maps were defined as the NVC biomarkers. NVC biomarkers in migraineurs were significantly lower in left inferior parietal gyrus (IPG), left superior marginal gyrus (SMG) and left angular gyrus (AG), but significantly higher in right superior occipital gyrus (SOG), right superior parietal gyrus (SPG), and precuneus. These brain regions were located mainly in parietal or occipital lobes and were related to visual or sensory information processing. ALFF-CBF in right SPG was positively correlated with disease history and that in right precuneus was negatively correlated with migraine persisting time. fALFF-CBF in left SMG was negatively related to headache frequency and positively related to health condition. fALFF-CBF in left AG was negatively related to headache frequency and positively related to disease history and health condition. In conclusion, multi-modal MRI could be used to detect NVC dysfunction in chronic migraine patients, which is a new method to assess the impact of chronic pain to the brain.
Learn More >Chemotherapy, nerve injuries, or diseases like multiple sclerosis can cause pathophysiological processes of persistent and neuropathic pain. Thereby, the activation threshold of ion channels is reduced in peripheral sensory neurons to normally noxious stimuli like heat, cold, acid, or mechanical due to sensitization processes. This leads to enhanced neuronal activity, which can result in mechanical allodynia, cold allodynia, thermal hyperalgesia, spontaneous pain, and may initiate persistent and neuropathic pain. The treatment options for persistent and neuropathic pain patients are limited; for about 50% of them, current medication is not efficient due to severe side effects or low response to the treatment. Therefore, it is of special interest to find additional treatment strategies. One approach is the control of neuronal sensitization processes. Herein, signaling lipids are crucial mediators and play an important role during the onset and maintenance of pain. As preclinical studies demonstrate, lipids may act as endogenous ligands or may sensitize transient receptor potential (TRP)-channels. Likewise, they can cause enhanced activity of sensory neurons by mechanisms involving G-protein coupled receptors and activation of intracellular protein kinases. In this regard, oxidized metabolites of the essential fatty acid linoleic acid, 9- and 13-hydroxyoctadecadienoic acid (HODE), their dihydroxy-metabolites (DiHOMEs), as well as epoxides of linoleic acid (EpOMEs) and of arachidonic acid (EETs), as well as lysophospholipids, sphingolipids, and specialized pro-resolving mediators (SPMs) have been reported to play distinct roles in pain transmission or inhibition. Here, we discuss the underlying molecular mechanisms of the oxidized linoleic acid metabolites and eicosanoids. Furthermore, we critically evaluate their role as potential targets for the development of novel analgesics and for the treatment of persistent or neuropathic pain.
Learn More >Fear of movement-related pain leads to two types of avoidance behavior: excessive avoidance and pain-inhibited movement. Excessive avoidance is an absence of movement by fear, and pain-inhibited movements involve a change in motor behavior for the purpose of protecting the painful part. Here, we sought to clarify the acquisition process and adaptation of fear for each avoidance behavior. Thirty-one female and 13 male (age 20.9 ± 2.1 years) subjects could decide persistent behaviors: approach with an intense pain stimulus, pain-inhibited movement with weak pain stimulus, or excessive avoidance with no pain in acquisition and test phases. In the subsequent extinction phase, the pain stimulus was omitted. Subjects were divided into an approach group ( = 24), a pain-inhibited movement group ( = 10), and an excessive avoidance group ( = 10) by cluster analysis. The response latencies in approach and pain-inhibited movement groups were not affected by conditioned pain. The subjects in the excessive avoidance group exhibited delayed response latencies, and their high-fear responses remained in the acquisition, test, and extinction phases. In addition, the excessive avoidance group showed high harm avoidance and high trait anxiety. This study demonstrated that differences in pain-related avoidance behaviors are affected by psychological traits. Pain-related excessive avoidance behavior indicated a maladaptive fear, but pain-inhibited movement did not.
Learn More >Several control conditions, such as penetrating sham acupuncture and non-penetrating placebo needles, have been used in clinical trials on acupuncture effects in chronic pain syndromes. All these control conditions are surprisingly effective with regard to their analgesic properties. These findings have fostered a discussion as to whether acupuncture is merely a placebo. Meta-analyses on the clinical effectiveness of placebo revealed that placebo interventions in general have minor, clinically important effects. Only in trials on pain and nausea, including acupuncture studies, did placebo effects vary from negligible to clinically important. At the same time, individual patient meta-analyses confirm that acupuncture is effective for the treatment of chronic pain, including small but statistically significant differences between acupuncture and sham acupuncture. All acupuncture control conditions induce , a distinct stimulation associated with pain and needling which has been shown to be a nociceptive/pain stimulus. Acupuncture therefore probably activates the pain matrix in the brain in a bottom-up fashion via the spino-thalamic tract. Central nervous system effects of acupuncture can be modulated through expectations, which are believed to be a central component of the placebo response. However, further investigation is required to determine how strong the influence of placebo on the attenuation of activity in the pain matrix really is. A meta-analysis of individual participant functional magnetic imaging data reveals only weak effects of placebo on the activity of the pain network. The clinical acupuncture setting is comprised of a combination of a distinct neurophysiological stimulus, the needling stimulus/experience, and a complex treatment situation. A broader definition of placebo, such as that proposed by Howick (2017) acknowledges a role for expectation, treatment context, emotions, learning, and other contextual variables of a treatment situation. The inclusion of particular treatment feature as a definitional element permits a contextual definition of placebo, which in turn can be helpful in constructing future clinical trials on acupuncture.
Learn More >Pain is a frequent clinical symptom with significant impact on the patient's well-being. Therefore, adequate pain management is of utmost importance. While cannabinoids have become a more popular alternative to traditional types of pain medication among patients, the quality of evidence supporting the use of cannabinoids has been questioned. The beneficial and harmful effects of cannabinoids in patients with pain is unknown. Accordingly, we aim to assess the efficacy, tolerability and safety of cannabinoids (herbal, plant-derived extracts and synthetic) compared with placebo or no intervention for any type of pain.
Learn More >Chronic, non-specific low back pain is a major global cause of disability. One factor which might potentially contribute to ongoing pain is maladaptive variation in the level of activity in the lumbar musculature. Several studies have investigated this activity using surface electromyography, in varied muscles and during a number of functional activities. Due to differences in the applied methodology, the results have been difficult to compare, and previous reviews have been limited in scope. In this protocol, we aim to perform a comprehensive review of the effect of chronic low back pain on lumbar muscle activity.
Learn More >Exposure to chronic stress can influence nociception and further induce hyperalgesia. Whether stress modulation of pain in female animals occurs in an estrous cycle-specific manner is still unclear. We profiled the changes in nociception (thermal, mechanical, formalin-evoked acute and inflammatory pain) of female Sprague-Dawley rats after treatment with chronic unpredictable mild stress (CUMS) and investigated whether these changes occur in an estrous cycle-dependent manner. The results showed that CUMS female rats exhibited a lower mechanical withdrawal threshold in proestrus and estrus, a longer formalin-evoked licking time in metestrus and diestrus, but no changes in the latency time on the tail-flick test. The present study findings suggest that chronic stress induces mechanical and formalin-evoked acute hyperalgesia of female rats in an estrous cycle-dependent manner.
Learn More >Virtual reality (VR) has demonstrated efficacy for distraction from pain-related thoughts and exposure to feared movements. Little empirical VR research has focused on chronic pain management.
Learn More >Headache disorders are currently the sixth leading cause of disability across the globe and therefore carry a significant disease burden. This systematic review and meta-analysis aims to investigate the effects of yoga on headache disorders.
Learn More >Macrophage-derived high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) protein, plays a key role in the development of chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel in rodents. Endothelial thrombomodulin (TM) promotes thrombin-induced degradation of HMGB1, and TMα, a recombinant human soluble TM, abolishes peripheral HMGB1-induced allodynia in mice. We thus examined whether HMGB1, particularly derived from macrophages, contributes to oxaliplatin-induced neuropathy in mice and analyzed the anti-neuropathic activity of the TM/thrombin system.
Learn More >Erenumab, a fully human monoclonal antibody directed against the calcitonin gene-related peptide receptor, was approved for the prevention of episodic (EM) or chronic migraine (CM) at the monthly dose of 70 mg or 140 mg. We reviewed the available literature to understand if patients with prior preventive treatment failures benefit more from the 140 mg dose than the 70 mg.
Learn More >A prospective observational study.
Learn More >In recent years, the importance and prevalence of cognitive biases has gained scholarly attention in medicine as well as management science regarding a wide range of human activities.
Learn More >Chronic pain is common in military veterans with traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). Neurofeedback, or electroencephalograph (EEG) biofeedback, has been associated with lower pain but requires frequent travel to a clinic. The current study examined feasibility and explored effectiveness of neurofeedback delivered with a portable EEG headset linked to an application on a mobile device.
Learn More >To investigate the prevalence of chronic pain and its association with health-related quality of life (HRQoL) in a group of women, diagnosed with autism spectrum disorder (ASD) and/or attention deficit hyperactive disorder (ADHD) in childhood.
Learn More >Neuropathic pain with complications greatly affects patients worldwide. High mobility group box 1 (HMGB1) has been shown to contribute to the pathogenesis of neuropathic pain; thus, suppression of HMGB1 may provide a novel therapeutic option for neuropathic pain. Electroacupuncture (EA) has been indicated to be effective in attenuating neuropathic pain, but the underlying mechanism remains to be fully clarified. We aim to explore whether 2Hz EA stimulation regulates the spinal HMGB1/NF-κB signaling in neuropathic pain induced by spared nerve injury (SNI).
Learn More >Chronic low back pain has been observed to decrease movement coordination. However, it is unclear whether the existing alteration of inter-hemispheric synchrony of intrinsic activity in patients with chronic low back-related leg pain (cLBLP). The present study aims to investigate the alteration of homotopic connectivity and its clinical association with the cLBLP patients.
Learn More >Chronic pain often occurs in the elderly, particularly in the patients with neurodegenerative disorders such as Alzheimer's disease (AD). Although studies indicate that chronic pain correlates with cognitive decline, it is unclear whether chronic pain accelerates AD pathogenesis. In this review, we provide evidence that supports a link between chronic pain and AD and discuss potential mechanisms underlying this connection based on currently available literature from human and animal studies. Specifically, we describe two intertwined processes, locus coeruleus noradrenergic system dysfunction and neuroinflammation resulting from microglial pro-inflammatory activation in brain areas mediating the affective component of pain and cognition that have been found to influence both chronic pain and AD. These represent a pathological overlap that likely leads chronic pain to accelerate AD pathogenesis. Further, we discuss potential therapeutic interventions targeting noradrenergic dysfunction and microglial activation that may improve patient outcomes for those with chronic pain and AD.
Learn More >Nonsteroidal anti-inflammatory drugs and acetaminophen are cyclooxygenase inhibitors commonly used as symptomatic medicines for myofascial pain syndrome. Using the selective inhibitors celecoxib and zaltoprofen, cyclooxygenase-2 has been shown to be involved in the initiation, but not the maintenance, of muscular mechanical hyperalgesia induced by lengthening contractions, which serves as a useful model for the study of myofascial pain syndrome. The effect of other cyclooxygenase-2 inhibitors, such as acetylsalicylic acid, ibuprofen, loxoprofen sodium, and acetaminophen, on muscular mechanical hyperalgesia during maintenance has not been studied. Here, we examined the analgesic effects of the nonsteroidal anti-inflammatory drugs and acetaminophen on the model. Consistent with previous studies, mechanical withdrawal threshold of the muscle was significantly decreased and reached its lowest level 24 h after lengthening contractions. Celecoxib had no effect on muscular mechanical hyperalgesia, when orally administered 24 h after lengthening contractions. In contrast, acetylsalicylic acid, ibuprofen, loxoprofen sodium, and acetaminophen increased the withdrawal threshold, which had decreased by lengthening contractions, in a dose-dependent manner. These results demonstrate the analgesic actions of nonsteroidal anti-inflammatory drugs and acetaminophen in the maintenance process of lengthening contraction-induced muscular mechanical hyperalgesia, which may occur through cyclooxygenase-2 independent mechanisms.
Learn More >The aim of this study was to analyze the potential association between personality traits and onabotulinumtoxin A (onabotA) response in patients with chronic migraine (CM).
Learn More >Chronic pain is commonly reported in individuals with spinal cord injuries (SCI), with recent prevalence reported as high as 80%. Uncontrolled pain is known to decrease quality of life, mood and impact sleep. Spinal cord stimulation (SCS) for the treatment of refractory pain was first used in the SCI population in 1972. To date there have been no RCTs examining the effect of SCS for neuropathic pain post-SCI. A literature review in 2009 identified 27 studies, the majority prior to 2000, which included at least one SCI patient. Given the significant advancements in the field of SCS, this review examines the updated evidence of SCS for the treatment of neuropathic pain in individuals with SCI and provides guidance on future investigations.
Learn More >To compare dimensionality, item-level characteristics, scale-level reliability and construct validity of PROMIS® Physical Function short forms (PROMIS-PF) and 24-item Roland Morris Disability Questionnaire (RMDQ-24) in patients with chronic low back pain (LBP).
Learn More >Multimorbidity and pain are both common among older adults, yet pain treatment strategies for older patients with multimorbidity have not been well characterized. To assess the prevalence and relationship between multimorbidity and opioid prescribing in hospitalized older medical patients with pain. We collected demographic, morbidity, pain, and analgesic treatment data through structured review of the electronic medical records of a consecutive sample of 238 medical patients, aged ≥65 years admitted between November 2014 and May 2015 with moderate-to-severe pain by numerical pain rating scale (range 4-10). We used the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) to assess multimorbidity and cumulative illness burden. We examined the relationship between morbidity measures and opioid prescribing at hospital discharge using multivariate regression analysis. The mean age was 75 ± 8 years, 57% were female and 50% were non-White. Mean CIRS-G total score was 17 ± 6, indicating high cumulative illness burden. Ninety-nine percent of patients had multimorbidity, defined as moderate-to-extremely severe morbidity in ≥2 organ systems. Sixty percent of patients received an opioid prescription at discharge. In multivariate analyses adjusted for age, race, and gender, patients with a discharge opioid prescription were significantly more likely to have higher cumulative illness burden and chronic pain. Among older medical inpatients, multimorbidity was nearly universal, and patients with higher cumulative illness burden were more likely to receive a discharge opioid prescription. More studies of benefits and harms of analgesic treatments in older adults with multimorbidity are needed to guide clinical practice.
Learn More >Acupuncture is used to reduce chronic musculoskeletal pain. The common mechanism underlying these types of pain are peripheral and/or central sensitization. In the clinical setting, it is difficult to separate the peripheral from the central component of pain. Heat/capsaicin 45°C/0.075%-induced hyperalgesia provides a stable, human central sensitization model in which the peripheral component is also assessed.
Learn More >Migraine headache (MH) is a common disorder affecting millions of people in the United States. MH is substantially more prevalent in women compared to men. An association between migraine with or without aura and risk of cardiovascular disease (CVD) has been extensively reported. There are several proposed theories that may explain the pathophysiologic relationship between MH and CVD. This review will summarize the recent literature on this topic and provide an evidence-based perspective regarding the current knowledge and controversies regarding association of MH and CVD.
Learn More >Data on clinical presentation of Hemiplegic Migraine (HM) are quite limited in the literature, particularly in the pediatric age. The aim of the present study is to describe in detail the phenotypic features at onset and during the first years of disease of sporadic (SHM) and familial (FHM) pediatric hemiplegic migraine and to review the pertinent literature. Retrospective study of a cohort of children and adolescents diagnosed with hemiplegic migraine, recruited from 11 Italian specialized Juvenile Headache Centers. Forty-six cases (24 females) were collected and divided in two subgroups: 32 SHM (16 females), 14 FHM (8 females). Mean age at onset was 10.5 ± 3.8 y (range: 2-16 y). Mean duration of motor aura was 3.5 h (range: 5 min-48 h). SHM cases experienced more prolonged attacks than FHM cases, with significantly longer duration of both motor aura and of total HM attack. Sensory (65%) and basilar-type auras (63%) were frequently associated to the motor aura, without significant differences between SHM and FHM. At follow-up (mean duration 4.4 years) the mean frequency of attacks was 2.2 per year in the first year after disease onset, higher in FHM than in SHM cases (3.9 vs. 1.5 per year, respectively). A literature review retrieved seven studies, all but one were based on mixed adults and children cohorts. This study represents the first Italian pediatric series of HM ever reported, including both FHM and SHM patients. Our cohort highlights that in the pediatric HM has an heterogeneous clinical onset. Children present fewer non-motor auras as compared to adults and in some cases the first attack is preceded by transient neurological signs and symptoms in early childhood. In SHM cases, attacks were less frequent but more severe and prolonged, while FHM patients had less intense but more frequent attacks and a longer phase of active disease. Differently from previous studies, the majority of our cases, even with early onset and severe attacks, had a favorable clinical evolution.
Learn More >Chronic musculoskeletal pain affects more than 20% of the population, and the prevalence is increasing, causing suffering, loss of quality of life, disability, and an enormous expenditure on healthcare resources. The most common location for chronic pain is the spine. Many of the treatments used are mainly passive (pharmacological and invasive) and poor outcomes. The treatments currently applied in the public health system do not comply with the recommendations of the main clinical practice guidelines, which suggest the use of educational measures and physical exercise as the first-line treatment. A protocol based on active coping strategies is described, which will be evaluated through a clinical trial and which could facilitate the transfer of the recommendations of the clinical practice guidelines to a primary care setting.
Learn More >Opioids are prescribed to manage moderate to severe pain and can be used with older adults; however, they may lead to several adverse effects, including cognitive impairment.
Learn More >The modular organization of brain networks in trigeminal neuralgia patients has remained largely unknown. We aimed to analyze the brain modules and intermodule connectivity in patients with trigeminal neuralgia before and after percutaneous radiofrequency rhizotomy treatment to identify specific modules that may be associated with the development and brain plasticity of trigeminal neuralgia and to test the ability of modularity analysis to be a predictive imaging biomarker for the treatment effect in patients with trigeminal neuralgia.
Learn More >Migraine is a heterogeneous condition with multiple clinical manifestations. Machine-learning algorithms permit the identification of population groups providing analytical advantages over other modeling techniques.
Learn More >Background and aims Cervicogenic headache (CEH) is a debilitating condition and analgesics have limited effect. Percutaneous cryoneurolysis is thus still in use although the clinical evidence is lacking. We present a randomized, controlled study to assess the clinical efficacy of cryoneurolysis compared with a corticosteroid combined with a local anaesthetic. Methods In a university-based outpatient pain clinic we performed a randomized, double blinded, comparative study with an 18-week follow-up. After positive diagnostic test blocks 52 eligible patients were randomly allocated in a ratio of 3:2, 31 participants to occipital cryoneurolysis and 21 participants to injections of 1 mL methylprednisolone 40 mg/mL (Depo-Medrol®) combined with 1 mL bupivacaine 5 mg/mL. Results We observed a significant pain reduction of more than 50% in both treatment groups, slightly improved neck function and reduced number of opioid consumers. After 6-7-weeks, however, pain intensity increased gradually, but did not reach baseline within 18 weeks. Although cryoneurolysis provided a more prolonged effect, the group differences did not reach statistical significance. Health related quality of life and psychological distress improved minimally. A large number reported minor and transient side effects, but we found no significant group differences. After 18 weeks, 29% rated the headache as much improved, and 12 (24%) somewhat improved, but a large proportion (78%) reported need for further intervention/treatment. Conclusions Cryoneurolysis provided substantial, but temporary pain relief, and the effect was not significantly different from injections of a corticosteroid combined with a local anaesthetic. Participants were selected by a single test block, and the neurolytic procedure was guided by anatomical landmarks and nerve stimulation. A stricter patient selection and an ultrasound-guided technique might have improved the results. Cryoneurolysis provides temporary pain relief not significantly superior to corticosteroid injection, and the results question the value of occipital cryoneurolysis for a chronic pain condition like CEH. Implications Occipital cryoneurolysis may be considered when non-invasive treatments appear insufficient, but only for patients who have responded substantially to test blocks. A risk of local scar and neuroma formation by repeated cryoneurolysis, leading to neuropathic pain has been discussed by other researchers.
Learn More >Individual differences in emotional functioning, pain appraisal processing, and perceived social support may play a relevant role in the subjective experience of pain. Due to the paucity of data regarding individuals with Rheumatoid Arthritis (RA), the present study aimed to examine pain intensity, emotional functioning (psychological distress and alexithymia), pain appraisal (pain beliefs, pain catastrophizing, and pain-related coping strategies) and social support, and their relationships with the health-related quality of life (HRQoL) in patients with RA. Data were collected from 108 female patients diagnosed with RA. Clinically relevant levels of depressive and anxiety symptoms assessed by the HADS subscales were present in 34% and 41% of the patients, respectively, and about 24% of them exhibited the presence of alexithymia. The results of hierarchical multiple regression analyses showed that pain intensity, alexithymia, the maladaptive beliefs regarding the stability of pain and the coping strategy of guarding explained 54% of the variance in the physical component of HRQoL (p < 0.001). Depression subscale of the HADS, alexithymia, the coping strategy of resting, and the rumination factor of pain catastrophizing significantly explained 40% of the variance in the mental component of HRQoL (p < 0.001). The present findings provide evidence regarding the importance of emotional functioning and pain appraisal in the negative impact of RA on patients' quality of life. These findings provide additional evidence for the biopsychosocial model of chronic pain, further supporting the complex interaction between emotional, cognitive, and behavioral processes in patients with chronic pain.
Learn More >Human beings have long consumed opiates and opioids for pleasure and as a treatment for numerous ailments, most notably pain. North America is currently in the grips of a crisis of opioid-related overdoses, and stigma is considered a major driver of the harms. While it is well established that substance use in general is highly stigmatized, stigma is a complex concept and opioid-related stigma is not well understood. A lack of clarity on opioid-related stigma has practice and policy implications in terms of understanding the sources of opioid stigma, how it manifests in various contexts, its impact on affected groups, and the development of effective strategies to redress it.
Learn More >Chronic postsurgical neuropathic pain (CPSNP) is frequent. While prevalence varies considerably according to type of operation and means of evaluation, it can reach 37% following breast surgery. Identification of risk factors related to the procedure and to the patient and taking into account the development of new, minimally invasive surgical techniques is increasingly nerve-sparing and reduces the likelihood of injury. CPSNP diagnosis in daily practice is facilitated by simple and quickly usable tools such as the NP4 4-question test. Management is based on pharmacological (analgesics, antiepileptics, antidepressants, local anesthetics) and non-pharmacological (kinesitherapy, neurostimulation, psychotherapy) approaches. In light of the present review of the literature, the authors, who constitute an expert group specialized in pain management, anesthesia and surgery, express their support for topical treatments (lidocaine, capsaicin) in treatment of localized postsurgical neuropathic pain in adults.
Learn More >Spinal cord stimulation (SCS), a minimally invasive treatment option for long-term neuropathic pain, has been shown to be effective in patients with persisting neuropathic pain after spine surgery. However, little is known about the long-term cost and quality-of-life (QoL) patterns in SCS-treated patients. The aim is to describe the use of SCS, costs, pre-spine-surgery and post-spine-surgery QoL, and reported pain intensity, in patients who have undergone spine surgery and subsequent SCS implantation. The results will be related to outcome and cost in spine surgery patients in general.
Learn More >Poor sleep is common among adults with chronic low back pain (cLBP), but the influence of cLBP treatments, such as yoga and physical therapy (PT), on sleep quality is under studied.
Learn More >Central Neuropathic Pain (CNP) is a frequent chronic condition in people with spinal cord injury (SCI). Previously, we showed that using laboratory brain-computer interface (BCI) technology for neurofeedback (NFB) training, it was possible to reduce CNP in people with SCI. In this study, we show results of patient self-managed treatment in their homes with a BCI-NFB using a consumer EEG device.
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