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The spinal dorsal horn is a major site for the induction and maintenance of mechanical allodynia, but the circuitry that underlies this clinically important form of pain remains unclear. The studies presented here provide strong evidence that the neural circuits conveying mechanical allodynia in the dorsal horn differ by the nature of the injury. Calretinin (CR) neurons in lamina II inner convey mechanical allodynia induced by inflammatory injuries, while protein kinase C gamma (PKCγ) neurons at the lamina II/III border convey mechanical allodynia induced by neuropathic injuries. Cholecystokinin (CCK) neurons located deeper within the dorsal horn (laminae III-IV) are important for both types of injuries. Interestingly, the Maf subset of CCK neurons is composed of transient vesicular glutamate transporter 3 (tVGLUT3) neurons, which convey primarily dynamic allodynia. Identification of an etiology-based circuitry for mechanical allodynia in the dorsal horn has important implications for the mechanistic and clinical understanding of this condition.
Learn More >Cutaneous somatosensory modalities play pivotal roles in generating a wide range of sensorimotor behaviors, including protective and corrective reflexes that dynamically adapt ongoing movement and posture. How interneurons (INs) in the dorsal horn encode these modalities and transform them into stimulus-appropriate motor behaviors is not known. Here, we use an intersectional genetic approach to functionally assess the contribution that eight classes of dorsal excitatory INs make to sensorimotor reflex responses. We demonstrate that the dorsal horn is organized into spatially restricted excitatory modules composed of molecularly heterogeneous cell types. Laminae I/II INs drive chemical itch-induced scratching, laminae II/III INs generate paw withdrawal movements, and laminae III/IV INs modulate dynamic corrective reflexes. These data reveal a key principle in spinal somatosensory processing, namely, sensorimotor reflexes are driven by the differential spatial recruitment of excitatory neurons.
Learn More >Delivering adeno-associated virus (AAV) vectors into the central nervous system of nonhuman primates (NHPs) via the blood or cerebral spinal fluid is associated with dorsal root ganglion (DRG) toxicity. Conventional immune-suppression regimens do not prevent this toxicity, possibly because it may be caused by high transduction rates, which can, in turn, cause cellular stress due to an overabundance of the transgene product in target cells. To test this hypothesis and develop an approach to eliminate DRG toxicity, we exploited endogenous expression of microRNA (miR) 183 complex, which is largely restricted to DRG neurons, to specifically down-regulate transgene expression in these cells. We introduced sequence targets for miR183 into the vector genome within the 3' untranslated region of the corresponding transgene messenger RNA and injected vectors into the cisterna magna of NHPs. Administration of unmodified AAV vectors resulted in robust transduction of target tissues and toxicity in DRG neurons. Consistent with the proposal that immune system activity does not mediate this neuronal toxicity, we found that steroid administration was ineffective in alleviating this pathology. However, including miR183 targets in the vectors reduced transgene expression in, and toxicity of, DRG neurons without affecting transduction elsewhere in the primate's brain. This approach might be useful in reducing DRG toxicity and the associated morbidity and should facilitate the development of AAV-based gene therapies for many central nervous system diseases.
Learn More >The sodium channel Nav1.7 is a master regulator of nociceptive input into the central nervous system. Mutations in this channel can result in painful conditions and produce insensitivity to pain. Despite being recognized as a "poster child" for nociceptive signaling and human pain, targeting Nav1.7 has not yet produced a clinical drug. Recent work has illuminated the Nav1.7 interactome, offering insights into the regulation of these channels and identifying potentially new druggable targets. Among the regulators of Nav1.7 is the cytosolic collapsin response mediator protein 2 (CRMP2). CRMP2, modified at lysine 374 (K374) by addition of a small ubiquitin-like modifier (SUMO), bound Nav1.7 to regulate its membrane localization and function. Corollary to this, preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in rats with neuropathic pain. Notably, loss of CRMP2 SUMOylation did not compromise other innate functions of CRMP2. To further elucidate the in vivo role of CRMP2 SUMOylation in pain, we generated CRMP2 K374A knock-in (CRMP2) mice in which Lys374 was replaced with Ala. CRMP2 mice had reduced Nav1.7 membrane localization and function in female, but not male, sensory neurons. Behavioral appraisal of CRMP2 mice demonstrated no changes in depressive or repetitive, compulsive-like behaviors and a decrease in noxious thermal sensitivity. No changes were observed in CRMP2 mice to inflammatory, acute, or visceral pain. By contrast, in a neuropathic model, CRMP2 mice failed to develop persistent mechanical allodynia. Our study suggests that CRMP2 SUMOylation-dependent control of peripheral Nav1.7 is a hallmark of chronic, but not physiological, neuropathic pain.
Learn More >The neurokinin-1 receptor (NK1R; encoded by ) is expressed in spinal dorsal horn neurons and has been suggested to mediate itch in rodents. However, previous studies relied heavily on neurotoxic ablation of NK1R spinal neurons, which limited further dissection of their function in spinal itch circuitry. To address this limitation, we leveraged a newly developed mouse line to characterize the role of NK1R spinal neurons in itch. We show that pharmacological activation of spinal NK1R and chemogenetic activation of spinal neurons increases itch behavior in male and female mice, whereas pharmacological inhibition of spinal NK1R suppresses itch behavior. We use fluorescence hybridization (FISH) to characterize the endogenous expression of throughout the superficial and deeper dorsal horn (DDH), as well as the lateral spinal nucleus (LSN), of mouse and human spinal cord. Retrograde labeling studies in mice from the parabrachial nucleus (PBN) show that less than 20% of superficial dorsal horn neurons are spinal projection neurons, and thus the majority of are local interneurons. We then use a combination of hybridization and two-photon Ca imaging of the mouse spinal cord to establish that NK1R and the gastrin-releasing peptide receptor (GRPR) are coexpressed within a subpopulation of excitatory superficial dorsal horn (SDH) neurons. These findings are the first to suggest a role for NK1R interneurons in itch and extend our understanding of the complexities of spinal itch circuitry. The spinal cord is a critical hub for processing somatosensory input, yet which spinal neurons process itch input and how itch signals are encoded within the spinal cord is not fully understood. We demonstrate neurokinin-1 receptor (NK1R) spinal neurons mediate itch behavior in mice and that the majority of NK1R spinal neurons are local interneurons. These NK1R neurons comprise a subset of gastrin-releasing peptide receptor (GRPR) interneurons and are thus positioned at the center of spinal itch transmission. We show NK1R mRNA expression in human spinal cord, underscoring the translational relevance of our findings in mice. This work is the first to suggest a role for NK1R interneurons in itch and extends our understanding of the complexities of spinal itch circuitry.
Learn More >Changing Behavior through Physical Therapy (CBPT), a cognitive-behavioral-based program, has been shown to improve outcomes after lumbar spine surgery in patients with a high psychosocial risk profile; however, little is known about potential mechanisms associated with CBPT treatment effects. The purpose of this study was to explore potential mediators underlying CBPT efficacy after spine surgery.
Learn More >Sex differences in the quality and prevalence of chronic pain are manifold, with females generally presenting higher incidence and severity. Uncovering chronic pain-related sex differences informs neural mechanisms and may lead to novel treatment routes. In a multi-center morphological study (total n=374), we investigated whether the shape of subcortical regions would reflect sex differences in back pain. Given the hormone-dependent functions of the hippocampus, and its role in the transition to chronic pain, this region constituted our primary candidate. We found that the anterior part of the left hippocampus (alHP) presented outer deformation in females with chronic back pain (CBP), identified in CBP in the USA (n=77 females vs. n=78 males) and validated in a Chinese dataset (n=29 females vs. n=58 males with CBP, in contrast to n=53 female and n=43 male healthy controls). Next, we examined this region in subacute back pain (SBP) who persisted with back pain a year later (SBPp; n=18 females vs. n=18 males), and in a subgroup with persistent back pain for 3-years. Weeks after onset of back pain there was no deformation within alHP, but at 1-year and 3-years females exhibited a trend for outer deformation. The alHP partly overlapped with the subiculum and entorhinal cortex, whose functional connectivity, in healthy subjects, was associated with emotional and episodic memory related terms (Neurosynth, reverse inference). These findings suggest that in females alHP undergoes anatomical changes with pain persistence, highlighting sexually-dimorphic involvement of emotional and episodic memory-related circuitry with chronic pain.
Learn More >Experimental data have suggested that in neuropathic pain, tricyclic antidepressants may work solely through a β2-agonist action. The aim of this study was to test if the β2-agonist terbutaline relieves painful polyneuropathy. The study was a randomized, double-blind, placebo- and active-controlled, 3-way, cross-over trial among patients with painful polyneuropathy. The treatment periods were of 5 weeks' duration and were preceded by 1 week for washout and 1 week for baseline observations. The patients received terbutaline (5 to 15 mg), imipramine (30 to 150 mg), or placebo in random order. Drug doses depended on age and metabolizer status. Change in total pain recorded from ratings in diaries (NRS 0-10) was the primary outcome and change in rating of specific pain symptoms (NRS 0-10), patient global impression of change and sleep disturbance were secondary outcomes. Forty-seven patients were randomized. Median score for total pain changed from NRS 6.4 to 6.1 from baseline to week 5 on terbutaline with an average effect during the treatment period as compared to placebo of 0.13 (95% CI -0.12;0.38, p = 0.32). Median score for total pain on imipramine changed from NRS 6.6 to 4.8 with an average effect as compared to placebo of -1.17 (95% CI -1.42; -0.92, p < 0.001). Secondary outcomes were also unaltered by terbutaline but improved by imipramine. The β2-agonist terbutaline has no effect in painful polyneuropathy. β2 -agonism seems not to be an important mechanism of action of TCAs in neuropathic pain.
Learn More >Cranial hypersensitivity is a prominent symptom of migraine, exhibited as migraine headache exacerbated with physical activity, and cutaneous facial allodynia and hyperalgesia. The underlying mechanism is believed to be, in part, activation and sensitization of dural-responsive trigeminocervical neurons. Validated preclinical models that exhibit this phenotype have great utility for understanding putative mechanisms, and as a tool to screen therapeutics. We have previously shown that nitroglycerin triggers cranial allodynia in association with migraine-like headache, and this translates to neuronal cranial hypersensitivity in rats. Further, responses in both humans and rats are aborted by triptan administration, similar to responses in spontaneous migraine. Here, our objective was to study the nitroglycerin model examining the effects on therapeutic targets with newly approved treatments, specifically gepants and ditans, for the acute treatment of migraine. Using electrophysiological methods, we determined changes to ongoing firing and somatosensory-evoked cranial sensitivity, in response to nitroglycerin, followed by treatment with a CGRP receptor antagonist, gepant (olcegepant), a 5-HT1F receptor agonist, ditan (LY344864) and an NK1 receptor antagonist (GR205171). Nitroglycerin induced activation of migraine-like central trigeminocervical neurons, and intracranial and extracranial neuronal hypersensitivity. These responses were aborted by olcegepant and LY344864. However, GR205171, which failed in clinical trial for both abortive and preventive treatment of migraine, had no effect. These data support the nitroglycerin model as a valid approach to study cranial hypersensitivity and putative mechanisms involved in migraine, and as a screen to dissect potentially efficacious migraine therapeutic targets.
Learn More >Capsaicin, the pungent ingredient in chili peppers, produces intense burning pain in humans. Capsaicin selectively activates the transient receptor potential vanilloid 1 (TRPV1), which is enriched in nociceptive primary afferents, and underpins the mechanism for capsaicin-induced burning pain. Paradoxically, capsaicin has long been used as an analgesic. The development of topical patches and injectable formulations containing capsaicin has led to application in clinical settings to treat chronic pain conditions, such as neuropathic pain and the potential to treat osteoarthritis. More detailed determination of the neurobiological mechanisms of capsaicin-induced analgesia should provide the logical rationale for capsaicin therapy and help to overcome the treatment's limitations, which include individual differences in treatment outcome and procedural discomfort. Low concentrations of capsaicin induce short-term defunctionalization of nociceptor terminals. This phenomenon is reversible within hours and, hence, likely does not account for the clinical benefit. By contrast, high concentrations of capsaicin lead to long-term defunctionalization mediated by the ablation of TRPV1-expressing afferent terminals, resulting in long-lasting analgesia persisting for several months. Recent studies have shown that capsaicin-induced Ca/calpain-mediated ablation of axonal terminals is necessary to produce long-lasting analgesia in a mouse model of neuropathic pain. In combination with calpain, axonal mitochondrial dysfunction and microtubule disorganization may also contribute to the longer-term effects of capsaicin. The analgesic effects subside over time in association with the regeneration of the ablated afferent terminals. Further determination of the neurobiological mechanisms of capsaicin-induced analgesia should lead to more efficacious non-opioidergic analgesic options with fewer adverse side effects.
Learn More >Nerve injury in somatosensory pathways may lead to neuropathic pain, which affects the life quality of ∼8% of people. Long-term enhancement of excitatory synaptic transmission along somatosensory pathways contributes to neuropathic pain. Caspase 3 (Casp3) plays a non-apoptotic role in the hippocampus and regulates internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. Whether Casp3-AMPAR interaction is involved in the maintenance of peripheral hypersensitivity after nerve injury remained unknown. Here, we show that nerve injury suppresses long-term depression (LTD) and downregulates Casp3 in the anterior cingulate cortex (ACC). Interfering with interactions between Casp3 and AMPAR subunits or reducing Casp3 activity in the ACC suppresses LTD induction and causes peripheral hypersensitivity. Overexpression of Casp3 restores LTD and reduces peripheral hypersensitivity after nerve injury. We reveal how Casp3 is involved in the maintenance of peripheral hypersensitivity. Our findings suggest that restoration of LTD via Casp3 provides a therapeutic strategy for neuropathic pain management.
Learn More >Itch can be induced by activation of small-diameter dorsal root ganglion (DRG) neurons which express abundant intracellular fibroblast growth factor 13 (FGF13). Although FGF13 is revealed to be essential for heat nociception, its role in mediating itch remains to be investigated. Here, we reported that loss of FGF13 in mouse DRG neurons impaired the histamine-induced scratching behavior. Calcium imaging showed that the percentage of histamine-responsive DRG neurons was largely decreased in FGF13-deficient mice, and consistently, electrophysiological recording exhibited that histamine failed to evoke action potential firing in most DRG neurons from these mice. Given that the reduced histamine-evoked neuronal response was caused by knockdown of FGF13 but not by FGF13A deficiency, FGF13B was supposed to mediate this process. Furthermore, overexpression of histamine type 1 receptor H1R, but not H2R, H3R nor H4R, increased the percentage of histamine-responsive DRG neurons, and the scratching behavior in FGF13-deficient mice was highly reduced by selective activation of H1R, suggesting that H1R is mainly required for FGF13-mediated neuronal response and scratching behavior induced by histamine. However, overexpression of H1R failed to rescue the histamine-evoked neuronal response in FGF13-deficient mice. Histamine enhanced the FGF13 interaction with Na1.7. Disruption of this interaction by a membrane-permeable competitive peptide, GST-Flag-Na1.7CT-TAT, reduced the percentage of histamine-responsive DRG neurons, and impaired the histamine-induced scratching, indicating that the FGF13/Na1.7 interaction is a key molecular determinant in the histamine-induced itch sensation. Therefore, our study reveals a novel role of FGF13 in mediating itch sensation via the interaction of Na1.7 in peripheral nervous system.Scratching induced by itch brings serious tissue damage in chronic itchy diseases and targeting itch-sensing molecules is crucial for its therapeutic intervention. Here, we reveal that FGF13 is required for the neuronal excitation and scratching behavior induced by histamine. We further provide the evidence that the histamine-evoked neuronal response is mainly mediated by histamine type 1 receptor H1R, and is largely attenuated in FGF13-deficent mice. Importantly, we identify that histamine enhances the FGF13/Na1.7 interaction, and disruption of this interaction reduces histamine-evoked neuronal excitation and highly impairs histamine-induced scratching behavior. Additionally, we also find that FGF13 is involved in 5-HT-induced scratching behavior and hapten 1-fluoro-2,4-dinitrobenzene (DNFB)-induced chronic itch.
Learn More >Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, which interferes with orofacial function including talking and eating. We report that legumain (Lgmn) cleaves protease-activated receptor-2 (PAR) in the acidic OSCC microenvironment to cause pain. Lgmn is a cysteine protease of late endosomes and lysosomes that can be secreted; it exhibits maximal activity in acidic environments. The role of Lgmn in PAR-dependent cancer pain is unknown. We studied Lgmn activation in human oral cancers and oral cancer mouse models. Lgmn was activated in OSCC patient tumors, compared to matched normal oral tissue. After intraplantar, facial or lingual injection, Lgmn evoked nociception in wild-type (WT) female mice but not in female mice lacking PAR in Na1.8-positive neurons (), nor in female mice treated with a Lgmn inhibitor, LI-1. Inoculation of an OSCC cell line caused mechanical and thermal hyperalgesia that was reversed by LI-1. and deletion attenuated mechanical allodynia in female mice with carcinogen-induced OSCC. Lgmn caused PAR-dependent hyperexcitability of trigeminal neurons from WT female mice. deletion, LI-1 and inhibitors of adenylyl cyclase or protein kinase A prevented the effects of Lgmn. Under acidified conditions, Lgmn cleaved within the extracellular N-terminus of PAR at Asn↓Arg, proximal to the canonical trypsin activation site. Lgmn activated PAR by biased mechanisms in HEK293 cells to induce Ca mobilization, cAMP formation and protein kinase A/D activation, but not β-arrestin recruitment or PAR endocytosis. Thus, in the acidified OSCC microenvironment Lgmn activates PAR by biased mechanisms that evoke cancer pain.Oral squamous cell carcinoma (OSCC) is one of the most painful cancers. We report that legumain (Lgmn), which exhibits maximal activity in acidic environments, cleaves protease-activated receptor-2 (PAR) on neurons to produce OSCC pain. Active Lgmn was elevated in OSCC patient tumors, compared to matched normal oral tissue. Lgmn evokes pain-like behavior through PAR Exposure of pain-sensing neurons to Lgmn decreased the current required to generate an action potential through PAR Inhibitors of adenylyl cyclase and protein kinase A prevented the effects of Lgmn. Lgmn activated PAR to induce calcium mobilization, cAMP formation and activation of protein kinase D and A, but not β-arrestin recruitment or PAR endocytosis. Thus, Lgmn is a biased agonist of PAR that evokes cancer pain.
Learn More >The serotonin receptor 2A (HTR2A) has been described as an important facilitation mediator of spinal nociceptive processing leading to central sensitization (CS) in animal models of chronic pain. However, whether HTR2A single nucleotide variants (SNVs) modulate neuropathic pain states in patients has not been investigated so far. The aim of this study was to elucidate the potential association of HTR2A variants with sensory abnormalities or ongoing pain in neuropathic pain patients.
Learn More >Chronic low back pain (cLBP) that cannot be attributable to a specific pathoanatomical change is associated with high personal and societal costs. Still, the underlying mechanism that causes and sustains such a phenotype is largely unknown. Emerging evidence suggests that epigenetic changes play a role in chronic pain conditions. Using reduced representation bisulfite sequencing (RRBS), we evaluated DNA methylation profiles of adults with non-specific cLBP (n = 50) and pain-free controls (n = 48). We identified 28,325 hypermethylated and 36,936 hypomethylated CpG sites (p < 0.05). After correcting for multiple testing, we identified 159 DMRs (q < 0.01and methylation difference > 10%), the majority of which were located in CpG island (50%) and promoter regions (48%) on the associated genes. The genes associated with the differentially methylated regions were highly enriched in biological processes that have previously been implicated in immune signaling, endochondral ossification, and G-protein coupled transmissions. Our findings support inflammatory alterations and the role of bone maturation in cLBP. This study suggests that epigenetic regulation has an important role in the pathophysiology of non-specific cLBP and a basis for future studies in biomarker development and targeted interventions.
Learn More >Purinergic signalling plays important roles in somatosensory and nociceptive transmission in the dorsal horn of the spinal cord under physiological and pathophysiological conditions. Physiologically, ATP mediates excitatory postsynaptic responses in nociceptive transmission in the superficial dorsal horn, and in transmission of innocuous primary afferent inputs in the deep dorsal horn. Additionally, extracellular conversion of ATP to adenosine mediates inhibitory postsynaptic responses from Pacinian corpuscle afferents, and is implicated in analgesia caused by transcutaneous electrical nerve stimulation in humans. In terms of pathological pain, P2X4 receptors de novo expressed on dorsal horn microglia are implicated in pain hypersensitivity following peripheral nerve injury. There is evidence that involvement of such P2X4 receptors is sexually dimorphic, occurring in males but not in females. Thus, the roles of purinergic signalling in physiological and pathological pain processing are complex and remain an ever-expanding field of research.
Learn More >Cannabidiol (CBD) is the second most abundant component of the Cannabis plant and is known to have effects distinct from Δ -tetrahydrocannabinol (THC). Many studies that examined the behavioral effects of CBD concluded that it lacks the psychotomimetic effects attributed to THC. However, CBD was shown to have a broad spectrum of effects on several conditions such as anxiety, inflammation, neuropathic pain, and epilepsy. It is currently thought that CBD engages different targets and hence CBD's effects are thought to be due to multiple molecular mechanisms of action. A well-accepted set of targets include GPCRs and ion channels, with the serotonin 5-HT receptor and the transient receptor potential cation channel TRPV1 channel being the two main targets. CBD has also been thought to target G protein-coupled receptors (GPCRs) such as cannabinoid and opioid receptors. Other studies have suggested a role for additional GPCRs and ion channels as targets of CBD. Currently, the clinical efficacy of CBD is not completely understood. Evidence derived from randomized clinical trials, in vitro and in vivo models and real-world observations support the use of CBD as a drug treatment option for anxiety, neuropathy, and many other conditions. Hence an understanding of the current status of the field as it relates to the targets for CBD is of great interest so, in this review, we include findings from recent studies that highlight these main targets.
Learn More >Peripheral neuropathy is associated with enhanced activity of primary afferents which is often manifested as pain. Voltage-gated sodium channels (VGSCs) are critical for the initiation and propagation of action potentials and are thus essential for the transmission of the noxious stimuli from the periphery. Human peripheral sensory neurons express multiple VGSCs, including Nav1.7, Nav1.8, and Nav1.9 that are almost exclusively expressed in the peripheral nervous system. Distinct biophysical properties of Nav1.7, Nav1.8, and Nav1.9 underlie their differential contributions to finely tuned neuronal firing of nociceptors, and mutations in these channels have been associated with several inherited human pain disorders. Functional characterization of these mutations has provided additional insights into the role of these channels in electrogenesis in nociceptive neurons and pain sensation. Peripheral tissue damage activates an inflammatory response and triggers generation and release of inflammatory mediators, which can act through diverse signaling cascades to modulate expression and activity of ion channels including VGSCs, contributing to the development and maintenance of pathological pain conditions. In this review, we discuss signaling pathways that are activated by pro-nociceptive inflammatory mediators that regulate peripheral sodium channels, with a specific focus on direct phosphorylation of these channels by multiple protein kinases.
Learn More >Meta-analyses indicate mindfulness meditation is efficacious for chronic and acute pain, but most available studies lack active control comparisons. This raises the possibility that placebo-related processes may account, at least in part, for mindfulness effects. The objective of this study was to develop a closely matched sham mindfulness condition to establish whether placebo effects contribute to mindfulness-based interventions for pain.
Learn More >Preliminary research in youth with chronic pain suggests differences in attention and working memory, which has been similarly demonstrated in adults with chronic pain. There has been little research on other aspects of executive functioning (EF) in this population despite its critical role in problem solving, school functioning, and coping. This study aimed to examine differences in several aspects of EF between youth with chronic pain and a non-chronic pain comparison group using performance-based neuropsychological tests and a behaviour rating scale.
Learn More >Growing evidence shows a critical role of network disturbances in the pathogenesis of migraine. Unilateral pattern of neurological symptoms of aura suggests disruption of interhemispheric interactions during the early phase of a migraine attack. Using local field potentials data from the visual and motor cortices, this study explored effects of unilateral cortical spreading depression, the likely pathophysiological mechanism of migraine aura, on interhemispheric functional connectivity in freely behaving rats.
Learn More >Migraine preventive medications are used to reduce headache frequency, severity, and duration. In patients with chronic migraine (CM), reversion to episodic migraine (EM) is an important treatment goal.
Learn More >Increased acute postoperative pain intensity has been associated with the development of persistent postsurgical pain (PPP) in mechanistic and clinical investigations, but it remains unclear which aspects of acute pain explain this linkage.
Learn More >To determine the onset of preventive efficacy with eptinezumab in patients with migraine.
Learn More >Patients with chronic pain report decreased general activity and emotional distress. Therefore, the development of various animal models that encompass different aspects of pain are crucial for the discovery of genetic differences and the assessment of novel analgesics to improve quality of life. C57BL/6 J and DBA/2 J mice received unilateral intraplantar injections of 100% CFA, Paclitaxel, or CCI surgery to compare their distance traveled in a voluntary wheel running assay, paw edema diameter, and mechanical sensitivity. Mechanical withdrawal thresholds were lower in both strains of mice that received CFA when compared to their vehicle. However, a decrease in distance traveled was observed in CFA-treated C57BL/6 J but not DBA/2 J mice. In a separate group, chemotherapy agent paclitaxel 8 mg/kg, i.p. was administered to both strains of mice to induce cause CIPN which was confirmed by lower mechanical thresholds in paclitaxel-treated mice compared to vehicle-treated mice. Only female C57BL/6 J mice showed attenuation of distance traveled following treatment whereas male C57BL/6 J and DBA/2 J mice did not. Lastly, C57BL/6 J mice underwent chronic constriction injury (CCI) or sham surgery to observe the impact of another chronic neuropathic pain model in wheel running assay. CCI mice showed a gradual decrease in mechanical withdrawal threshold and a decrease in distance traveled compared to sham 5 days following the procedure. Comparing these chronic inflammatory and neuropathic pain models in different mouse strains may help us better understand genetic differences underlying pain perception and its impact on reflexive and nonreflexive outcome measures.
Learn More >We previously demonstrated that automated, Web-based pain coping skills training (PCST) can reduce osteoarthritis pain. The present secondary analyses examined whether this program also changed coping strategies participants identified for use in hypothetical pain-related situations.
Learn More >Up to 90% of patients with postural tachycardia syndrome (PoTS) report headaches, and comorbid migraine headaches are common. Given this, pathophysiological interaction is possible, which may reveal key aspects of disease expression and treatment opportunities. We hypothesized that PoTS subjects-both with and without migraine-would show features of central sensitization, including allodynia and photophobia.
Learn More >The peripheral mu-opioid receptor (MOR) has been recognized as a potential target to provide safer analgesia with reduced central side effects. Although analgesic incompetence of the peripheral MOR in the absence of inflammation was initially identified more than a decade ago, there has been very limited investigation into the underlying signaling mechanisms. Here we identify that G protein-coupled receptor kinase 2 (GRK2) constitutively interacts with the MOR in peripheral sensory neurons to suppress peripheral MOR activity. Brief exposure to bradykinin (BK) causes uncoupling of GRK2 from the MOR and subsequent restoration of MOR functionality in dorsal root ganglion (DRG) neurons. Interestingly, prolonged BK treatment induces constitutive activation of the MOR through a mechanism that involves protein kinase C (PKC) activation. After silencing Raf kinase inhibitory protein (RKIP) by RNA interference, BK-induced constitutive MOR activation is completely abrogated, which agrees with previous findings that BK activates PKC signaling to initiate GRK2 sequestration by RKIP. Furthermore, we demonstrate that constitutive, peripheral MOR activity requires GRK2 uncoupling and that the FDA-approved SSRI paroxetine promotes this state of uncoupling. Collectively, these results indicate that GRK2 tightly regulates MOR functional states and controls constitutive MOR activity in peripheral sensory neurons, supporting the potential for targeting the kinase to provide safer analgesia.
Learn More >Migraine patients often report (inter)ictal hypersensitivity to light, but the underlying mechanisms remain an enigma. Both hypo- and hyperresponsivity of the visual network have been reported, which may reflect either intra-individual dynamics of the network or large inter-individual variation in the measurement of human visual evoked potential data. Therefore, we studied visual system responsivity in freely behaving mice using combined epidural electroencephalography and intracortical multi-unit activity to reduce variation in recordings and gain insight in visual cortex dynamics. For better clinical translation, we investigated transgenic mice that carry the human pathogenic R192Q missense mutation in the α subunit of voltage-gated Ca 2.1 Ca channels leading to enhanced neurotransmission and familial hemiplegic migraine type 1 in patients. Visual evoked potentials were studied in response to visual stimulation paradigms with flashes of light. Following intensity-dependent visual stimulation, FHM1 mutant mice displayed faster visual evoked potential responses, with lower initial amplitude, followed by less pronounced neuronal suppression compared to wild-type mice. Similar to what was reported for migraine patients, frequency-dependent stimulation in mutant mice revealed enhanced photic drive in the EEG beta-gamma band. The frequency-dependent increases in visual network responses in mutant mice may reflect context-dependent enhancement of visual cortex excitability, which could contribute to our understanding of sensory hypersensitivity in migraine.
Learn More >Osteoarthritis (OA) is an extraordinarily prevalent and disabling disease [1]. Current management options for pain and functional limitation are constrained by modest efficacy or a range of unwanted side effects. Our society is being impacted through underemployment and the opioid epidemic and our health care systems are overstretched, as a consequence of the trajectory of increasing joint replacement requirements [2]. In this context, development of new treatments or identification of efficacy of existing therapies to address the huge unmet need of pain are strongly desired.
Learn More >Migraine occurs 2-3 times more often in females than in males and is in many females associated with the onset of menstruation. The steroid hormone, 17β-estradiol (estrogen, E2), exerts its effects by binding and activating several estrogen receptors (ERs). Calcitonin gene-related peptide (CGRP) has a strong position in migraine pathophysiology, and interaction with CGRP has resulted in several successful drugs for acute and prophylactic treatment of migraine, effective in all age groups and in both sexes.
Learn More >An Exploratory Study Testing Autonomic Reactivity to Pain in Women with Sensory Over-Responsiveness.
Difficulty modulating sensory input related to multi-sensory integration dysfunction, specifically the sensory over-responsive (SOR) type, is associated with psychological distress and hyperalgesia in children and adults. Scares reports suggest atypical autonomic nervous system (ANS) reactivity to innocuous sensory stimuli in children with SOR. Thus, the ANS may contribute to sensory stimuli responses and psychological distress. This exploratory study aimed to characterize the ANS reactivity to single and dual pain stimulation, and in relation to psychological distress in adults with SOR.
Learn More >The transient receptor potential vanilloid-1 (TRPV1) is a non-specific cation channel known for its sensitivity to pungent vanilloid compound (i.e. capsaicin) and noxious stimuli, including heat, low pH or inflammatory mediators. TRPV1 is found in the somatosensory system, particularly primary afferent neurons that respond to damaging or potentially damaging stimuli (nociceptors). Stimulation of TRPV1 evokes a burning sensation, reflecting a central role of the channel in pain. Pharmacological and genetic studies have validated TRPV1 as a therapeutic target in several preclinical models of chronic pain, including cancer, neuropathic, postoperative and musculoskeletal pain. While antagonists of TRPV1 were found to be a valuable addition to the pain therapeutic toolbox, their clinical use has been limited by detrimental side effects, such as hyperthermia. In contrast, capsaicin induces a prolonged defunctionalisation of nociceptors and thus opened the door to the development of a new class of therapeutics with long-lasting pain-relieving effects. Here we review the list of TRPV1 agonists undergoing clinical trials for chronic pain management, and discuss new indications, formulations or combination therapies being explored for capsaicin. While the analgesic pharmacopeia for chronic pain patients is ancient and poorly effective, modern TRPV1-targeted drugs could rapidly become available as the next generation of analgesics for a broad spectrum of pain conditions.
Learn More >Neuropathic pain (NP) is a chronic condition that results from a lesion or disease of the nervous system, greatly impacting patients' quality of life. Current pharmacotherapy options deliver inadequate and/or insufficient responses and thus a significant unmet clinical need remains for alternative treatments in NP. Neuroinflammation, oxidative stress and their reciprocal relationship are critically involved in NP pathophysiology. In this context, new pharmacological approaches, aiming at enhancing the resolution phase of inflammation and/or restoring redox balance by targeting specific reactive oxygen species (ROS) sources, are emerging as potential therapeutic strategies for NP, with improved efficacy and safety profiles. Several reports have demonstrated that administration of exogenous specialized pro-resolving mediators (SPMs) ameliorates NP pathophysiology. Likewise, deletion or inhibition of the ROS-generating enzyme NADPH oxidase (NOX), particularly its isoforms 2 and 4, results in beneficial effects in NP models. Notably, SPMs also modulate oxidative stress and NOX also regulate neuroinflammation. By targeting neuroinflammatory and oxidative pathways, both SPMs analogues and isoform-specific NOX inhibitors are promising therapeutic strategies for NP.
Learn More >Up to 17%-20% of pediatric patients with chronic pain are prescribed opioid pharmacotherapy and face an increased risk of opioid misuse in adulthood. Little is known about the way clinical presentation may influence which children with chronic pain are prescribed opioids. This study examines the associations between child's and caregiver's report of child's pain, physical function, and socioemotional indices with opioid prescriptions in pediatric patients initiating treatment for chronic pain.
Learn More >The goal of this paper is to give a narrative review of the racial/ethnic disparities in African-Americans (AA) found in headache medicine and provide plausible responses to the National Institute of Neurological Disorders and Stroke (NINDS) issued Request for information (RFI); "Soliciting Input on Areas of Health Disparities and Inequities in Neurological Disease and/or Care in the United States (US)" as it relates to AA and headache medicine.
Learn More >Chronic pain is a distressing symptom that older adults with osteoarthritis (OA) seek to minimize through management. Research consistently points out the disparities that older African Americans face when managing chronic pain conditions, but a major gap in the literature is how pain care policy at the federal, state, and local level protects or exposes older African Americans to disadvantaged care.
Learn More >Metformin is currently first line therapy for type 2 diabetes (T2D). The mechanism of action of metformin involves activation of AMP-activated protein kinase (AMPK) to enhance mitochondrial function (for example, biogenesis, refurbishment and dynamics) and autophagy. Many neurodegenerative diseases of the central and peripheral nervous systems arise from metabolic failure and toxic protein aggregation where activated AMPK could prove protective. Areas covered: The authors review literature on metformin treatment in Parkinson's disease, Huntington's disease and other neurological diseases of the CNS along with neuroprotective effects of AMPK activation and suppression of the mammalian target of rapamycin (mTOR) pathway on peripheral neuropathy and neuropathic pain. The authors compare the efficacy of metformin with the actions of resveratrol. Expert opinion: Metformin, through activation of AMPK and autophagy, can enhance neuronal bioenergetics, promote nerve repair and reduce toxic protein aggregates in neurological diseases. A long history of safe use in humans should encourage development of metformin and other AMPK activators in preclinical and clinical research. Future studies in animal models of neurological disease should strive to further dissect in a mechanistic manner the pathways downstream from metformin-dependent AMPK activation, and to further investigate mTOR dependent and independent signaling pathways driving neuroprotection.
Learn More >The multitude of treatments available for tens of millions of US adults with moderate/severe chronic pain have limited efficacy. Long-term opioid therapy (LTOT) is a widely available option for controlling pain among patients with chronic pain refractory to other treatments. The recent recognition of LTOT inefficacy and complications has led to more frequent opioid tapering, which in turn has revealed its own set of complications. The occurrence of the same set of symptoms-worsening pain, declining function, and clinical instability-in contrasting contexts of LTOT ineffectiveness and opioid tapering has led to increasing recognition of the utility of complex persistent opioid dependence (CPOD), a clinically distinct but biologically similar state compared with opioid use disorder as an explanatory diagnosis/heuristic. Recent guidelines for LTOT tapering have incorporated buprenorphine treatment based on CPOD concepts as a recommended treatment for problems due to opioid tapering with limited supportive evidence. The increasing utilization of buprenorphine for both LTOT ineffectiveness and opioid tapering problems raises the urgent need for a review of the clinical definition, mechanisms, and treatment of CPOD and pertinent policies. In this manuscript, we discuss various issues related to CPOD that requires further clarification through research and policy development.
Learn More >Temperature-sensitive Transient Receptor Potential Vanilloid ion channel subtypes 1-4 (thermoTRPV1-4) play important roles in a wide range of physiological processes, including temperature sensing and body temperature regulation, inflammation, pain, itch, maintenance of skin, bone and hair and osmotic regulation. ThermoTRPV function is modulated by numerous natural product compounds, such as capsaicin, camphor and cannabinoids. Because of their physiological importance and their druggability, these channels have made attractive potential targets for drug development. Since the beginning of the cryo-EM "resolution revolution" a lot of progress has been made towards dissecting the activation mechanisms of thermoTRPVs and mapping the binding sites for modulatory compounds. Here we review the thermoTRPV physiology and pharmacology and summarize the current knowledge of their mechanisms of gating and ligand binding sites.
Learn More >Randomized controlled trial with 1-year follow up.
Learn More >Establish the impact of pain severity on the cost-effectiveness of generic duloxetine for knee osteoarthritis (OA) in the United States.
Learn More >This study sought to investigate the relationship between allodynia, psychological variables, and disability among individuals with migraine.
Learn More >Cluster headache (CH) is a highly disabling primary headache disorder. To date, characterization of outcomes in the preventive treatment of episodic CH, including precise definitions of clinically meaningful attack frequency reduction and impact on acute treatment management, is lacking.
Learn More >To review studies examining the proportion of people with chronic noncancer pain who report consuming opioids and characteristics associated with their use.
Learn More >The Sigma-1 receptor (σ1R) has emerged as an interesting pharmacological target because it inhibits analgesia mediated by mu-opioid receptors (MOR), and also facilitates the development of neuropathic pain. Based on these findings, the recent cloning of the Sigma-2 receptor (σ2R) led us to investigate its potential role as a regulator of opioid analgesia and of pain hypersensitivity in σ2R knockout mice. In contrast to σ1R deficient mice, σ2R knockout mice developed mechanical allodynia following establishment of chronic constriction injury-induced neuropathic pain, which was alleviated by the σ1R antagonist S1RA. The analgesic effects of morphine, [D-Ala, N-MePhe, Gly-ol]-encephalin (DAMGO) and β-endorphin increased in σ1R mice and diminished in σ2R mice. The analgesic effect of morphine was increased in σ2R mice by treatment with S1RA. However, σ2R mice and wild-type mice exhibited comparable antinociceptive responses to the delta receptor agonist [D-Pen2,5]-encephalin (DPDPE), the cannabinoid type 1 receptor agonist WIN55,212-2 and the α2-adrenergic receptor agonist clonidine. Therefore, while σR1 inhibits and σ2R facilitates MOR-mediated analgesia these receptors exchange their roles when regulating neuropathic pain perception. Our study may help identify new pharmacological targets for diminishing pain perception and improving opioid detoxification therapies.
Learn More >Severe chronic postsurgical pain has a prevalence of 4-10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile ('high-sensitizers' [n = 20]) and the lower quartile ('low-sensitizers' [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between 'high-sensitizers' and 'low-sensitizers' (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for 'high-sensitizers' (P < 0.001), but not 'low-sensitizers' (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.
Learn More >Emotional and cognitive impairments are common comorbidities of chronic neuropathic pain that significantly impact the quality of life of patients. While the nociceptive components of the peripheral nerve chronic constriction injury (CCI) animal model have been extensively analyzed, data related to the development of mood and cognitive disorders, and especially its impact on female rats remains fragmented. We systematically reviewed the literature analyzing the methods used to induce and evaluate the development of emotional- and cognitive-like impairments and sex-specific differences in the CCI model.
Learn More >Central neuropathic extremity pain (CNEP) is the most frequent type of pain in multiple sclerosis (MS). The aim of the present study was to evaluate sensory and pain modulation profiles in MS patients with CNEP. In a single-centre observational study, a group of 56 CNEP MS patients was compared with 63 pain-free MS patients and with a sex- and age-adjusted control group. Standardized quantitative sensory testing (QST) and dynamic QST (dQST) protocols comprising temporal summation and conditioned pain modulation tests were used to compare sensory profiles. Loss-type QST abnormalities in both thermal and mechanical QST modalities prevailed in both MS subgroups and correlated significantly with higher degree of disability expressed as Expanded Disability Status Scale (EDSS). Comparison of sensory phenotypes disclosed a higher frequency of the "sensory loss" prototypic sensory phenotype in the CNEP subgroup (30%) compared with pain-free MS patients (6%; p = 0.003). The role of aging process and higher lesion load in the spinothalamocortical pathway might be possible explanation for pain development in this particular "deafferentation" subtype of central neuropathic pain in MS. We were unable to support the role of central sensitization or endogenous facilitatory and inhibitory mechanisms in the development of CNEP in MS.
Learn More >The "funnel effect" of Fibromyalgia (FM) assumes that as patients access healthcare services, they present greater severity and a more complex clinical situation than individuals with FM from the general population, but the studies comparing patients treated in different levels of healthcare are scarce. The aim of this study is to analyse the "funnel effect" hypothesis by comparing patients from secondary and tertiary healthcare services.
Learn More >The "pain-inhibits-pain"' effect stems from neurophysiological mechanisms involving endogenous modulatory systems termed diffuse noxious inhibitory controls (DNIC) or conditioned pain modulation (CPM). Laser-evoked potentials (LEPs) components, the N2/P2 complex, and the N1 wave, reflect the medial and lateral pain pathway, respectively: anatomically, the lateral thalamic nuclei (LT) project mainly to the somatosensory cortex (N1 generator), while the medial thalamic nuclei (MT) are bound to the limbic cortices (N2/P2 generators).
Learn More >To quantify the social burden among Japanese migraine patients in the context of currently available migraine treatments, by comparison with non-migraine controls, and comparison of migraine patients currently taking prescription medication versus not taking prescription medication.
Learn More >For more than ten years, gene therapy for neurological diseases has experienced intensive research growth and more recently therapeutic interventions for multiple indicationsBeneficial results in several phase 1/2 clinical studies, together with improved vector technology have advanced gene therapy for the central nervous system (CNS) in a new era of development. While most initial strategies have focused on orphan genetic diseases, such as lysosomal storage diseases, more complex and widespread conditions like Alzheimer's disease, Parkinson's disease, epilepsy or chronic pain are increasingly targeted for gene therapy. Increasing numbers of applications and patients to be treated will require improving and simplifying gene therapy protocols to make them accessible to the largest number of affected people. While vectors and manufacturing are a major field of academic research and industrial development, there is a growing need to improve, standardize and simplify delivery methods. Delivery is the major issue for CNS therapies in general, and particularly for gene therapy. The blood brain barrier restricts the passage of vectors; and strategies to bypass this obstacle are a central focus of research. Here, we present the different ways that can be used to deliver gene therapy products to the CNS. We focus on results obtained in large animals that have allowed the transfer of protocols to human patients and have resulted in the generation of clinical data. We discuss the different routes of administration, their advantages and their limitations. We describe techniques, equipment and protocols and how they should be selected for safe delivery and improved efficiency for the next generation of gene therapy trials for CNS diseases.
Learn More >The lack of effective treatments against diabetic sensorimotor polyneuropathy demands the search for new strategies to combat or prevent the condition. Since reduced magnesium and increased methylglyoxal levels have been implicated in the development of both type 2 diabetes and neuropathic pain, we aimed to assess the putative interplay of both molecules with diabetic sensorimotor polyneuropathy.
Learn More >The current knowledge on the role of SI and ACC in acute pain processing and how these contribute to the development of chronic pain is limited. Our objective was to investigate differences in and modulation of intracortical responses from SI and ACC in response to different intensities of peripheral presumed noxious and non-noxious stimuli in the acute time frame of a peripheral nerve injury in rats.
Learn More >The relationship between habitual physical activity (PA) and experimental pain tolerance has been investigated in small samples of young, healthy, and/or single-sex volunteers. We used a large, population-based sample to assess this relationship in men and women with and without chronic pain.
Learn More >Persistent or recurrent pain is common among adolescents and is associated with poor functioning. The purpose of this study was to determine whether preteens who present with pain, and higher, co-occurring psychologic and somatic symptoms (PSS) are at higher risk for persistent pain than other children.
Learn More >Adenosine (ADO) is an essential biomolecule for life that provides critical regulation of energy utilization and homeostasis. Adenosine kinase (ADK) is an evolutionary ancient ribokinase derived from bacterial sugar kinases that is widely expressed in all forms of life, tissues and organ systems that tightly regulates intracellular and extracellular ADO concentrations. The facile ability of ADK to alter ADO availability provides a "site and event" specificity to the endogenous protective effects of ADO in situations of cellular stress. In addition to modulating the ability of ADO to activate its cognate receptors (P1 receptors), nuclear ADK isoform activity has been linked to epigenetic mechanisms based on transmethylation pathways. Previous drug discovery research has targeted ADK inhibition as a therapeutic approach to manage epilepsy, pain, and inflammation. These efforts generated multiple classes of highly potent and selective inhibitors. However, clinical development of early ADK inhibitors was stopped due to apparent mechanistic toxicity and the lack of suitable translational markers. New insights regarding the potential role of the nuclear ADK isoform (ADK-Long) in the epigenetic modulation of maladaptive DNA methylation offers the possibility of identifying novel ADK-isoform selective inhibitors and new interventional strategies that are independent of ADO receptor activation.
Learn More >Rotigotine-loaded microspheres (RoMS) are sustained-release formulations with prolonged anti-Parkinson's effects. Given that pain is a non-motor symptom of Parkinson's disease, this study investigated the antinociceptive effects of RoMS and their synergistic effects with analgesics on inflammatory pain. A model of inflammatory pain was prepared by intraplantarly injecting male Sprague-Dawley rats with carrageenan. The antinociceptive effects of RoMS, acetaminophen, and tramadol, both alone and in combination, were evaluated using the hind paw withdrawal latency in the hot plate test and Randall-Selitto test. The rotigotine concentrations in serum and tissues were assayed using ultra-performance liquid chromatography-tandem mass spectrometry. Isobolographic analysis was performed to evaluate the nature of the interactions of RoMS with acetaminophen or tramadol. The results showed that hind paw withdrawal latency to thermal and mechanical stimuli was significantly increased on day 3 and 7 after RoMS administered. Rotigotine could be detected in serum and tissues 3 and 7 days after an intramuscular injection of RoMS. However, the rotigotine concentration fell the detection limit of the assay on day 14 after administration. RoMS produced synergistic antinociceptive effects in the inflammatory pain model when RoMS is combined with acetaminophen or tramadol. These findings suggest that RoMS can relieve inflammatory pain in rats. Furthermore, the combination of RoMS with acetaminophen or tramadol produces synergistic antinociception, which may be clinically worthy because combination therapies may reduce the drug doses required for antinociception.
Learn More >To evaluate the feasibility of recruitment, preliminary efficacy, and acceptability of auricular percutaneous electrical nerve field stimulation (PENFS) for the treatment of fibromyalgia in veterans, using neuroimaging as an outcome measure and a biomarker of treatment response.
Learn More >The relationship between chronic pain (CP) and cognitive decline (CD) is bidirectional among older adults. The CP-CD comorbidity can progressively worsen cognitive, physical, emotional, and social functioning with aging. We explored the feasibility and outcomes associated with two mind-body activity programs for CP and CD that focus on increasing walking using time goals (Active Brains) or step-count reinforced via Fitbit (Active Brains-Fitbit).
Learn More >Pain in chronic pancreatitis is subdivided in a continuous or intermittent pattern, each thought to represent a different entity, requiring specific treatment. Because evidence is missing, we studied pain patterns in a prospective longitudinal nationwide study.
Learn More >Partner's responses to pain behaviours play a pivotal role in the patient's adjustment. This study aims to further our knowledge regarding patients' and partners' interpretation of partners' responses to pain behaviours, and the possible discrepancies between patients' and partners' perceptions. Further, this study examines patients' preferred responses to pain behaviours and possible discrepancies between received and preferred responses to pain behaviours.
Learn More >Trigeminal neuralgia (TN) causes severe episodic, unilateral facial pain and is initially treated with antiepileptic medications. For patients not responding or intolerant to medications, surgery is an option.
Learn More >Pain is a frequent symptom of atopic dermatitis (AD).
Learn More >Fibromyalgia (FM) is a frequent comorbidity in patients with chronic migraine (CM). PREEMPT trials, which demonstrated the efficacy of OnabotulinumtoxinA (OnabotA) on CM, excluded patients with FM. Our aim was to evaluate the effectiveness of OnabotA in a series of patients with CM and FM. We analyzed patients with a previous diagnosis of CM and FM who had received sessions of OnabotA quarterly between January 2014 and January 2020 in a specialized Headache Clinic. Primary endpoint was the reduction in moderate to severe headache days at 3, 6, 9, and 12 months. Data were collected from 31 patients with CM and FM that received OnabotA (100% females). Mean age at first procedure was 50.2 ± 11.3 years. Depression (93.5%), other central sensitization syndromes (irritable bowel syndrome, interstitial cystitis, multiple chemical sensitivity, endometriosis, and chronic fatigue syndrome) (48.4%), and medication overuse headache (90.3%) were frequent comorbidities. 48.4% of patients had failed ≥3 preventives previously. The percentage of patients who achieved ≥30 and ≥50% moderate-severe headache reduction on the third month was 65.4 and 48.2%, respectively. Twenty-three patients completed four cycles of treatment, with 13.4 fewer headache days per month than at baseline ( < 0.001). By 1 year, 69.5% had ≥50% reduction of headache frequency and 39.1% had a ≥75% reduction. In 4 cases (21%), OnabotA was interrupted due to a lack of response. Only mild adverse effects were recorded. OnabotA is an effective treatment for CM in patients with FM.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent, painful side effect which arises due to a number of chemotherapy agents. CIPN can have a prolonged effect on quality of life. Chemotherapy treatment is often reduced or stopped altogether because of the severe pain. Currently, there are no FDA-approved treatments for CIPN partially due to its complex pathogenesis in multiple pathways involving a variety of channels, specifically, voltage-gated ion channels. One aspect of neuropathic pain is hyperexcitability in dorsal root ganglia (DRG) peripheral sensory neurons. Our study employs bifurcation theory to investigate the role of voltage-gated ion channels in inducing hyperexcitability as a consequence of spontaneous firing due to the common chemotherapy agent paclitaxel. Our mathematical investigation of a reductionist DRG neuron model comprised of sodium channel Na1.7, sodium channel Na1.8, delayed rectifier potassium channel, A-type transient potassium channel, and a leak channel suggests that Na1.8 and delayed rectifier potassium channel conductances are critical for hyperexcitability of small DRG neurons. Introducing paclitaxel into the model, our bifurcation analysis predicts that hyperexcitability is highest for a medium dose of paclitaxel, which is supported by multi-electrode array (MEA) recordings. Furthermore, our findings using MEA reveal that Na1.8 blocker A-803467 and delayed rectifier potassium enhancer L-alpha-phosphatidyl-D-myo-inositol 4,5-diphosphate, dioctanoyl (PIP) can reduce paclitaxel-induced hyperexcitability of DRG neurons. Our approach can be readily extended and used to investigate various other contributors of hyperexcitability in CIPN.
Learn More >Chronic pain disorders have been associated separately with neuropsychiatric conditions such as depression and alcohol abuse. However, in individuals who suffer from non-cancer chronic pain disorders, it is not clear if the burden of depressive disorders is similar for those with and without a history of alcohol abuse. Using data from the Collaborative Psychiatric Epidemiology Surveys (CPES), we found depressive disorders to have a high burden in men and women with a history of alcohol abuse, independently of the presence or absence of chronic pain. We also found that, although the incidence of persistent depressive disorder was comparable in men and women with a history of alcohol abuse, and significantly higher than in control men and women, the incidence of a major depressive episode was higher in women with a history of alcohol abuse independently of the presence or absence of chronic pain. The age of onset of depressive disorders, independently of pain status, was younger for individuals with a history of alcohol abuse. The findings of this study have important implications for the clinical management of individuals who suffer from chronic pain comorbidly with depression and/or alcohol abuse.
Learn More >The ongoing COVID-19 pandemic and the lockdown measures have forced clinicians across the world to look on telemedicine. Although migraine as such seems an ideal option for telemedicine, a systematic study reviewing feasibility, efficacy, and advantages of current advanced telecommunication technologies in children with migraine is lacking.
Learn More >Opioids are the most widely used therapy for pain during the postoperative period. It has been suggested by some that hydromorphone is clinically superior. Our primary objective was to determine if there is a difference in postoperative pain score ratings between adult patients receiving intravenous hydromorphone vs intravenous morphine on discharge from the post-anesthesia care unit (PACU).
Learn More >This study retrospectively investigated psychological factors contributing to chronic post-surgical pain (CPSP) in pediatric patients after limb-sparing or amputation surgery for extremity osteosarcoma. Psychological factors were identified and analyzed by the Wilcoxon rank-sum and median two-sample tests. Univariate and multivariate Cox regressions were performed using gender, age, psychological factors, and psychological interventions related to CPSP duration as covariates. Duration of pain treatment was significantly longer in patients resistant to psychological interventions (p = 0.01) than those receptive to interventions. Shorter duration of pain treatment was associated with older age (p = 0.03) and receptiveness to psychological interventions (HR = 4.19, 95% CI [1.22, 14.35]). Older age and receptiveness to psychological interventions as part of pain management care are associated with needing a shorter duration of pain treatment. Our results highlight the importance of prospective investigations evaluating motivation to engage in psychotherapy and psychological interventions and identify risk factors for CPSP in pediatric oncology.
Learn More >Migraine affects how the brain processes sensory information at multiple levels. The aberrant integration of visual and somatosensory stimuli is thought to underlie Alice in Wonderland Syndrome, a disorder often reported as being associated with migraine. However, there is still a lack of knowledge about the epidemiology of this syndrome in migraineurs and the association between Alice in Wonderland Syndrome episodes and migraine attacks. Therefore, we conducted a prospective cohort study to systematically evaluate the prevalence and the clinical features of Alice in Wonderland Syndrome in a large sample of patients with migraine.
Learn More >We compared the effects of therapeutic exercise (TE) combined with pain neurophysiology education (PNE) to those of TE in isolation on pain intensity, general fibromyalgia impact, mechanical pain sensitivity, pain catastrophizing, psychological distress and quality of life in women with fibromyalgia syndrome (FMS).
Learn More >Chronic pain is one of the major causes of disability in the general population. Even though there are effective treatment options available for reducing symptoms, these treatments often do not have consistent lasting effects. As the usage of mobile devices has increased enormously during the last few years, mobile application-based treatment options are widespread. Such app-based programs are not yet empirically proven but might enable patients to become more independent in their pain management in order to prevent relapse. The aim of this meta-analysis was to summarize the literature on mobile application-based interventions for chronic pain patients. Therefore, three electronic bibliographic databases, PubMed, PsycINFO, and Web of Science, were searched for studies that investigated the effectiveness of mobile application-based intervention for chronic pain on pain intensity. The final sample comprised twenty-two studies, with a total of 4679 individuals. Twelve of these twenty-two studies used a randomized control trial (RCT) design, while ten studies only used an observational design. For all twenty-two studies, a small but significant effect ( = -0.40) was found when compared to baseline measures or control groups. The results suggest that apps-based treatment can be helpful in reducing pain, especially in the long-term.
Learn More >Rheumatoid arthritis (RA) is chronic, painful, disabling condition resulting in significant impairments in physical, emotional, and social health. We used different methods and perspectives to evaluate the responsiveness of PROMIS® short forms (SFs) and identify minimal and meaningful score changes.
Learn More >Upregulation of P2X4 receptor (P2X4R), brain-derived neurotrophic factor (BDNF), and interleukin-1 beta (IL-1β) in activated microglia is associated with hyperalgesia. This study investigated whether nicotine increases pain hypersensitivity by altering the expression of these molecules in microglia. We also examined the role of interferon regulatory factor 8 (IRF8) in this process.
Learn More >Prevalence estimates of severe chronic pain in pediatric community samples are rare and inconclusive. This study aimed to (1) examine the prevalence of chronic pain severity grades in school children and (2) investigate differences between pain severity grades for pain-related characteristics, including pain locations, sociodemographic characteristics, emotional functioning, insomnia, school factors and health care utilization.
Learn More >Colorectal cancer surgery is commonly performed with adequate analgesia essential for patient recovery. This study assessed the effectiveness of intrathecal morphine and patient-controlled analgesia (ITM + PCA) vs patient-controlled analgesia alone (PCA) for postoperative pain management in colorectal cancer surgery.
Learn More >The transition of HIV from an acute, fatal illness to a chronic health condition has shifted the treatment needs of people living with HIV (PLWH). PLWH, including sexual minority men (SMM), are living longer and are subject to health concerns often associated with aging. A major health concern of older SMM living with HIV who report problematic substance use is chronic pain. This qualitative analysis of 15 one-on-one interviews with older SMM living with HIV and chronic pain aimed to characterize this population's experiences with pain, engagement in HIV care, and problematic substance use. This study was conducted in a community health center in Boston, MA. We also solicited suggestions for preferred intervention strategies.
Learn More >To assess the prevalence of chronic neck pain (CNP), chronic low back pain (CLBP), and migraine headache (MH) in the Spanish population and to identify sociodemographic and health-related variables associated with CNP, CLBP, and MH.
Learn More >Oliceridine, an investigational IV opioid, is a first-in-class G-protein selective agonist at the -opioid receptor. The G-protein selectivity results in potent analgesia with less recruitment of -arrestin, a signaling pathway associated with opioid-related adverse events (ORAEs). In randomized controlled studies in both hard and soft tissue models yielding surgical pain, oliceridine provided effective analgesia with a potential for an improved safety and tolerability profile at equianalgesic doses to morphine. The phase 3, open-label, single-arm, multicenter ATHENA trial demonstrated the safety, tolerability, and effectiveness of oliceridine in moderate to severe acute pain in a broad range of patients undergoing surgery or with painful medical conditions warranting use of an IV opioid. This retrospective, observational chart review study compared respiratory depression events associated with oliceridine administration as found in the ATHENA trial to a control cohort treated with conventional opioids.
Learn More >The contribution of psychological risk factors to the intensification of pain experienced among individuals with fibromyalgia syndrome (FMS) is relatively under-studied. The present study aims to explore associations between FMS-related somatic symptom severity and two personality tendencies: anxiety sensitivity (AS) and socially prescribed perfectionism (SPP). Furthermore, the relative contributions of these personality tendencies are examined vis-à-vis the experience of potentially traumatic events (PTEs) and the psychopathology of posttraumatic stress symptoms (PTSS).
Learn More >Despite classic analgesic or effective treatments in rheumatic diseases, such as synthetic DMARDs in RA, patients remain in pain and often turn to non-prescribed pharmacological alternatives, such as cannabis self-therapeutic use. However, this medical use of cannabis has not been thoroughly studied.
Learn More >Chronic low back pain (CLBP) is a major contributor to societal disease burden and years lived with disability. Nonspecific low back pain (LBP) is attributed to physical and psychosocial factors, including lifestyle factors, obesity, and depression. Mechanical low back pain occurs related to repeated trauma to or overuse of the spine, intervertebral disks, and surrounding tissues. This causes disc herniation, vertebral compression fractures, lumbar spondylosis, spondylolisthesis, and lumbosacral muscle strain.
Learn More >Chronic pain is prevalent in the United States, with impact on physical and psychological functioning as well as lost work productivity. Minority and lower socioeconomic populations have increased prevalence of chronic pain with less access to pain care, poorer outcomes, and higher risk of fatal opioid overdose. Acupuncture therapy is effective in treating chronic pain conditions including chronic low back pain, neck pain, shoulder pain, and knee pain from osteoarthritis. Acupuncture therapy, including group acupuncture, is feasible and effective, and specifically so for underserved and diverse populations at risk for health outcome disparities. Acupuncture therapy also encourages patient engagement and activation. As chronic pain improves, there is a natural progression to want and need to increase activity and movement recovery. Diverse movement approaches are important for improving range of motion, maintaining gains, strengthening, and promoting patient engagement and activation. Yoga therapy is an active therapy with proven benefit in musculoskeletal pain disorders and pain associated disability. The aim of this quasi-experimental pilot feasibility trial is to test the bundling of these 2 effective care options for chronic pain, to inform both the design for a larger randomized pragmatic effectiveness trial as well as implementation strategies across underserved settings.
Learn More >