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Chronic pain is a highly prevalent disease with poorly understood pathophysiology. In particular, the brain mechanisms mediating the transition from acute to chronic pain remain largely unknown. Here, we identify a subcortical signature of back pain. Specifically, subacute back pain patients who are at risk for developing chronic pain exhibit a smaller nucleus accumbens volume, which persists in the chronic phase, compared to healthy controls. The smaller accumbens volume was also observed in a separate cohort of chronic low-back pain patients and was associated with dynamic changes in functional connectivity. At baseline, subacute back pain patients showed altered local nucleus accumbens connectivity between putative shell and core, irrespective of the risk of transition to chronic pain. At follow-up, connectivity changes were observed between nucleus accumbens and rostral anterior cingulate cortex in the patients with persistent pain. Analysis of the power spectral density of nucleus accumbens resting-state activity in the subacute and chronic back pain patients revealed loss of power in the slow-5 frequency band (0.01 to 0.027 Hz) which developed only in the chronic phase of pain. This loss of power was reproducible across two cohorts of chronic low-back pain patients obtained from different sites and accurately classified chronic low-back pain patients in two additional independent datasets. Our results provide evidence that lower nucleus accumbens volume confers risk for developing chronic pain and altered nucleus accumbens activity is a signature of the state of chronic pain.
Learn More >Gamma band oscillations (GBOs) elicited by transient nociceptive stimuli are one of the most promising biomarkers of pain across species. Still, whether these GBOs reflect stimulus encoding in the primary somatosensory cortex (S1) or nocifensive behavior in the primary motor cortex (M1) is debated. Here we recorded neural activity simultaneously from the brain surface as well as at different depths of the bilateral S1/M1 in free-moving male rats receiving nociceptive stimulation. GBOs measured from superficial layers of S1 contralateral to the stimulated paw not only had the largest magnitude, but also showed the strongest temporal and phase coupling with epidural GBOs. Also, spiking of superficial S1 interneurons had the strongest phase coherence with epidural GBOs. These results provide the first direct demonstration that scalp GBOs, one of the most promising pain biomarkers, reflect neural activity strongly coupled with the fast-spiking of interneurons in the superficial layers of the S1 contralateral to the stimulated side. Our results provide the direct demonstration that nociceptive-induced gamma band oscillations (GBOs) measured at population level, one of the most promising biomarker of pain perception, reflect neural activity coupled with the spike firing of interneurons in the superficial layers of the primary somatosensory cortex (S1) contralateral to the side of nociceptive stimulation. These results conclusively solve the ongoing debate about whether nociceptive-induced GBOs recorded with scalp electroencephalogram (EEG) or epidurally reflect stimulus encoding in the S1 or nocifensive behavior in the primary motor cortex (M1), and will therefore influence how experiments in pain neuroscience will be designed and interpreted.
Learn More >Complex regional pain syndrome type I (CRPS-I) is characterized by intractable chronic pain. Poor understanding of the underlying mechanisms of CRPS-I accounts for the current unsatisfactory treatment. Antioxidants and antagonists of the oxidative stress-sensitive channel, the transient receptor potential ankyrin 1 (TRPA1), have been found to attenuate acute nociception and delayed allodynia in models of CRPS-I, evoked by ischemia and reperfusion (I/R) of rodent hind limb (chronic post ischemia pain, CPIP). However, it is unknown how I/R may lead to chronic pain mediated by TRPA1. Here, we report that the prolonged (day 1-15) mechanical and cold allodynia in the hind limb of CPIP mice was attenuated permanently in Trpa1 mice and transiently after administration of TRPA1 antagonists (A-967079 and HC-030031) or an antioxidant (α-lipoic acid). Indomethacin treatment was, however, ineffective. We also found that I/R increased macrophage (F4/80 cell) number and oxidative stress markers, including 4-hydroxynonenal (4-HNE), in the injured tibial nerve. Macrophage-deleted MaFIA (Macrophage Fas-Induced Apoptosis) mice did not show I/R-evoked endoneurial cell infiltration, increased 4-HNE and mechanical and cold allodynia. Furthermore, Trpa1 mice did not show any increase in macrophage number and 4-HNE in the injured nerve trunk. Notably, in mice with selective deletion of Schwann cell TRPA1 (Plp1-Cre;Trpa1 mice), increases in macrophage infiltration, 4-HNE and mechanical and cold allodynia were attenuated. In the present mouse model of CRPS-I, we propose that the initial oxidative stress burst that follows reperfusion activates a feed forward mechanism that entails resident macrophages and Schwann cell TRPA1 of the injured tibial nerve to sustain chronic neuroinflammation and allodynia. Repeated treatment one hour before and for 3 days after I/R with a TRPA1 antagonist permanently protected CPIP mice against neuroinflammation and allodynia, indicating possible novel therapeutic strategies for CRPS-I.
Learn More >Although pain is a prevalent nonmotor symptom in Parkinson's disease (PD), it is undertreated, in part because of our limited understanding of the underlying mechanisms. Considering that the basal ganglia are implicated in pain sensation, and that their synaptic outputs are controlled by the subthalamic nucleus (STN), we hypothesized that the STN might play a critical role in parkinsonian pain hypersensitivity. To test this hypothesis, we established a unilateral parkinsonian mouse model with moderate lesions of dopaminergic neurons in the substantia nigra. The mice displayed pain hypersensitivity and neuronal hyperactivity in the ipsilesional STN and in central pain-processing nuclei. Optogenetic inhibition of STN neurons reversed pain hypersensitivity phenotypes in parkinsonian mice, while hyperactivity in the STN was sufficient to induce pain hypersensitivity in control mice. We further demonstrated that the STN differentially regulates thermal and mechanical pain thresholds through its projections to the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi)/ventral pallidum (VP), respectively. Interestingly, optogenetic inhibition of STN-GPi/STN-VP and STN-SNr projections differentially elevated mechanical and thermal pain thresholds in parkinsonian mice. In summary, our results support the hypothesis that the STN and its divergent projections play critical roles in modulating pain processing under both physiological and parkinsonian conditions, and suggest that inhibition of individual STN projections may be a therapeutic strategy to relieve distinct pain phenotypes in PD.
Learn More >Constipation is the most common adverse event (AE) of opioid therapy. This multicenter, phase 2 study evaluated the efficacy and safety of linaclotide in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain syndromes (NCT02270983). Adults with OIC (<3 spontaneous bowel movements [SBMs]/week) related to chronic noncancer pain were randomized 1:1:1 to receive linaclotide 145 µg, linaclotide 290 µg, or placebo once daily for 8 weeks. The primary endpoint was change from baseline in 8-week SBM frequency rate (SBMs/week). Secondary efficacy endpoints included 6/8-week SBM 3 + 1 responders, time to first SBM, and changes from baseline in 8-week stool consistency, abdominal bloating, and straining. Additional endpoints included treatment satisfaction and adequate relief responders. In total, 254 patients were randomized: 87, 88, and 79 received linaclotide 145 µg, linaclotide 290 µg, and placebo, respectively. The mean changes from baseline in SBMs/week during the treatment period were 2.9 and 3.5 in the linaclotide 145 and 290 µg groups (P < 0.01 for both doses), respectively, vs 1.6 in the placebo group. Diarrhea, the most common AE, was generally mild, resulting in 1.1%, 5.7%, and 1.3% of patients discontinuing in the linaclotide 145 μg, linaclotide 290 μg, and placebo groups, respectively. No serious AEs related to diarrhea were reported in any treatment group. Compared with placebo, linaclotide-treated patients had significant improvements in stool consistency, straining, abdominal bloating, and treatment satisfaction scores (P < 0.05). Linaclotide significantly improved OIC symptoms and was well tolerated in patients with chronic noncancer pain.
Learn More >Morphine-induced alterations in sphingolipid metabolism in the spinal cord and increased formation of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) have been implicated in the development of morphine-induced hyperalgesia (OIH; increased pain sensitivity) and antinociceptive tolerance. These adverse effects hamper opioid use for treating chronic pain and contribute to dependence and abuse. S1P produces distinct effects through five G protein-coupled receptors (S1PR1-5) and several intracellular targets. How S1P exerts its effects in response to morphine remains unknown. Here, we report that S1P contributes to the development of OIH and tolerance through S1P1 receptor subtype 1 (S1PR1) signaling in uninjured male and female rodents that can be blocked by targeting S1PR1 with S1PR1 antagonists or RNA silencing. In mouse neuropathic pain models, S1PR1 antagonists blocked the development of tolerance to the anti-allodynic effects of morphine without altering morphine pharmacokinetics and prevented prolonged morphine-induced neuropathic pain. Targeting S1PR1 reduced morphine-induced neuroinflammatory events in the dorsal horn of the spinal cord: increased glial marker expression, mitogen-activated protein kinase p38 and nuclear factor κB activation and increased inflammatory cytokine expression, such as interleukin-1β, a cytokine central in the modulation of opioid-induced neural plasticity. Our results identify S1PR1 as a critical path for S1P signaling in response to sustained morphine and reveal downstream neuroinflammatory pathways impacted by S1PR1 activation. Our data support investigating S1PR1 antagonists as a clinical approach to mitigate opioid-induced adverse effects and repurposing the functional S1PR1 antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.
Learn More >Heat shock protein 90 (Hsp90) is a ubiquitous signal transduction regulator, and Hsp90 inhibitors are in clinical development as cancer therapeutics. However, there have been very few studies on the impact of Hsp90 inhibitors on pain or analgesia, a serious concern for cancer patients. We previously found that Hsp90 inhibitors injected into the brain block opioid-induced anti-nociception in tail flick, paw incision, and HIV neuropathy pain. This study extended from that initial work to test the cancer-related clinical impact of Hsp90 inhibitors on opioid anti-nociception in cancer-induced bone pain (CIBP) in female BALB/c mice and chemotherapy-induced peripheral neuropathy (CIPN) in male and female CD-1 mice. Mice were treated with Hsp90 inhibitors (17-AAG, KU-32) by the intracerebroventricular, intrathecal, or intraperitoneal routes, and after 24 hours pain behaviors were evaluated following analgesic drug treatment. Hsp90 inhibition in the brain or systemically completely blocked morphine and oxymorphone anti-nociception in CIPN; this effect was partly mediated by decreased ERK and JNK MAPK activation and by increased protein translation, was not altered by chronic treatment, and Hsp90 inhibition had no effect on gabapentin anti-nociception. We also found that the Hsp90 isoform Hsp90α and the co-chaperone Cdc37 were responsible for the observed changes in opioid anti-nociception. In contrast, Hsp90 inhibition in the spinal cord or systemically partially reduced opioid anti-nociception in CIBP. These results demonstrate that Hsp90 inhibitors block opioid anti-nociception in cancer-related pain, suggesting that Hsp90 inhibitors for cancer therapy could decrease opioid treatment efficacy.
Learn More >Skeletal metastases are frequently accompanied by chronic pain that is mechanoceptive in nature. Mechanistically, cancer-induced bone pain (CIBP) is mediated by peripheral sensory neurones innervating the cancerous site, the cell bodies of which are housed in the dorsal root ganglia (DRG). How these somatosensory neurons encode sensory information in CIBP remains only partly explained. Using a validated rat model, we first confirmed cortical bone destruction in CIBP but not sham-operated rats (day 14 post-surgery, designated 'late' stage bone cancer). This occurred with behavioural mechanical hypersensitivity (Kruskal-Wallis H for independent samples; CIBP vs. Sham-operated, day 14; p < 0.0001). Next, hypothesising that the proportion and phenotype of primary afferents would be altered in the disease state, DRG in vivo imaging of genetically-encoded calcium indicators and Markov Cluster Analysis were employed to analyse 1748 late-stage CIBP (n=10), and 757 sham-operated (n=9), neurons. Distinct clusters of responses to peripheral stimuli were revealed. In CIBP rats, upon knee compression of the leg ipsilateral to the tumour: (1) three times as many sensory afferents responded (RM-ANOVA: p < 0.0001 (vs. sham)); (2) there were significantly more small neurons responding (Kruskal-Wallis for independent samples (vs. sham): p < 0.0001) and (3) approximately 13% of traced tibial cavity afferents responded (no difference observed between CIBP and sham-operated animals). We conclude that an increased sensory afferent response is present in CIBP rats and this is likely to reflect afferent recruitment from outside of the bone rather than increased intraosseous afferent activity.
Learn More >In contrast to pain processing neurons in the spinal cord, where the importance of chloride conductances is already well established, chloride homeostasis in primary afferent neurons has received less attention. Sensory neurons maintain high intracellular chloride concentrations through balanced activity of Na-K-2Cl cotransporter 1 (NKCC1) and K-Cl cotransporter 2 (KCC2). Whereas in other cell types activation of chloride conductances causes hyperpolarization, activation of the same conductances in primary afferent neurons may lead to inhibitory or excitatory depolarization depending on the actual chloride reversal potential and the total amount of chloride efflux during channel or transporter activation. Dorsal root ganglion (DRG) neurons express a multitude of chloride channel types belonging to different channel families, such as ligand-gated, ionotropic γ-aminobutyric acid (GABA) or glycine receptors, Ca-activated chloride channels of the anoctamin/TMEM16, bestrophin or tweety-homolog family, CLC chloride channels and transporters, (CFTR) as well as volume-regulated anion channels (VRACs). Specific chloride conductances are involved in signal transduction and amplification at the peripheral nerve terminal, contribute to excitability and action potential generation of sensory neurons, or crucially shape synaptic transmission in the spinal dorsal horn. In addition, chloride channels can be modified by a plethora of inflammatory mediators affecting them directly, via protein-protein interaction, or through signaling cascades. Since chloride channels as well as mediators that modulate chloride fluxes are regulated in pain disorders and contribute to nociceptor excitation and sensitization it is timely and important to emphasize their critical role in nociceptive primary afferents in this review.
Learn More >Genetic and environmental factors are thought to contribute to cluster headache, and cluster headache can affect multiple members of a family. A thorough understanding of its inheritance is critical to understanding the pathogenesis of this debilitating disease.
Learn More >Interpersonal touch and social support can influence physical health, mental well-being, and pain. However, the mechanisms by which supportive touch promotes analgesia are not well understood. In Study 1, we tested how three kinds of social support from a romantic partner (passive presence, gentle stroking, and handholding) affect pain ratings and skin conductance responses (SCRs). Overall, support reduced pain ratings in women, but not men, relative to baseline. Support decreased pain-related SCRs in both women and men. Though there were no significant differences across the three support conditions, effects were largest during handholding. Handholding also reduced SCRs in the supportive partner. Additionally, synchronicity in couples' SCR was correlated with reductions in self-reported pain, and individual differences in synchrony were correlated with the partner's trait empathy. In Study 2, we re-analyzed an existing dataset to explore fMRI activity related to individual differences in handholding analgesia effects in women. Increased activity in a distributed set of brain regions, including valuation-encoding frontostriatal areas, was correlated with lower pain ratings. These results may suggest that social support can reduce pain by changing the value of nociceptive signals. This reduction may be moderated by interpersonal synchrony and relationship dynamics.
Learn More >Neuromodulatory approaches add to our armamentarium of therapeutic tools for the treatment of primary headaches. This review provides a comprehensive overview of current controlled studies on the different neuromodulation techniques and recommendations for clinical practice.
Learn More >This basic mechanistic study examined the changes in brain activation and resting-state connectivity after 8 weeks of CBT in youth with migraine.
Learn More >Opioids have, at most, small benefits for non-cancer pain in the medium and long-term but there is good evidence that they cause harm. The current study describes the characteristics and clinical status of people taking regular opioids in Great Britain and determines whether use is associated with mortality risk.
Learn More >Most clinical trials assessing systemic immunomodulatory treatments for patients with atopic dermatitis are placebo-controlled.
Learn More >The gabapentinoid drugs gabapentin and pregabalin (Neurontin® and Lyrica®) are mainstay treatments for neuropathic pain and for preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the alpha2-delta subunit, α2δ-1 or Cava2d1) is the high-affinity binding site for gabapentin and pregabalin, and is required for the efficacy of these drugs. The α2δ-1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that α2δ-1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of NMDA-sensitive glutamate receptors, neurexin-1, and thrombospondin proteins by binding to α2δ-1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action. SIGNIFICANCE STATEMENT: It is widely believed that gabapentin and pregabalin act by modestly reducing the membrane localization and activation of voltage-gated calcium channels at synaptic endings in spinal cord and neocortex via binding to the α2δ-1 protein. However, recent findings show that the α2δ-1 protein also interacts with NMDA-sensitive glutamate receptors, neurexin-1α, thrombospondins (adhesion molecules), and other presynaptic proteins. These newly discovered interactions, in addition to actions at calcium channels, may be important mediators of gabapentin and pregabalin therapeutic effects.
Learn More >In the United States (US), long-term opioid therapy has been commonly prescribed for chronic pain. Since recognition of the opioid overdose epidemic, clinical practice guidelines have recommended tapering long-term opioids to reduced doses or discontinuation. The Effects of Prescription Opioid Changes for veterans (EPOCH) study is a national population-based prospective observational study of US Veterans Health Administration primary care patients designed to assess effects of evolving opioid prescribing practice on patients treated with long-term opioids for chronic pain. A stratified random sampling design was used to identify a survey sample from the target population of patients treated with opioid analgesics for ≥ 6 months. Demographic, diagnostic, visit, and pharmacy dispensing data were extracted from existing datasets. A 2016 mixed-mode mail and telephone survey collected patient-reported data, including the main patient-reported outcomes of pain-related function (Brief Pain Inventory interference; BPI-I scores 0-10, higher scores = worse) and health-related quality of life. Data on survey participants and non-participants were analyzed to assess potential nonresponse bias. Weights were used to account for design. Linear regression models were used to assess cross-sectional associations of opioid treatment with patient-reported measures. Of 14,160 patients contacted, 9253 (65.4%) completed the survey. Participants were older than non-participants (63.9 ± 10.6 vs. 59.6 ± 13.0 years). The mean number of bothersome pain locations was 6.8 (SE 0.04). Effectiveness of pain treatment and quality of pain care were rated fair or poor by 56.1% and 45.3%, respectively. The opioid daily dosage range was 1.6 to 1038.2 mg, with mean = 50.6 mg (SE 1.1) and median = 30.9 mg (IQR 40.7). Among the 73.2% of patients who did not receive long-acting opioids, the mean daily dosage was 30.4 mg (SE 0.6) and mean BPI-I was 6.4 (SE 00.4). Among patients who received long-acting opioids, the mean daily dosage was 106.2 mg (SE 2.8) and mean BPI-I was 6.8 (SE 0.07). Higher daily dosage was associated with worse pain-related function and quality of life among patients without long-acting opioids, but not among patients with long-acting opioids. Future analyses will use follow-up data to examine effects of opioid dose reduction and discontinuation on patient outcomes.
Learn More >Chronic pain represents a substantial unmet medical need globally. In recent years, the quest for a new generation of novel, safe, mechanism-based analgesic treatments has focused on neurotrophic factors, a large group of secreted proteins that control the growth and survival of different populations of neurons, but that postnatally are involved in the genesis and maintenance of pain, with biological activity in both the periphery and the central nervous system. In this narrative review, we discuss the two families of neurotrophic proteins that have been extensively studied for their role in pain: first, the neurotrophins, nerve growth factor (NGF) and brain-derived growth factor (BDNF), and secondly, the GDNF family of ligands (GFLs). We provide an overview of the pain pathway, and the pain-producing effects of these different proteins. We summarize accumulating preclinical and clinical findings with a focus on musculoskeletal pain, and on osteoarthritis in particular, because the musculoskeletal system is the most prevalent source of chronic pain and of disability, and clinical testing of these novel agents – often biologics- is most advanced in this area.
Learn More >Mindfulness meditation can alleviate acute and chronic pain. It has been proposed that mindfulness meditation reduces pain by uncoupling sensory and affective pain dimensions. However, studies to date have reported mixed results, possibly due to a diversity of styles of and expertise in mindfulness meditation. Furthermore, the interrelations between mindfulness meditation and pain catastrophizing during acute pain remain little known.
Learn More >Following an infection, cytokines not only regulate the acute immune response, but also contribute to symptoms such as inflammatory hyperalgesia. We aimed to characterize the acute inflammatory response induced by a human endotoxemia model, and its effect on pain perception using evoked pain tests in two different dose levels. We also attempted to determine whether combining a human endotoxemia challenge with measurement of pain thresholds in healthy subjects could serve as a model to study drug effects on inflammatory pain.
Learn More >Posttraumatic headache (PTH) attributed to mild traumatic brain injury is common and debilitating. In up to one-half of those with acute PTH, the PTH becomes persistent (PTH), enduring for longer than 3 months. The high incidence and persistence of PTH necessitate research into PTH pathophysiology and treatment. In this review, recent developments regarding the diagnostic criteria for PTH, the pathophysiology of PTH, and PTH treatment are discussed.
Learn More >Injury to the cervical spinal cord has been suggested as a mechanism that may underpin chronic whiplash-associated disorder (WAD). This study aimed to assess metabolite concentrations indicative of neuronal injury or pathology in the cervical cord in people with chronic WAD.
Learn More >This randomized trial will evaluate the mechanisms of three chronic pain treatments: cognitive therapy (CT), mindfulness meditation (MM), and activation skills (AS). We will determine the extent to which late-treatment improvement in primary outcome (pain interference) is predicted by early-treatment changes in cognitive content, cognitive process, and/or activity level. The shared versus specific role of these mechanisms across the three treatments will be evaluated during treatment (Primary Aim), and immediately post-treatment to examine relapse mechanisms (Secondary Aim). We will enroll 300 individuals with chronic pain (with low back pain as a primary or secondary condition), with 240 projected to complete the study. Participants will be randomly assigned to eight, 1.5 h telehealth group sessions of CT, MM, or AS. Mechanisms and outcomes will be assessed twice daily during 2-week baseline, 4-week treatment period, and 4-week post-treatment epoch via random cue-elicited ecological momentary assessment (EMA); activity level will be monitored during these time epochs via daily monitoring with ActiGraph technology. The primary outcome will be measured by the PROMIS 5-item Pain Interference scale. Structural equation modeling (SEM) will be used to test the primary aims. This study is pre-registered on clinicaltrials.gov (Identifier: NCT03687762). This study will determine the temporal sequence of lagged mediation effects to evaluate rates of change in outcome as a function of change in mediators. The findings will provide an empirical basis for enhancing and streamlining psychosocial chronic pain interventions. Further, results will guide future efforts towards optimizing maintenance of gains to effectively reduce relapse risk.
Learn More >Class B G protein-coupled receptors are highly therapeutically relevant but challenges remain in identifying suitable small-molecule drugs. The calcitonin-like receptor (CLR) in particular is linked to conditions such as migraine, cardiovascular disease, and inflammatory bowel disease. The CLR cannot act as a cell-surface receptor alone but rather must couple to one of three receptor activity-modifying proteins (RAMPs), forming heterodimeric receptors for the peptides adrenomedullin and calcitonin gene-related peptide. These peptides have extended binding sites across their receptors. This is one reason why there are few small-molecule ligands that can modulate these receptors. Here we describe small molecules that are able to positively modulate the signaling of the CLR with all three RAMPs but are not active at the related calcitonin receptor. These compounds were selected from a β-arrestin recruitment screen, coupled with rounds of medicinal chemistry to improve their activity. Translational potential is shown as the compounds can positively modulate cAMP signaling in a vascular cell line model. Binding experiments do not support an extracellular domain binding site; however, molecular modeling reveals potential allosteric binding sites in multiple receptor regions. These are the first small-molecule positive modulators described for the CLR:RAMP complexes.
Learn More >Whereas decades of research have been devoted to psychological factors that confer vulnerability to disability and other negative outcomes in the face of chronic pain, recent studies have begun to emphasize psychological characteristics that contribute to enhanced adaptation and better clinical outcomes. Accordingly, the present study was conducted as a longitudinal assessment of the predictive utility of pain resilience and pain catastrophizing as indicators of clinical outcomes among patients receiving a standardized treatment for chronic pain.
Learn More >The use of diet and physical activity in alleviating the burden of migraine is unclear, therefore, more scientific study on the role of positive health behaviors in migraine management is needed.
Learn More >The objective of this study was to design, code, and pilot test the feasibility and preliminary efficacy of a self-management digital therapeutic tool for adolescents with migraine.
Learn More >Attentional distraction from pain has been shown to be largely ineffective for obtaining a hypoalgesic effect in patients with chronic pain when compared to a control condition. It has been hypothesized that this may be due to the non-engaging types of distraction that have been used so far. Moreover, it is suggested that the hypoalgesic effects of distraction may be attenuated by pain-related cognitions and emotions, as they may increase the attention to pain.
Learn More >To investigate the association of OA risk factors with number of painful joint sites in a representative population sample.
Learn More >A recent randomized controlled study showed that 66.7% (66/99) and 37.4% (37/99) of people undergoing remote electrical neuromodulation (REN), a novel non-pharmacological migraine treatment, achieve pain relief and pain freedom, respectively, at 2 h post-treatment. The participants who completed the 6-weeks double-blind phase of this study were offered to participate in an open-label extension (OLE) with an active REN device. This study investigated the clinical use of REN, focusing on its potential in reducing the use of acute migraine medications. The parent study for this open-label extension (OLE) was a randomized, double-blind, sham-controlled study of acute treatment conducted on 296 participants enrolled at 12 sites in the USA and Israel. This study included a run-in phase, in which migraine attacks were treated with usual care, and an 8-weeks double-blind treatment phase. One hundred sixty participants continued in an 8-weeks OLE phase in which they could incorporate a REN device into their usual care. Medication use rate (percentage of participants who treated their attacks only with REN and avoided medications in all their attacks) and pain outcomes at 2 h post-treatment were compared between the OLE and the run-in phase in a within-subject design. The analyses were performed on 117 participants with episodic migraine. During the OLE, 89.7% of the participants treated their attacks only with REN and avoided medications in all their attacks compared with 15.4% in the run-in phase ( < 0.0001). The rates of pain relief and pain-free in at least 50% of the treatments at 2 h post-treatment were comparable (pain relief: 58.1% in the run-in phase and 57.3% in the OLE, = 0.999; pain-free: 23.1% in the run-in vs. 30.8% in the OLE, = 0.175). REN may reduce the use of acute migraine medications. Thus, incorporating REN into usual care may reduce the risk for medication overuse headache (MOH). Future studies should evaluate whether REN reduces the use of acute migraine medications in a population at risk for MOH.
Learn More >Up to 90% of people with neurological deficits following whiplash injury report chronic symptoms. A recent unique study of neck-specific exercise showed positive results (post-intervention at 12 weeks), regarding arm pain and neurological deficits in people with chronic whiplash associated disorders (WAD). This 1-year follow-up of that randomised controlled study with assessor blinding aimed to examine whether neck-specific exercise with (NSEB) or without (NSE) a behavioural approach has long-term benefits over physical activity prescription (PPA) regarding arm pain and neurological deficits (n = 171). Interventions were: NSE, NSEB, or PPA. Follow-up of arm pain, paraesthesia bothersomeness (questionnaires) and clinical neurological tests were performed after 3, 6 and 12 months and analysed with Linear Mixed Models and General Estimating Equations. The NSE and/or NSEB groups reported significantly less pain and paraesthesia bothersomeness as well as higher odds of normal key muscle arm strength and of normal upper limb neural tension over the year (all p < 0.03), compared with PPA. In conclusion, results suggest that neck-specific exercise with or without a behavioural approach may have persisting long term benefits over PPA regarding arm pain and clinical signs associated with neurological deficits in chronic WAD.
Learn More >Pain persists in a moderate number of patients following hip or knee replacement surgery. Persistent pain may subsequently lead to the prolonged consumption of analgesics after surgery and expose patients to the adverse drug events of opioids and NSAIDs, especially in older patients and patients with comorbidities. This study aimed to identify risk factors for the increased use of opioids and other analgesics 1 year after surgery and focused on comorbidities and surgery-related factors.
Learn More >Diffuse noxious inhibitory control (DNIC) is a phenomenon to reflect descending pain modulation in animals. Conditioned pain modulation (CPM) is the human counterpart of DNIC and is reduced in patients with several chronic pain conditions. Duloxetine is a serotonin and noradrenaline reuptake inhibitor that ameliorates CPM impairment in patients with diabetic neuropathy. Although some studies have reported the effects of different pharmacological agents on CPM, few studies have compared the effects of some analgesics in both humans and rodents. Therefore, we established a stable evaluation method for DNIC in rats and determined whether duloxetine and other specific analgesics affect DNIC impairment in rat models of peripheral neuropathic pain and osteoarthritis pain, two types of chronic pain. As a conditioning stimulus, capsaicin was injected into the forepaw of rats. The paw withdrawal threshold (PWT) in response to mechanical pressure was measured for the hindpaw. Peripheral neuropathic pain and osteoarthritis pain models were developed by partial sciatic nerve ligation (PSNL) and the intra-articular injection of 2 mg monoiodoacetate (MIA), respectively. Capsaicin (30-100 μg/site) increased the PWT, in a dose-dependent manner, in naive rats. The threshold significantly increased at 30 μg and reached its maximal level at 100 μg. The change in PWT following capsaicin injection was significantly reduced in PSNL-treated rats, but the threshold was increased by the subcutaneous administration of duloxetine (10 mg/kg). The oral administrations of pregabalin (10 mg/kg) and celecoxib (3 mg/kg) did not affect the PWT in PSNL-treated rats. Similarly, MIA-injected rats also showed a reduced change in PWT following capsaicin injection. Duloxetine, but not pregabalin and celecoxib, significantly increased the PWT in MIA-injected rats. These results suggested that duloxetine can directly ameliorate DNIC impairment in rat models of chronic pain. Duloxetine may be useful for modulating chronic pain by restoring function to the endogenous, descending, inhibitory pathway.
Learn More >Dry skin itch is one of the most common skin diseases and elderly people are believed to be particularly prone to it. The inflammasome has been suggested to play an important role in chronic inflammatory disorders including inflammatory skin diseases such as psoriasis. However, little is known about the role of NLRP1 inflammasome in dry skin-induced chronic itch.
Learn More >The amygdala circuitry and P2X7 receptor (P2X7R) have both been shown to play important roles in the modulation of neuropathic pain (NP). However, little is known about the functional role of P2X7R in the amygdala for the regulation of NP. This study aims to evaluate the alleviative effect of intra-amygdala microinfusion of a pharmacological antagonist of P2X7R (A-438079) on NP and explore its possible mechanism of action. Male Sprague-Dawley rats were used to construct the animal model of NP through spared nerve injury (SNI). The SNI rats randomly received chronic bilateral microinjection of A-438079 (100 pmol/side) or saline into the amygdalae via cannulas. Mechanical paw withdrawal threshold (MWT) and thermal withdrawal duration (TWD) were measured by von Frey monofilaments. Besides, tail suspension test (TST), forced swimming test (FST), open field test (OFT) and sucrose preference test (SPT) were performed to assess depression- and anxiety-like behaviors. Immunofluorescence assay was employed to determine the levels of glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (IBA-1) and connexin 43 (Cx43) in the spinal cord. In addition, the change of growth associated protein 43 (GAP43) level in the spinal cord was assessed by Western blot. Our data showed that chronic treatment with A-438079 increased MWT and decreased TWD on days 11-21 post-SNI while decreased depression-like and anxiety-like behaviors. A-438079 administration significantly attenuated the elevated immunoreactivities of IBA-1 and GFAP in microglia and astrocytes after SNI. Furthermore, the decreased expression of GAP-43 in the spinal cord due to SNI was significantly attenuated by A-438079. However, when A-438079 and a pharmacological agonist (BzATP) of P2X7R were given simultaneously, all the effects caused by A-438079 alone were reversed. In brief, our study revealed the protective role of inhibiting P2X7R in the amygdala against symptoms associated with NP, possibly attributing to its inhibitory effects on spinal microglia and astrocytes.
Learn More >Individual understanding of and expectations for chronic pain treatment can influence treatment adherence and thus success, but little is known about these critical factors in parents and children presenting with pain-predominant functional gastrointestinal disorders (p-FGIDs). The aim of this study was to identify parent and patient understanding of p-FGIDs, expectations for treatment, and interventions utilized prior to presenting to a multidisciplinary clinic.
Learn More >Visceral hypersensitivity of the lower gastrointestinal tract, defined as an increased response to colorectal distension, frequently prompts episodes of debilitating abdominal pain in Irritable Bowel Syndrome (IBS). Although the pathophysiology of IBS is not yet fully elucidated, it is well known that stress is a major risk factor for development and acts as a trigger of pain sensation. Stress modulates both immune responses as well as the gut microbiota and vice versa. Additionally, either microbes themselves or through involvement of the immune system, activate or sensitize afferent nociceptors. In this paper, we review current knowledge on the influence of stress along the gut-brain-microbiota axis and exemplify relevant neuro-immune crosstalk mechanisms in visceral hypersensitivity, working towards understanding how gut microbiota-neuro-immune cross-talk contributes to visceral pain sensation in IBS patients.
Learn More >Chronic pain patients often complain of their poor memory. The mechanisms underlying chronic pain-related memory impairment remain elusive, and there are few clinical therapeutic strategies available for this condition.
Learn More >To determine whether alcohol intake is associated with occurrence of headaches on the following day. In this prospective cohort study, adults with episodic migraine completed electronic diaries every morning and evening for at least six weeks in March 2016-October 2017. Every day, participants reported alcohol intake, lifestyle factors, and details about each headache. We constructed within-person fixed-effect models adjusted for time-varying factors to calculate odds ratios for the association between 1,2,3,4, or 5+ servings of alcohol and headache the following day. We also calculated the adjusted risk of headache the following day for each level of intake. Among 98 participants who reported 825 headaches over 4,467 days, there was a statistically significant linear association (p-trend =0.03) between alcohol and headache the following day. Compared to no alcohol, 1-2 servings were not associated with headaches, but 5+ servings were associated with a 2.08-fold (95% confidence interval [CI] 1.16-3.73) odds of headache. The adjusted absolute risk of headaches was 20% (95%CI 19%-22%) on days following no alcohol compared with 33% (95%CI 22%-44%) on days following 5+ servings. 1-2 servings of alcoholic beverages were not associated with higher risk of headaches the following day, but 5+ servings were associated with higher risk. Key Messages:1-2 servings of alcoholic beverages were not associated with a higher risk of headaches on the following day, but higher levels of intake may be associated with higher risk.Five or more servings were associated with 2.08 times (95% confidence interval 1.16-3.73 the odds of headache on the following day.The adjusted absolute risk of headaches was 20% (95%CI 19%-22%) on days following no alcohol consumption compared with 33% (95% CI 22%-44%) on days following 5+ servings.
Learn More >C-nociceptors (C-Ncs) and non-nociceptive C-low threshold mechanoreceptors (C-LTMRs) are two subpopulations of small unmyelinated non-peptidergic C-type neurons of the dorsal root ganglia (DRGs) with central projections displaying a specific pattern of termination in the spinal cord dorsal horn. Although these two subpopulations exist in several animals, remarkable neurochemical differences occur between mammals, particularly rat/humans from one side and mouse from the other. Mouse is widely investigated by transcriptomics. Therefore, we here studied the immunocytochemistry of murine C-type DRG neurons and their central terminals in spinal lamina II at light and electron microscopic levels. We used a panel of markers for peptidergic (CGRP), non-peptidergic (IB4), nociceptive (TRPV1), non-nociceptive (VGLUT3) C-type neurons and two strains of transgenic mice: the TAFA4 knock-in mouse to localize the TAFA4 C-LTMRs, and a genetically engineered ginip mouse that allows an inducible and tissue-specific ablation of the DRG neurons expressing GINIP, a key modulator of GABAR-mediated analgesia. We confirmed that IB4 and TAFA4 did not coexist in small non-peptidergic C-type DRG neurons and separately tagged the C-Ncs and the C-LTMRs. We then showed that TRPV1 was expressed in only about 7% of the IB4 non-peptidergic C-Ncs and their type Ia glomerular terminals within lamina II. Notably, the selective ablation of GINIP did not affect these neurons, whereas it reduced IB4 labeling in the medial part of lamina II and the density of C-LTMRs glomerular terminals to about one half throughout the entire lamina. We discuss the significance of these findings for interspecies differences and functional relevance.
Learn More >The first official health registry dates back to the 19th century and was proven to be very useful for gathering important information regarding a specific disease. Since then, data collection through registries is gaining more popularity, as it can offer useful information not only to health providers but also to healthcare planning services. Health registries could come along with randomized controlled trials and support or reject their findings in the "real world". Pain registries and neuropathic pain registries have proven to be very potent weapons in the armory of the pain specialist and are growing rapidly, offering substantial information for this challenging pain entity.
Learn More >The cycling of sex hormones is one of the factors affecting pain in females, and the mechanisms are not fully understood. G-protein coupled estrogen receptor 30 (GPR30) is the estrogen receptor known to be involved in mechanical hyperalgesia. Studies have demonstrated that matrix metalloproteinase-9 (MMP-9) is a critical component in peripheral/central nervous system hypersensitivity and neuroinflammation, both of which participate in hyperalgesia. Here, ovariectomized rats were treated with low or high dose estrogen replacement, and then plantar incisions were made. Subsequently, mechanical allodynia was evaluated by determining the paw withdrawal mechanical threshold before and after the incision. In rats with incisions, high estrogen levels induced postoperative hyperalgesia and upregulation of GPR30 and MMP-9 in dorsal root ganglia (DRGs). MMP-9 was expressed primarily in DRG neurons co-expressing GPR30, and led to the activation of IL-1β. After intrathecal injection of the GPR30 agonist G1, female rats with low estrogen and plantar incisions continued to exhibit significant hyperalgesia until 48 h post-incision. In high estrogen level rats with plantar incisions, intrathecal injection of GPR30 antagonist G15 significantly attenuated postoperative hyperalgesia. Intraperitoneal injection of N-acetyl-cysteine, a source of cysteine that prevents the oxidation of cysteine residues on MMP-9, significantly relieved high estrogen-induced postoperative hyperalgesia via suppression of MMP-9 and IL-1β activation in DRGs. These results demonstrate that high estrogen level in rats with incisions elicit GPR30 and MMP-9 upregulation in DRGs and subsequently activate IL-1β, leading to induced postoperative hyperalgesia.
Learn More >Early diagnosis, treatment, and prevention of a vaso-occlusive crisis (VOC) is critical to the management of patients with sickle cell disease. It is essential to differentiate between VOC-associated pain and chronic pain, hyperalgesia, neuropathy, and neuropathic pain. The pathophysiology of VOCs includes polymerization of abnormal sickle hemoglobin, inflammation, and adhesion. Hydroxyurea, L-glutamine, crizanlizumab, and voxelotor have been approved by the US Food and Drug Administration for reducing the frequency of VOCs; the European Medicines Agency has approved only hydroxyurea. Other novel treatments are in late-stage clinical development in both the United States and the European Union. Development of agents for prevention and treatment of VOCs should be driven by our understanding of its pathophysiology.
Learn More >Lateral elbow pain (LEP) due to tendinosis is one of the most common musculoskeletal pains of the upper limbs, yet there is no satisfactory treatment. This study was an international, prospective, multi-center, randomized, controlled, clinical trial to evaluate the efficacy of acupuncture compared to sham laser in the treatment of LEP.
Learn More >Short-latency afferent inhibition (SAI) consists of motor cortex inhibition induced by sensory afferents and depends on the excitatory effect of cholinergic thalamocortical projections on inhibitory GABAergic cortical networks. Given the electrophysiological evidence for thalamo-cortical dysrhythmia in migraine, we studied SAI in migraineurs during and between attacks and searched for correlations with somatosensory habituation, thalamocortical activation, and clinical features.
Learn More >Older adults are the fastest growing segment of the population and surgical procedures in this group increase each year. Chronic post-surgical pain is an important consideration in the older adult as it affects recovery, physical functioning, and overall quality of life. It is increasingly recognized as a public health issue but there is a need to improve our understanding of the disease process as well as the appropriate treatment and prevention. Frailty, delirium, and cognition influence post-operative outcomes in older adults and have been implicated in the development of chronic post-surgical pain. Further research must be conducted to fully understand the role they play in the occurrence of chronic post-surgical pain in the older adult. Additionally, careful attention must be given to the physiologic, cognitive, and comorbidity differences between the older adult and the general population. This is critical for elucidating the proper chronic post-surgical pain treatment and prevention strategies to ensure that the older adult undergoing surgical intervention will have an appropriate and desirable post-operative outcome.
Learn More >Tenascin-X (TNX) is a member of the extracellular matrix glycoprotein tenascin family, and TNX deficiency leads to Ehlers-Danlos syndrome, a heritable human disorder characterized mostly by skin hyperextensibility, joint hypermobility, and easy bruising. TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. However, the molecular mechanisms by which TNX deficiency complicates pain are unknown. Here, we examined the nociceptive behavioral responses of TNX-deficient mice. Compared with wild-type mice, TNX-deficient mice exhibited mechanical allodynia but not thermal hyperalgesia. TNX deficiency also increased pain sensitivity to chemical stimuli and aggravated early inflammatory pain elicited by formalin. TNX-deficient mice were significantly hypersensitive to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aβ fiber responses), but not to stimuli at frequency of 5 Hz (C fiber responses). In addition, the phosphorylation levels of extracellular signal-related kinase, an active neuronal marker, and the activity of NADPH-diaphorase, a neuronal nitric oxide activation marker, were enhanced in the spinal dorsal horns of TNX-deficient mice. These results suggest that TNX deficiency contributes to the development of mechanical allodynia and hypersensitivity to chemical stimuli, and it induces hypersensitization of myelinated A fibers and activation of the spinal dorsal horn.
Learn More >Globally every year, millions of patients sustain traumatic injuries and require acute care surgeries. A high incidence of chronic opioid use (up to 58%) has been documented in these populations with significant negative individual and societal impacts. Despite the importance of this public health issue, optimal strategies to limit the chronic use of opioids after trauma and acute care surgery are not clear. We aim to identify existing strategies to prevent chronic opioid use in these populations.
Learn More >To assess the effectiveness of an Individualized Comprehensive Rehabilitation Program (ICPR) on impaired postural control, pain, self-perceived health status and functionality in women with CPP.
Learn More >To systematically identify risk factors for the development of post-traumatic headache (PTH) attributed to traumatic brain injury (TBI) as defined in the International Classification of Headache Disorders (ICHD).
Learn More >This study evaluated headaches among Parkinson's disease (PD) patients and whether there was any correlation between the motor symptoms and the severity of the headaches presented.
Learn More >Robust activation of glial cells has been reported to occur particularly during the pathogenesis of bone cancer pain (BCP). Researchers from our group and others have shown that histone deacetylases (HDACs) play a significant role in modulating glia-mediated immune responses; however, it still remains unclear whether HDACs are involved in the activation of glial cells during the development of BCP.
Learn More >Itch is an unpleasant sensation that can be debilitating, especially if it is chronic and of non-histaminergic origin, as treatment options are limited. Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that also has the ability to induce a burning, non-histaminergic pruritus when exogenously administered, by activating the endothelin A receptor (ETR) on primary afferents. ET-1 is released endogenously by several cell-types found in the skin, including macrophages and keratinocytes. Mast cells express ETRs and can thereby be degranulated by ET-1, and mast cell proteases chymase and carboxypeptidase A3 (CPA3) are known to either generate or degrade ET-1, respectively, suggesting a role for mast cell proteases in the regulation of ET-1-induced itch. The mouse mast cell proteases (mMCPs) mMCP4 (chymase), mMCP6 (tryptase), and CPA3 are found in connective tissue type mast cells and are the closest functional homologs to human mast cell proteases, but little is known about their role in endothelin-induced itch.
Learn More >Nearly a fifth of the world's population suffer from migraine headache, yet risk factors for this disease are poorly characterized.
Learn More >Deciding whether or not to perform neuroimaging in primary headache is a dilemma for headache physicians. The aim of this study was to identify clinical predictors of incidental neuroimaging abnormalities in new patients with primary headache disorders.
Learn More >Migraine is a debilitating neurologic disease. People who experience migraine can have substantial disability, impaired functioning and a decreased quality of life (QoL). Expert recommendations suggest that people with frequent migraine attacks or severe impairment related to attacks may benefit from preventive treatment. Despite these recommendations and the existence of evidence-based guidelines for the use of preventive medication, many people who are candidates for preventive therapies do not receive them. Thus, there is still a substantial unmet need for preventive migraine treatment. Calcitonin gene-related peptide (CGRP) has a demonstrated role in the pathophysiology of migraine. Galcanezumab-gnlm (galcanezumab) is a humanized monoclonal antibody that binds to the CGRP ligand and prevents binding to its receptor. It is administered as a once-monthly subcutaneous injection. The aim of this review is to present a comprehensive overview of the existing short- and long-term efficacy and safety data for galcanezumab in patients with migraine. Data from the phase 3, randomized, double-blind, placebo-controlled EVOLVE-1, EVOLVE-2 and REGAIN studies show that galcanezumab treatment for 3 or 6 months results in overall reduction in mean monthly migraine headache days in patients with episodic (EVOLVE-1 and EVOLVE-2) and chronic (REGAIN) migraine. Greater proportions of patients with episodic migraine receiving galcanezumab versus placebo demonstrated a ≥ 50%, ≥ 75% and 100% response to therapy and reported a lower level of disability and an improvement in functioning and QoL. Similarly, when compared with placebo, greater proportions of patients with chronic migraine treated with galcanezumab demonstrated a ≥ 50% and ≥ 75% response and reported improved functioning. A 12-month open-label study demonstrated the continued efficacy of galcanezumab for up to 12 months. In all studies galcanezumab was well tolerated. In conclusion, data from pivotal studies show that galcanezumab may fulfill an unmet need in the treatment of patients with migraine who require preventive therapy.
Learn More >Does P2X ligand-gated ion channel 3 (P2X3) play a role in endometriosis pain?
Learn More >To explore the structural and functional alterations of the whole brain in patients with chronic cervical spondylotic pain (cCSP).
Learn More >Oxaliplatin is a platinum-based antineoplastic drug commonly used for treating colorectal, gastric, and pancreatic cancer. However, it frequently causes peripheral neuropathy as dose-limiting toxicity and is lacking a strategy for prevention. Alogliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, is an oral antidiabetic drug. Previous studies have shown that DPP-4 inhibitors have pleiotropic effects, including neuroprotection. In this study, we investigated the effects of alogliptin on oxaliplatin-induced peripheral neuropathy using in vitro and in vivo models. In PC12 cells, alogliptin attenuated neurite disorders induced by oxaliplatin and cisplatin. The repeated injection of oxaliplatin caused mechanical allodynia and axonal degeneration of the sciatic nerve in rats. These neuropathies were ameliorated by co-administration of alogliptin. Moreover, alogliptin did not attenuate tumor cytotoxicity of oxaliplatin in the cultured colon, gastric, or pancreatic cancer cell lines and tumor-bearing mice. These findings suggest that alogliptin may be beneficial for preventing oxaliplatin-induced peripheral neuropathy.
Learn More >Therapies to treat chronic neuropathic pain and its associated comorbidities are limited. Recent studies demonstrated that the administration of slow-releasing hydrogen sulfide (HS) donors inhibited chemotherapy-induced neuropathic pain. However, the antidepressant or anxiolytic effects of these compounds and their mechanisms of action during chronic neuropathic pain have not been evaluated.
Learn More >This study aimed to understand long-term changes of the osteoarthritic temporomandibular joint (TMJ) condyle using computed tomography (CT) and to verify its correlation with clinical characteristics of temporomandibular disorders. Eighty-nine patients (152 joints; 76 female, 13 male) who had taken follow-up CTs (mean follow-up period: 644.58 ± 325.71 days) at least once in addition to their initial evaluation were selected. Cross-sectional demographic and clinical data and longitudinal CT images were collected. Data were analyzed by analysis of variance and logistic regression. Overall destructive change index (number of TMJ condyle sections in which destructive change was observed) decreased from 1.56 to 0.66. Improvement was seen in 93 joints (61.2%) and 27 joints (17.8%) worsened. In the pain positive group, both initial and final destructive change index were significantly higher compared to the pain negative group (p = 0.04). Occlusal stabilization splint therapy and nonsteroidal anti-inflammatory drug administration showed a significant effect on improving the prognosis of TMJ osteoarthritis (p = 0.015 and 0.011). In conclusion, TMJ osteoarthritis showed long-term improvement in the majority of cases. TMJ osteoarthritis accompanied by pain showed unfavorable prognosis with additional bone destruction. Occlusal stabilization splint and nonsteroidal anti-inflammatory drug administration were beneficial on the prognosis of TMJ osteoarthritis.
Learn More >Omiganan is an indolicidin analogue with antimicrobial properties that could be beneficial for patients with atopic dermatitis. This randomized, double-blind, placebo-controlled phase II trial explored efficacy, pharmacodynamics and safety of topical omiganan once daily in 36 patients with mild to moderate AD. Patients were randomized to apply topical omiganan 1%, omiganan 2.5% or vehicle gel to one target lesion once daily for 28 consecutive days. Small but significant improvements of the local oSCORAD index and morning itch were observed in the omiganan 2.5% group compared to the vehicle gel group (-18.5%; 95%CI=-32.9,-1.0; p=0.04 and -8.2; 95%CI=-16.3,-0.2; p=0.05 respectively). A shift from lesional to non-lesional skin microbiota was observed in both omiganan treatment groups, in contrast to the vehicle group. In conclusion, treatment with topical omiganan improved dysbiosis in patients with mild to moderate atopic dermatitis and small but statistically significant improvement of clinical scores were detected. Our findings warrant further exploration in future clinical trials.
Learn More >Research suggests that itch and psychiatric diseases are intimately related. In efforts to examine the prevalence of psychiatric diagnoses in patients with chronic itch not due to psychogenic causes, we conducted a retrospective chart review of 502 adult patients diagnosed with chronic itch in an outpatient dermatology clinic specializing in itch and assessed these patients for a co-existing psychiatric disease. Psychiatric disease was identified and recorded based on ICD-10 codes made at any point in time which were recorded in the patient's electronic medical chart, which includes all medical department visits at the University of Miami. Fifty-five out of 502 (10.9%) of patients were found to have a comorbid psychiatric diagnosis based on ICD-10 codes. The most common psychiatric diagnoses were anxiety disorders (45.5%), followed by major depressive disorder (36.4%). There was no significant association of any specific type of itch to a particular psychiatric disorder. No unique itch characteristics were noted in patients with underlying psychiatric diagnoses.
Learn More >Anti-nerve growth factor (NGF) monoclonal antibodies (anti-NGF mAbs) have been reported to significantly attenuate pain, but the mechanism involved has not been fully elucidated, and the serious adverse events associated with mAbs seriously limit their clinical use. This study further investigated the mechanism by which peripheral NGF is involved in neuropathic pain and found safe, natural compounds that target NGF to attenuate neuropathic pain.
Learn More >Acute pain is common following surgery, with opioids frequently employed in its management. Studies indicate that commencing an opioid during a hospital admission increases the likelihood of long-term use. This study aimed to identify the prevalence of opioid persistence amongst opioid-naïve patients following surgery as well as the indication for use.
Learn More >To investigate the preventive effects of a combined antioxidant drug known as NEC (N-acetylcysteine, Vitamin E and C) on migraine outcomes. Migraine is characterised by increased oxidative stress and neurogenic inflammation in the brain; therefore antioxidants may have a migraine preventive effect.
Learn More >Childhood burns are common and distressing for children and their parents. Pain is the most common complaint and often thought to be undertreated, which can negatively influence the child's care and increase the risk of posttraumatic stress disorder. There is limited literature on the role of opioids and multimodal therapy in the treatment of pediatric outpatient burns. We sought to evaluate the current use of opioids (including the use of multimodal therapies), storage, and disposal of opioids in this patient population. Parents of burn-injured children 8 months to 18 years old, who were seen in an outpatient setting within 2 weeks of their burn injury, were queried from April to December 2019 regarding their child's pain control, opioid medication use, over-the-counter pain medication use, opioid storage, and disposal. A total of 142 parents of burn-injured children and their parents were surveyed. The median age of the burn-injured children was 2.7 years old and the majority (54.2%; 77/142) were male. The mean total body surface area (TBSA) was 1.8% and half sustained burn injuries to one or both hands. The most frequently used regimens for constant and/or breakthrough pain control were acetaminophen (62.7%) and nonsteroidal anti-inflammatory drugs (NSAIDs; 68.3%). Less than one fifth (26/142;18%) of patients were prescribed opioids and 88% filled their prescription. The median number of doses of opioids prescribed was eight doses, with a median of four doses of opioids unused. Only three patients used all of their prescribed opioids and no patient ≥12 years old used their entire prescription. Burns greater than 3% TBSA, irrespective of burn injury location, were associated with opioid prescription (P = .003). Approximately 40% (10/26) of parents who filled their child's opioid prescription stored the opioid in a locked area. Fewer than one third (7/26) of patients were educated on how to dispose of excess opioid pain medication. Overall, most pediatric outpatient burn injuries can be successfully managed with over-the-counter medications. Providers, who care for burn-injured children ≤ 12 years old with burns that cover ≥3% TBSA in the outpatient setting, should consider no more than four opioid doses for initial pain control. This guideline, coupled with family and provider-centered education on multimodal therapy at the time of initial presentation and safe use of opioids, are important first steps to minimizing the use of opioids in the management of small area burns in children.
Learn More >High mobility group box 1 (HMGB1) released from sensory nerve tissues can induce neuropathic pain. Whether HMGB1 is implicated in the mechanism underlying the effect of lidocaine in pain management remains to be determined. This study aims to explore the effect of lidocaine in a rat model of spared nerve injury (SNI) and the underlying mechanism. An SNI model was established via nerve ligation. Two weeks after the SNI model was established, rats were intrathecally injected with lidocaine, an HMGB1 antibody (HMG Ab), an MIP-1α antibody (MIP-1α Ab), a CCR1 inhibitor (CCR1-RS) or a CCR5 antagonist (CCR5-Mar). Pain behaviors were assessed before and after model establishment to calculate the number of spontaneous flinches (NSF), paw withdrawal threshold (PWT), paw withdrawal thermal latency (PWL) and sciatic function index (SFI). Cell apoptosis and the inflammatory response in the cerebrospinal fluid (CSF) were detected by TUNEL staining and ELISA. The mRNA and protein expression levels of MIP-1α, CCR1 and CCR5 were determined by RT-PCR and Western blotting. The expression levels of HMGB1, MIP-1α, CCR1 and CCR5 were measured by Western blotting and immunofluorescence. Pain behavior testing in SNI rats showed that SNI rats exhibited an increased NSF and a decreased PWT, PWL and SFI. Cell apoptosis in the spinal dorsal horn and the generation of inflammatory cytokines were enhanced in SNI rats, and the expression levels of HMGB1, MIP-1α, CCR1 and CCR5 were upregulated. HMGB1 cytoplasmic translocation, the coexpression of MIP-1α with NeuN, and the coexpression of CCR1 and CCR5 with OX42 were also observed in SNI rats. Neuropathic pain and neuroinflammation were suppressed by the intrathecal injection of lidocaine, HMG Ab, MIP-1α Ab, CCR1-RS or CCR5-Mar. Lidocaine inhibited the expression levels of HMGB1, MIP-1α, CCR1 and CCR5, and the HMGB1 antibody suppressed the expression of MIP-1α, CCR1 and CCR5. Lidocaine attenuates neuropathic pain and neuroinflammation by inhibiting HMGB1 to regulate the MIP-1α/CCR1/CCR5 pathway. Graphical Abstract.
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